UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
+ + + + +
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY
COMMITTEE
MEETING
THURSDAY,
FEBRUARY 12, 2004
This transcript has not been edited
Or corrected, but appears as received
From the commerical transcribing
Service.
Accordingly, the Food and
Drug Administration makes no
Representation as to its accuracy.
The
Advisory Committee met at 8:00 a.m. in the Kennedy Ballroom of the Holiday Inn
Silver Spring, 8777 Georgia Avenue, Silver Spring, Maryland, Dr. Suzette A.
Priola, Chairperson, presiding.
PRESENT:
SUZETTE A. PRIOLA, Ph.D. Chairperson
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):
LISA FERGUSON, D.V.M. Consultant
PIERLUIGI GAMBETTI, M.D. Member
R. NICK HOGAN, M.D., Ph.D. Member
ALLEN JENNY, D.V.M. Consultant
RICHARD T. JOHNSON, M.D. Member
RIMA KHABBAZ, M.D. Consultant
JEANNE LINDEN, M.D., M.P.H. Consultant
KENRAD NELSON, M.D. Consultant
GEORGE NEMO, Ph.D. Consultant
STEPHEN R. PETTEWAY, JR., Ph.D. Non-Voting
Industry Representative
JAMES SEJVAR, M.D. Consultant
SIDNEY WOLFE, M.D. Consultant
WILLIAM FREAS, Ph.D. Executive Secretary
PRESENTERS:
PAUL BROWN, M.D., NIH - Laboratory of Central
Nervous
System
Studies
JOSHUA COHEN, Ph.D., Harvard Center for Risk
Analysis
LISA FERGUSON, D.V.M., USDA - APHIS
ALLEN JENNY, D.V.M., National Veterinary Service
Laboratory
MARY PORRETTA, USDA - FSIS
ROBERT ROHWER, Ph.D., VA Medical Center -
Baltimore
PRESENTERS (Continued):
JAMES SEJVAR, M.D., Centers for Disease Control
and
Prevention
ROBERT G. WILL, M.D., National CJD Surveillance
Unit,
United
Kingdom
FDA REPRESENTATIVES:
STEVEN ANDERSON, Ph.D. CBER
DAVID M. ASHER, M.D. CBER
JAY EPSTEIN, M.D. CBER
JESSE GOODMAN, M.D. CBER
STEPHEN SUNDLOF Center
for Veterinary Medicine
C O N T E N
T S
PAGE
Introductions .................................. 6
Conflict of Interest Statement ................. 9
Retirement Awards ............................. 12
Opening Remarks:
Dr.
Jesse Goodman ....................... 14
Possible Transfusion Transmitted Case of vCJD,
Dr.
Robert Will ......................... 20
CJD Surveillance in the United States, Dr.
James
Sejvar ............................ 58
Comparison of the Transfusion Risk for CJD v.
vCJD,
Dr. Steve Anderson ................ 75
Experimental Studies in Animals Re TSE
Infectivity:
Review
of Recent Experiments in Rodents and
Sheep,
Dr. Robert Rohwer ................ 91
Review
of Recent Experiments in Non-human
Primates,
Dr. Paul Brown ............... 136
Open Public Hearing
Dr.
Michael Fitzpatrick ................ 162
Dr.
Hatte Blejer ....................... 165
Review of Reported Case of BSE in Washington
State:
Case Presentation and USDA Surveillance Program,
Dr.
Lisa Ferguson ...................... 201
Confirmation of BSE in the Affected Cow,
Dr. Al
Jenny ........................... 229
Food Safety Regulations for BSE, Mary
Porretta
............................... 236
C O N T E N T S
(Continued)
PAGE
Status of U.S. Feed Ban, Dr. Stephen
Sundlof
................................ 257
FDA Presentation, Dr. David Asher ............ 268
P-R-O-C-E-E-D-I-N-G-S
(8:04
a.m.)
DR.
FREAS: Mr. Chairman, members of the
committee, invited speakers, and members of the public, I would like to welcome
all of you to this, our 15th meeting of the Transmissible Spongiform
Encephalopathies Advisory Committee.
The
entire meeting, both today and tomorrow, will be open to the public, and you're
welcome to attend.
I
am Bill Freas. I am the Executive
Secretary for this Advisory Committee.
At this time I would like to go around the head table and introduce the
members seated at the head table to the public. We'll be starting on the public's right-hand side of the room.
When
I call your name, if you would raise your hand. The first hand will not be raised, but that seat will soon be
occupied by Dr. Richard Johnson, Professor of Neurology, Johns Hopkins
University.
Next
is Dr. Lisa Ferguson, Senior Staff Veterinarian, U.S. Department of
Agriculture.
Next,
Dr. Arthur Bracey, Associate Chief, Department of Pathology, St. Luke's
Episcopal Hospital.
Next,
Dr. Rima Khabbaz, Associate Director for Epidemiologic Science, National Center
for Infectious Diseases, Atlanta, Georgia.
Next,
Dr. George Nemo, Division of Blood Diseases and Resources, National Institutes
of Health.
Next
we have an empty chair. Unfortunately
Shirley Walker, our Consumer Representative had a medical emergency and she
could not be with us this morning.
Next,
Dr. John Bailar hopefully will be joining us later. Dr. Bailar is Professor Emeritus, University of Chicago.
Next,
Dr. Sidney Wolfe, Director, Public Citizen Health Research Group.
Around
the corner of the table, Dr. Nick Hogan, Associate Professor of Ophthalmology,
University of Texas Southwestern Medical School.
Next,
Dr. Kenrad Nelson, Professor, Department of Epidemiology, Johns Hopkins
University School of Hygiene and Public Health. Dr. Nelson is also the Chair of CBER's Blood Products Advisory
Committee.
Next
is the chair of this committee, the Transmissible Spongiform Encephalopathies
Advisory Committee, Dr. Suzette Priola, Investigator, Laboratory of Persistent
and Viral Diseases, Rocky Mountain Laboratories.
Next,
we have Dr. Allen Jenny from the Pathobiology Laboratory, National Veterinary
Services Laboratory, Ames, Iowa.
Around
the corner of the table we have Dr. James Sejvar, Neural Epidemiologist,
Division of Viral and Rickettsial Diseases, CDC.
Next,
we have Dr. Stephen DeArmond, Professor of Pathology, University of California,
San Francisco.
Next,
we have Mr. Val Bias, Co-Chairman, Blood Safety Working Group, National
Hemophilia Foundation.
Next,
Dr. Pierluigi Gambetti, Professor and Director, Division of Neural Pathology,
Case Western Reserve University.
Next,
we have Dr. Lynn Creekmore, Staff Veterinarian, APHIS, USDA.
Next,
we have Dr. Jeanne Linden, Director of
Blood and Tissue Resources, New York State Department of Health.
Next,
we have our non-voting Industry Representative, Dr. Stephen Petteway, Director
of Pathogen Safety and Research, Bayer Corporation.
I
would like to thank all of our committee members and consultants for joining
with us this morning.
Now,
I would like to read into the public record the conflict of interest statement
that is required for this meeting.
The
following announcement is made part of the public record to preclude even the
appearance of a conflict of interest at this meeting. Pursuant to the authority granted under the committee charter,
the director, Center for Biologics Evaluation and Research, has appointed for
this meeting the following participants as temporary voting members. They are Drs. Lisa Ferguson, Allen Jenny,
Rima Khabbaz, Jeanne Linden, Kenrad Nelson, George Nemo, James Sejvar, Sidney
Wolfe, and Ms. Shirley Walker.
Based
on the agenda, it has been determined that the committee will not be providing
advice on specific firms or products at this meeting. 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 and Drug Administration prepared
general matters waivers for participants who required a waiver under 18 U.S.
Code 208. Because 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 general nature of the discussion 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 the 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
the interest of fairness, FDA is disclosing that Dr. Petteway is also 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 the participants
to objectively evaluate any presentation and/or comments made by these
speakers.
Dr.
Joshua Cohen has a grant from FDA to study BSE, and he is receiving consulting
fees from the USDA.
Dr.
Robert Rohwer has financial interests with various firms that could be affected
by the committee discussions.
Dr.
Robert Will is employed by the National CJD Surveillance Unit, Western General
Hospital in Edinburgh, U.K. He also
consults and advises with firms that could be affected by the committee
discussions.
Members
and consultants are aware of the need to exclude themselves from discussions
involving specific products or firms for which they have not been screened for
conflict of interest. Their exclusion
will be 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 products you wish to comment upon.
Waivers are available by written request under the Freedom of
Information Act.
So
ends the reading of the conflict of interest statement.
Dr.
Priola, I turn the meeting over to you.
CHAIRPERSON
PRIOLA: Thank you, Bill.
Before
we get started, Dr. Jesse Goodman is going to present some retirement awards
for retiring members of the committee.
DR.
GOODMAN: Okay. We're very happy to present these awards for
people who are retiring from the committee, and the first one is Lisa Ferguson,
the Senior Staff Veterinarian from the USDA.
So,
Lisa, if you'd come up, we thank you for all of your good service. Okay.
There's a plaque, which is very nice, and there's a letter.
(Laughter.)
DR.
GOODMAN: There's a letter which will
probably be of high value. I didn't
sign it, but it's signed by the Associate Commissioner for External Affairs, my
colleague Peter Pitts, and it says that he'd like to express his deepest
admiration for your efforts. And, of
course, all of us appreciate these efforts in behalf of public health and the
incredibly useful advice that you give all of us at FDA.
So
thank you, Lisa.
(Applause.)
DR.
GOODMAN: Do you want a picture?
This
is actually the first recorded USDA-FDA handshake.
(Laughter.)
DR.
GOODMAN: I probably closed my eyes.
You'll have that to remember me by.
Okay. And then my dear colleague from CDC Rima
Khabbaz who has been one year on the TSEAC and also serves on our Blood Product
Advisory Committee, right?
Okay. So does she get, like, eight plaques?
(Laughter.)
DR.
GOODMAN: No, just one plaque, the same
plaque, same letter from Dr. Pitts, but addressed to you. So thank you.
(Photograph
taken.)
DR.
GOODMAN: Thank you.
(Applause.)
DR.
GOODMAN: Okay. And then we have Dr. Sid Wolfe, who's the
Director, as you know, of the Public Citizen Health Research Group. Again, Sid, we tremendously appreciate your
input here, and again, all you do on this committee and elsewhere as an
advocate for public health. We really
appreciate that.
(Photograph
taken.)
(Applause.)
DR.
GOODMAN: I have a brief introduction
for the Committee and also a little bit of an apology in advance to the members
that, as usual, I can't stay for the whole thing, but Karen Midthun over there
who is Acting Deputy Director of the Center will be trying to stay for the
whole thing. And this is a particularly
important Advisory Committee for us because of the concerns that have occurred
and our desire to really be on top of this issue.
Anyhow,
I'm pleased to welcome the members of the TSE Advisory Committee; in addition,
our invited speakers; and also certainly the public who are here today. And we welcome public interest and input.
The
purpose of this meeting is to discuss with the Committee current safeguards to
minimize the risk of transmission of CJD and variant CJD by FDA medical
products. Although we discuss these
kinds of issues periodically with this committee, as everybody knows, this
discussion is coming at a particularly timely moment. This is really because of two important events that have occurred
just within the last couple of months.
First
of all, in the United Kingdom, a case of variant CJD was recognized in a blood
transfusion recipient who had received packed red cells six and a half years
earlier from the donor who later developed variant CJD. Although it's possible, of course, that both
the donor and the recipient were infected independently and coincidentally
related to their food exposure in the U.K., given a consideration of the odds
of these events, FDA considers this observation to at least be presumptive
evidence that variant CJD can be transmitted by some components of human blood,
again, not proven, but highly suggestive and presumptive when one approaches it
in a cautious manner.
The
theoretical possibility for such a transmission was recognized for at least 15
years, but this case would represent the first actual evidence for blood-borne
transmission in humans. The FDA has
actually, since 1987, recommended a series of precautionary steps to reduce the
risk of blood-borne CJD even when it was a theoretical risk.
So
this recent event may not necessitate any dramatic change in our thinking, but
it does draw our attention to this issue and the need for what we have been
doing, which is a periodic reevaluation of our blood policies, and the public
health protections that we have in place, and also the consideration of whether
there are additional steps or thoughts that you may have to help us deal with
this issue.
Okay. The second issue is that later in December
of this last year, the USDA reported the presence of bovine spongiform
encephalopathy that had been diagnosed in postmortem examination of brain of a
disabled dairy cow in Washington State, and this was later determined, as folks
know, to have originated in Canada.
There have been a number of subsequent investigations ? and I think we'll hear a little more about that ? and in these the USDA has not identified to date
any other cows with BSE, but certainly this finding, together with the
recognition of BSE in a Canadian beef breeder cow earlier last year, again,
provide what we consider a significant impetus to continue an ongoing
evaluation and consideration of related issues of medical product safety.
So,
therefore, we have asked the TSE Advisory Committee in the next two days to
discuss possible implications of these two events for the safety of medical
products, and that includes devices, drugs, and biologics that are regulated by
the FDA. And as members of the
Committee know, what we ask the FDA advisory committees to do is to discuss
underlying scientific questions that may bear on our regulatory policies to
protect public health.
To
assist the Committee, the first topic of the meeting will be a review of
available information about the presumptive transfusion-transmitted case,
related experimental and epidemiological data that are available, and a risk
assessment.
The
second informational topic will be a review of the recent North American BSE
case, as we mentioned, the second indigenous case found on this continent; and
summaries of existing USDA and FDA policies and regulations; as well as those
new steps planned in response to the recent findings.
The
third session will provide an analysis of risk in animals and humans as they
relate to product safety.
And,
finally, tomorrow morning in the fourth session, FDA staff will review efforts
in various parts of the Agency to reduce the potential risks of TSE agents that
might be associated with regulated medical products.
And
I think we must keep in mind something that is not always readily apparent,
that the risk and the issues with all of these diverse products are not
necessarily the same.
Okay. Later today the FDA?s Center for Veterinary Medicine will review the
regulations regarding TSE and feeds, ruminant feeds, and tomorrow morning the
committee will hear from the FDA?s Center for
Food Safety and Nutrition regarding bovine materials in cosmetics, foods, and
dietary supplements.
This
is important background information, but in this meeting, really, the Committee
is being asked specifically to look at the medical products issues and not to
examine the non-medical products.
Also,
please consider that while we know the risks associated with BSE and variant
CJD can't be understood fully outside the context of risk of contamination of
beef and beef products, that this Advisory Committee is an FDA advisory
committee and advises the FDA and not the USDA, which is the agency responsible
for most of the relevant food products.
Therefore,
we ask that the Committee focus its discussion at this meeting on the science
underlying FDA's regulatory policies and responsibilities rather than those of
the USDA.
Well,
all of that said in advance, again, I really thank not just the past and
transitioning members of this Committee, but the present and future ones. We thank you for being here. We thank the invited speakers from the
public, from affected industries and others for their contributions. We really welcome the input. We really need to understand BSEs better. So we welcome those contributions and a better understanding of
the risks that they could pose to FDA-regulated medical products.
And
what we really hope to do here is to discuss the latest science in an effort to
keep us well ahead of the curve and keep medical products as safe as is
possible.
So
with that background, again, thanks for being here, and we really will listen
carefully to your discussion.
Thank
you.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Goodman.
So
it's important to remember that we're not here to vote on anything, just to
discuss the relevant science in terms of the safeguards that are currently in
place to prevent transmission of BSE or variant CJD.
So
it's no voting, which is good. Don't
get locked into anything.
So
our first presentation will be by Dr. Robert Will, who will present the
information on this possible case of transmission of variant CJD via blood
transfusion.
Dr.
Will, yes, please.
DR.
WILL: Good morning. It's a privilege to have the opportunity to
give a presentation to this Committee, and I'm going to review the evidence on
the possible case of transfusion-transmitted variant CJD and then provide some
background of this study and of the general situation in the U.K.
Variant
CJD was identified first in 1996, and the belief then was that it was a
likelihood that this was related causally to BSE, and we now believe there is
now really compelling evidence that this is the case, and the presumption is
that infection of humans is through food-borne transmission.
However,
when variant CJD was identified in 1996, a number of issues arose about
potential other routes of transmission, and therefore, in 1997, a study was set
up to look at the possibility of transfusion- transmitted infection.
Could
I have the next slide, please?
This
was the TMER study, the Transfusion Medicine Epidemiology Review, which is a
collaboration between the various blood services in the United Kingdom, the
National Blood Service, the SNBTS, the Welsh Blood Service, the Northern
Ireland Blood Transfusion Service, the National CJD Surveillance Unit, and the
Office of National Statistics.
And
in brief, the methodology of this study is as follows. Whenever we have identified a case of
variant CJD which has been classified as probable in life or the minority, the
very small minority of cases that are identified after death, then the details of
these cases are notified to the relevant regional blood authority, and a search
is made to find out whether any of these individuals had been blood donors,
regardless of whether we were told that they were blood donors or not by the
family.
If
individuals are found to be blood donors, then a search is made for those
donations to find out who the recipients are, and we keep a note of the names
and details of the recipients in order that if any of those should appear in
our CJD register, we would note that they had developed CJD themselves.
Now,
as I say, this study was set up in 1997.
It was a long-term study. There
is also a safety net in that we get death certificates from the Office of
National Statistics on all the recipients who have been identified in order
that we can find out the cause of death, as on a death certificate, should any
of them have died.
Now,
we also carry out a reverse study in which individuals who are said to have
received a blood transfusion ? we try and
identify the donors to see whether they themselves have developed variant CJD,
and I'll mention this in brief in passing, and we have also been carrying out a
similar study in sporadic CJD.
Next
slide, please.
On
the 8th of December 2003, a death certificate was received from the Office of
National Statistics which identified one of the recipients as having developed
dementia and having died of this condition.
Independently
of this, following the postmortem which mentioned CJD, the clinician involved
reported the case to the Surveillance Unit and also tissues from the
neuropathological examination were sent to the CJD Surveillance Unit for
review. So we were able to identify (a)
that a recipient was said to have developed CJD, and independently we had other
notifications. And I think an important
issue for what I'm going to say later is that there are a number of levels of
surveillance by which we can identify such cases.
Next
slide, please.
Now,
as far as the donor was concerned, this was a 24-year-old individual who
donated two units in 1996. One unit was
transfused to the index case, red cells; and one unit was transfused to a
patient who died of cancer after five months.
Platelets
were included in a platelet pool from this donor but have not been traced, and
plasma from both donations were included in different plasma pools. The donor, who was, of course, healthy at
the time of the donation, died three and a half years later of pathologically
confirmed variant CJD.
Next
slide, please.
Now,
in 1996, the recipient, age 62 at that time, was transfused five units of red
cells, one from the variant CJD donor.
Now, I should stress at this point that it may seem to you some of the
details I'm going to give you about this case are somewhat sketchy, but that is
quite deliberate because the family of the individual are very keen that they
should retain their anonymity, and I am not going to go into details of the
reason for the transfusion or any of the other specific details regarding this
case.
The
recipient developed depression six and
a half years after the blood transfusion, and within months developed
ataxia, painful sensory symptoms,
apraxia, cognitive impairment and myoclonus. An MRI scan was said to be normal, and on review post hoc, this
indeed was a normal scan, although it was only a rather simple scan without
flare sequences, which have a higher sensitivity for variant CJD.
The
individual died 13 months after the onset of symptoms, and the post mortem
which I stress was restricted to the brain, confirmed the diagnosis of variant
CJD.
In
addition, the patient, was a codon 129 methionine homozygote, consistent with
all of the other cases that have been tested with variant CJD to date; and was
a Type 2B prion protein pattern on Western blot, which again is consistent with
variant CJD and, indeed, with BSE.
There
are a couple of things I should say in addition. First of all, the clinical presentation was highly suggestive of
variant CJD and consistent with previous published data on this issue, and the
post mortem, the regional distribution of florid plaques, for example, was
typical of variant CJD.
However,
because we think this may be a case of secondary transmission, further detailed
studies are ongoing in order to determine that the pathology is, indeed,
identical to previous cases, and transmission studies have been set up in order
to identify whether the transmission characteristics of this case are similar
to previous experience.
Next
slide, please.
Now,
statistical analysis has been done by Simon Cousens, who is at London School of
Hygiene and Tropic Medicine, and he analyzed this by looking at the expected
number of cases of variant CJD in the recipient population who had received a
blood transfusion from a variant CJD donor in the absence of transfusion-
transmitted infection. And on a crude
analysis he felt that the chances that this was unrelated to the transfusion
was one in 15,000; and accounting for the age of the recipient population and
the age of the recipient who developed variant CJD, one in 30,000.
Now,
this assumes that all of the recipients are susceptible. Now, of course, we do not have PrP gene
analysis on the recipient population, and it is possible that only a proportion
of them are methionine homozygotes. So
one could argue that these statistical analyses are rather conservative.
So
we believe that it is possible that this is a case of transfusion-transmitted
variant CJD. It is, of course,
impossible to exclude the possibility that both individuals were infected
through dietary exposure, but we believe that this is unlikely.
Furthermore,
in my view, because of this particular occurrence and the importance for public
health, I think for the purposes of protecting the public it should be regarded
as a case of transfusion- transmitted variant CJD.
Next
slide, please.
Now,
this is a shocking discovery, as Adriano Aguzzi said in his editorial in The Lancet, but he also suggested that
it was not surprising, and, indeed, that has been the view of some of the
individuals who we discussed this with in December. And one reason for this is this study by Nora Hunter and Fiona
Houston. There have been two
publications on the transmission of BSE and scrapie by blood transfusion, and I
think this will be discussed later by Bob Rohwer.
But,
in brief, if this is transfusion- transmitted variant CJD, it means that the
donor contained infectivity in the blood three and a half years before
developing clinical symptoms, and it means that the incubation period in the
recipient was six and a half years.
And
I would argue that these incubation periods are consistent with this study in
which BSE was transmitted by blood transfusion from donor sheep during the
incubation period and with an incubation period in the recipient sheep that is
fairly similar to direct intracerebral inoculation.
So
we think the intravenous route is probably fairly efficient, and I think that
the possibility of transfusion-transmitted variant CJD is consistent with
previous scientific data.
Next
slide, please.
Now,
one thing I should stress is that there has been one study in which blood
components for variant CJD were inoculated into mice to determine whether there
was infectivity in variant CJD blood, and these studies in the blood were
negative, although Moira Bruce and colleagues showed that in variant CJD there
was infectivity in brain and spleen.
And my own opinion is that it is probable that such studies in which
small volumes of blood or blood components are inoculated intracerebrally have
a problem with sampling in a tissue with potentially very low levels of
infectivity. And I think that this may
be an important issue because I think, as far as I'm aware, this is the first
evidence of transmission in humans from a low-dose tissue.
Next
slide, please.
Now,
just to give you the background of this study, there are 146 cases of variant
CJD identified in the U.K. to date, and 136 of these were eligible to donate
because they were older than 17 years.
The
number of cases from whom components were actually issued that we have
identified through this study was 15, and the number of recipients identified
from the 15 cases, where recipient and component information is available, is
48.
Now,
this is labile blood components, blood transfusion.
Next
slide, please.
And
these are the components that were transfused, and this is from The Lancet paper showing the year of
transfusion, the component transfused, and the number of recipients. As you can see, there were a whole range of
materials transfused, but the great majority were red cells.
Some
of these were later leukodepleted. This
was introduced around 1998 in the U.K. to try and minimize risk, but many of
the individuals were exposed to red cells that were not leukodepleted,
including the case I have just described.
We
have an important question as to whether leukodepletion may have reduced the
risk of transmission of variant CJD, and my own opinion about this is that the
evidence on this is somewhat uncertain, and I do not think we can assume that
leukodepletion will have removed the risk of transmission.
Next
slide, please.
Here's
the age of the transfusion recipients, the 48 patients, and as you can see, the
great majority of these individuals were in the older age groups. This is important partly because in the U.K.
it is very unlikely that any of these individuals would themselves act as blood
donors because of their age. And, in
fact, none of the individuals who were identified through this process have
themselves acted as blood donors in the U.K., to our knowledge.
Next
slide, please.
Now,
I'm sorry about this slide, but this is showing the dead recipients; that is,
31 individuals who were recipients of a labile product from a variant CJD donor
have died. The great majority of them
have died within two years, and in fact, the absolutely majority within one
year of the transfusion, and this reflects the severity of the underlying
disease process.
But
it also means that, if the incubation period by blood transfusion was measured
in six, seven, eight, ten years -- we don't know -- it is very unlikely that
any of these individuals would have had time to develop variant CJD.
The
blood components transfused are listed here, and the interval between donation
and onset of clinical symptoms in the donor are listed here.
Now,
because of the methodology of this study, all we have on the individuals who
have died is the cause of death on a death certificate, and you can see the
list here if you can read it. Cancer
figures prominently, of course, not surprisingly; a number of hematological
conditions; but in the patients who survive for longer, there are other
conditions, such as ischemic heart disease, bronchopneumonia, chronic
obstructive airways disease, and of course, dementia in the index case I have
described.
So
how confident are we that none of these other individuals have developed
variant CJD? Well, I have given you the
information that is available on these cases.
For ethical reasons we have not been able to track them in anymore
detail, but I stress that we have a number of levels of surveillance, including
direct referral of cases if there's a suspicion of CJD, and a neuropathological
network such that brain tissue will be sent to the Surveillance Unit if any
such patient dies.
So
we cannot be certain about these individuals.
All I can say is that we have no good evidence that any of these other
individuals themselves developed variant CJD.
Next
slide, please.
We
have 17 individuals who are alive, having received a transfusion from a variant
CJD donor; and this is the list. This
is the current age in these individuals, the time elapsed since the
transfusion, the blood component transfused, and the interval between donation
and onset of clinical symptoms in the donor, which may be an important
parameter in relation to risk.
I
stress that we have two cases with a minus here, minus three months and minus
five months. This means that the
individuals were actually suffering from variant CJD at the time they donated
blood, but it is highly unlikely that these individuals could have been
identified at the time they were donating blood as suffering from variant CJD
because of the nature of the clinical presentation in variant CJD. It presents with nonspecific psychiatric
symptoms which are insidious in onset and often progress, and it may be six
months on average before any neurological signs develop.
There
is a possibility, however, although we do not know for sure, that the closer
you are to clinical onset when you donate blood, the higher the risks that the
blood will contain infectivity.
Next
slide, please.
Here
is the time elapsed in these 17 individuals since the transfusion, and as you
can see, a significant proportion of them have survived only for a limited
period in relation to the one case in which variant CJD developed after six and
a half years. But we do have a number
of individuals who have survived for longer and have not yet been identified as
suffering from variant CJD, and to our current knowledge are not suffering from
variant CJD. The longest survival in
this group is 11 years.
Just
in passing I should mention that the ethical issues in relation to this study
have been discussed repeatedly. We got
ethical permission to do the study originally in 1997 and received separate
ethical permission to flag the individuals with the Office of National
Statistics.
Our
original ethical permission was that we would not inform the recipients that
they had received a potentially contaminated blood transfusion. However, in our original ethical form, we
put in that if there should be a test, if there should be a treatment, or if
evidence should evolve of a risk through this route, then the whole ethical
position would be reviewed.
And,
in fact, independently of this study, the CJD incidence panels in the U.K. had
decided that individuals in this situation should be informed. And since December the 8th, all of these
individuals -- or measures have been put in place to inform all of these
individuals of the risk.
That
having happened, four of the individuals have already contacted either a
neurologist or the Surveillance Unit directly because of extreme concerns about
the situation that they are in.
Next
slide, please.
Now,
this issue has caused public concern in the United Kingdom. Here is December the 18th, the day after the
announcement in the House of Parliament, "CJD Time Bomb: Hundreds Face
Wait."
Next
slide, please.
"Thousands
at risk of vCJD from Blood Transfusion."
And,
of course, the question is: What is the
risk to the U.K. population? We do not
know how many individuals are incubating variant CJD and may be acting as blood
donors. So there may be a population of
individuals who have been exposed to blood transfusion that would not have been
identified by the TMER study.
Next
slide, please.
The
only evidence we have on this, and I'll just discuss this briefly is evidence
from a surveillance system run by James Ironside and Dr. Hilton of
appendicectomy and a smaller proportion of tonsillectomy samples in the U.K.
general population that have been analyzed to determine whether there is
evidence of immunostaining for prion protein in these samples.
And
this was published in 2002. The interim
results: one out of 8,318 positive with an estimated prevalence of prion
protein accumulation of 120 per million in the U.K. population, but as you can
see, with very wide confidence intervals of .5 to 900. And this study is ongoing.
Next
slide, please.
Now
I mentioned already that two of the units from the donor have been sent for
plasma fractionation, but in fact, we now know that 20 units from vCJD donors
were sent for plasma fractionation in the U.K., and this means that thousands
of individuals were potentially exposed to products derived from plasma
fractionation in which a pool will have been contaminated with a vCJD donor.
We
do not have a surveillance system in place to identify these individuals.
One
thing I should say, of course, is that sourcing of plasma for fractionation in
the U.K. was introduced during 1998 because of the theoretical risk, and this
involves importation of plasma from the United States in England and Wales, and
from the United States to Germany and Scotland, which would suggest that the
risks from plasma originating in the U.K. in relation to fractionated products
has been stopped since 1998.
However,
there were individuals exposed prior to that date, and looking through the
surveillance system information, we have no case of variant CJD with a history
of exposure to fractionated plasma products to date, and indeed, one could
argue that the risk from fractionated products are likely to be much less than
from labile products because of processing and perhaps because of the volume to
which patients are exposed.
Next
slide.
Now,
this is the reverse TMER. This is
individuals who were said to have received a blood transfusion. This is derived from information from the
family, and it is very difficult to check in the same way as we can with blood
donations. In these, four records have
been found of individuals with variant CJD who had received a blood
transfusion, 117 components received, 111 donors traced, and none of them are
on the Surveillance Unit register.
Next
slide, please.
Now,
it's not my role today to discuss the evidence in relation to sporadic
CJD. This is going to be done later, I
think, this morning, but just to stress that in relation to sporadic CJD, the
evidence on iatrogenic transmission -- this is a summary slide from Dr. Brown
from last year -- all of these cases have involved implication of tissues
either in or adjacent to the central nervous system. And within the surveillance system, the U.K., Europe, and other
studies, which I think will also be discussed, we do not currently have
evidence of transmission of sporadic CJD through blood transfusion.
Next
slide, please.
We
have done a similar study on sporadic CJD, and this is somewhat unsatisfactory
data. What we do is we take sporadic
CJD cases and controls, as we have also done with variant CJD. This is a blinded study. We found 224 components that have been
donated, 65 recipients have been traced, and none are on the Surveillance Unit
register.
One
of the reasons why there is only a small proportion that has been traced is
because sporadic CJD cases tend to be very much older than variant cases and
may have donated decades in the past, and it's very difficult to track these
donations because of the record system.
We
also have a reverse study in sporadic CJD, which is also negative.
Next
slide, please.
Now,
just briefly at the end to summarize the overall situation with variant CJD, we
have 146 cases in the U.K. to date, 82 males, 64 females, and all tested cases
are methionine homozygotes on codon 129 of the PrP gene.
Next
slide, please.
One
hundred and three are neuropathologically confirmed. Seven are alive currently.
Next
slide, please.
This
is the age distribution of variant CJD cases, of the 146, and as you can see,
the great majority of cases are age less than 40 at death or are currently
alive, and cases over the age of 60 are extremely rare on current evidence. And it's important to stress that the
recipient I described earlier was in their late 60s when they died, which is
unusual for presumed food-borne variant CJD.
Next
slide, please.
The
trends in the U.K. are very important in relation to assessing the potential
risk of secondary transmission. Here
are the number of deaths per annum of variant CJD in the U.K. showing the steep
rise and then the decline or a possible leveling off in the last year.
Next
slide, please.
This
is the number of onsets of variant CJD per annum in the U.K. showing a rather
smoother pattern with this increase and then a decline which seems to have been
sustained.
I
should just stress that we identify about 95 percent of cases within a year of
onset. So this Figure 14 is almost
certainly nearly complete. This is
reassuring data, but, of course, is not definitive because of the possibility
of second waves either due to different exposures -- I mean different patterns
of dietary exposure or perhaps in relation to different genotypes being
susceptible.
Next
slide, please.
This
is the latest statistical analysis from January. This is the exponential trend in relation to the onsets. The next slide is the same data with a
quadratic trend, and this is a better fit, suggesting that. in relation to
onsets, there is a significant decline in the U.K. currently in variant CJD.
Next
slide, please.
This
is the deaths, and there's an equally good fit between a quadratic model with a
decline and a plateau model. So there
is uncertainty in relation to the deaths about the trend in the U.K.
Next
slide, please.
vCJD
worldwide, September 2003; this has been updated. One hundred forty-six cases in the U.K., six in France, one
Republic of Ireland, one Italy, one USA, one Canada, and of course, the case in
the Republic of Ireland, USA, and Canada had a history of residence in the U.K.
and could have been exposed to BSE in the U.K.
And indeed, in my view is far more likely than the exposure in the
Canadian and the American cases were in the U.K. than anywhere else.
That
is not true of the French and Italian cases that were exposed almost certainly
in their own country.
Next
slide, please.
This
is the duration of residence in the U.K. and the U.S., Canadian, and Irish
case. The Hong Kong case is classified
as U.K. because it developed the disease while resident in the U.K., but as you
can see, at least on this data, it looks as though individuals who were exposed
to BSE in the U.K. required an extended period of residence to be exposed
sufficiently to cause disease.
Next
slide, please. I'm nearly at the end.
I
just thought I'd better mention something about the perspective in other
European countries, and this is the BSE epidemic, which is not quite up to date
in some countries in Europe. And this
shows a pattern in Portugal which looks like this.
In
Switzerland, which has an excellent surveillance system, there was an increase
and a decline, and then as you can see, an increase again around 1999-2000,
which was due to the introduction of active testing rather than passive
surveillance for BSE.
The
pattern in some other countries is very unusual for an infectious
epidemic. Germany had a sudden increase
in the number of cases; similarly in Spain and Italy, and it is probable that
this was due to the introduction of active testing, with the implication that
it is possible that cases of BSE were missed in those countries by passive
surveillance during the 1990s.
The
reason I mention this is that it's often asked whether we're going to see other
cases of variant CJD in Europe, out with France and U.K. and Italy. My own opinion is that it is probable that
in some of the European countries the dietary exposure of the human population
to BSE was later in the U.K., and it is too early to say that those countries
will not themselves get variant CJD, albeit in very much lower numbers than in
the U.K. in relation to the potential exposure.
Next
slide, please.
These
are the acknowledgments within the Surveillance Unit: James Ironside; Richard Knight; Hester Ward; Jan Mackenzie, who
has been coordinating the study and the TMER since we started in May 1990;
Sarah Cooper and Craig Heath, who do all of the work; they're the registrars;
the National Blood Service, Pat Hewitt and Charlotte Llewelyn; and the SNBTS;
the Northern Ireland Blood Transfusion Service; and the Wales Blood Transfusion
Service.
However,
I think I'd like to finish by stressing that none of this research would be
possible without the cooperation of the families of patients with variant CJD
who allow us to forward details to the National Blood Services, and I'd
particularly like to acknowledge the family of the index case of the recipient
who were good enough to give us permission to publish the case and also to
discuss it at meetings like this.
Thank
you very much.
(Applause.)
CHAIRPERSON
PRIOLA: Are there any questions for Dr.
Will from the Committee? Yes, Dr.
Wolfe.
DR.
WOLFE: Dr. Will, of the 30 or so people
listed in, I guess, your Table 2 in the paper, of people who died who turn out
to be recipients, how many of them have had pathologic examination of the brain
looking for prion protein A and B?
Since this index case, are you thinking of changing the surveillance
system with respect to looking for that?
With this intriguing group of people, you might be able to find out more
about latency period.
DR.
WILL: Yes. I mean, I think they're both very important questions. The answer to the first question is that
because of the ethical strictures on the study, which I think were entirely
appropriate, we do not have information on neuropathology on those that have
been certified and have died.
The
actual rule of the ONS is that if we are to do this study, we are not allowed
to use the death certificate to retrospectively go and discuss things with the
family or the clinician. So we could
not do that.
However,
I think the point that we may need to change that in order to obtain more
information is under active discussion.
Although one thing I would say is that -- and perhaps this is a bit
self-serving -- but I think it really does show that surveillance systems can
be important in identifying actual risks, and it's important to have these
different levels of surveillance, and I personally think that it is quite
likely that we would have identified the variant CJD in one of those recipients
if it had happened, although, of course, I can't be sure, and actually taking
further action to be certain about that is a very important issue.
CHAIRPERSON
PRIOLA: Dr. Bracey.
DR.
BRACEY: Yes. In terms of the index case, there were two components. One went to the patient with pancreatic
cancer. Which of the donations was the
first donation?
And
kind of aligned with Dr. Wolfe's question, are the materials available from
that patient pathologic materials?
DR.
WILL: I didn't say pancreatic
cancer. I think I just said cancer.
DR.
BRACEY: Cancer, okay.
DR.
WILL: Yes, who died five months afterwards.
Well, I think, but I'll have to confirm to you, that the first donation
was to the index case and the second donation was to the other individual, but
I can check that and let you know, but I think they were both given, you know,
within a relatively near period.
And
the other question was in relation to?
DR.
BRACEY: Oh, well, the other question
actually relates to the counseling system.
One of the real challenges that we face in the states ? we currently have systems where there are
recalls for patients at risk for CJD, with the notion that there might be some
discussion, but in truth, the many physicians at the bench level out in the
field really don't know how to counsel folks with regard to issues related to
CJD.
So
I'm kind of intrigued in terms of how you all have set up your system so that
you have an effective counseling system.
DR.
WILL: Well, I think that's a critically
important issue. I would agree with you
that it is extremely difficult for most doctors to counsel people on this issue
because they don't have the relevant information.
In
the U.K. with the 17 individuals who were informed, some information sheets
were produced and were provided to the relevant doctors in order to counsel the
individuals, but this does have difficulties because most doctors, even with an
information sheet, may not be fully informed as to what to say.
What
actually happened with the cases I have mentioned who contacted a neurologist
is that the neurologist phoned us up and asked us about the details of the
study and what we would say about it, and then discussed it with the
individuals.
And
I cannot help but agree with you that it is a major challenge as to how to
inform these individuals in a sensitive way that allows them to have accurate
information.
So
I think that thinking about that in advance is a very important issue if you're
going to inform members of the general public of a specific risk.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Hi, Bob. The question I have is regarding the older
age people who died of variant CJD.
Maybe you mentioned it. How many
of them had a transfusion history, since the three over the age of 60 is
unusual, and the ten over 50 is even somewhat unusual?
DR.
WILL: Yeah. The oldest individual who died at the age of 74 did not have a
transfusion history, and I don't think the other 60 year old did either. And, of course, if those individuals had
themselves developed variant CJD with a history of transfusion, we would have
known that from the study.
So
I don't think that you can say -- I understand exactly what you're saying,
Steve. The implication could be that
this was transfusion- transmitted. We don't actually believe that in relation
to the evidence that we have in relation to those cases.
CHAIRPERSON
PRIOLA: Dr. Nemo
DR.
NEMO: That was an excellent
presentation, Dr. Will. Thank you.
One
question I have is your platelet components.
You didn't trace them in the index case, and I noticed in all the other
traces that there are very few platelet components. Is there a problem tracing platelets?
DR.
WILL: I'm not an expert at this, but I
believe that, of course, this sounds like a very simple study. You just find out who received the donations
and then you compare it with a list.
But
in fact, it took an enormous amount of work by the National Blood Service going
down to the level of hospital notes.
And, of course, the confirmation that individuals received a blood
transfusion depends on the quality of the notes themselves.
My
understanding, although as I say I'm not expert at this, is that tracing
platelets is particularly difficult in relation to this, although in that one
case that I had mentioned up there, active efforts are still being made to try
and trace that, but I think it is more difficult than it is with actual blood
donations, perhaps because of the difficulties in record-keeping and following
things up.
CHAIRPERSON
PRIOLA: Dr. Nelson.
DR.
NELSON: Yes. Some of the studies in sheep that were transmitted by blood
transfusion, I think they reported less prion in the peripheral tissues and just were limited to the central nervous
system than the oral, than those transmitted orally, and I wondered if you had
any data.
I
realize you said that the autopsy was limited, but I wondered even prior to the
autopsy was there any data about the distribution of prion in this human case
that was probably transfusion-transmitted.
DR.
WILL: Sadly, we do not have any
information on that, and my understanding is that even though there is PrP in
fairly high levels in variant CJD in peripheral tissues, this does not have any
clinical accompaniment. And it is
unfortunately the case that a brain-only post mortem was carried out, so we do
not know about the levels of PrP in the peripheral tissues in this case.
However,
I think that Dr. Lasmezas and colleagues did publish an article in The Lancet, the same issue of The Lancet, suggesting that in their
experiment with intravenous inoculation of brain, I think, that there was
significant PrP presence in peripheral tissues, including the gut.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
GAMBETTI: Bob, what are your thoughts
about the fact that out of 15 donors with variant CJD and 48 recipients, only
one case really came down with variant CJD acquired from the transfusion? What do you think is the factor that may
have limited this phenomenon or the
factor that allowed the phenomenon to occur?
DR.
WILL: Yes. Well, firstly, there are a significant proportion of the 48
recipients who did not survive long enough to observe variant CJD, should it
have occurred, because of death due to the underlying illness.
Secondly,
the study is not yet complete because we have 17 individual who we know
received the blood component who are still alive and who, sadly, I think are at
greater risk of developing variant CJD.
The
incubation period by intravenous transmission may be very variable, and we
simple cannot know whether individuals have survived long enough after the
transfusion to suggest that they're not going to get variant CJD. And, of course, as I showed on the slide, a
significant proportion of the 17 have not yet survived the six and a half
years, which is the presumed incubation period in the index case.
So
I think, firstly, we cannot say that one out of 48 is the final figure, nor may
it be an accurate reflection of the relative risk.
The
other variable, of course, is the time that the blood was donated in relation
to clinical onset in the donor, and some of those intervals are really very
long before clinical onset, and although there is contradictory data in the
scientific literature, it is possible that infectivity in blood may be present
particularly near clinical onset rather than many years prior to clinical
onset.
There's also the possibility that
infectivity in blood may be intermittent.
We don't know that it's consistent throughout the incubation
period. So it could be that some of those
donations from variant CJD donors didn't contain any infectivity.
The
only relevant data that I have in relation to that is the fact that we did
identify an appendix specimen from an individual who had died of variant CJD I
think about ten years prior to clinical onset, and James Ironside stained that
for PrP, and it was negative.
So
there are a number of variables that we cannot control for, and I'd very much
like to say that the risk is one out of 48, but I don't think we can say that
at all.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: I have a question about the
completeness of your register. Do you
think it's at all likely that any recent cases have been missed, misdiagnosed
or not reported?
And
what about 5, 10, 20 years ago, before people were as sensitive to this?
DR.
WILL: Well, I'll deal with the first
one first because the issue of whether variant CJD was around many, many years
ago is an important question not only in relation to this study, but in
relation to the hypothesis of a link with BSE.
So
that has been looked at in a number of ways.
One of the ways of looking at it is the hallmark of variant CJD is the
neuropathology, and James Ironside has looked extensively in the past in
relation to previous cases that we knew about, and we did that before the paper
was published in 1996. Any young cases
with neuropathology were reviewed in order to see whether there was evidence of
florid plaque deposition, and that included a 16-year-old who died in 1986,
pre-BSE. Slides from that were
reviewed, and it was sporadic CJD.
There's
a thing called the National Retrospective Review, which is coordinated by James
Ironside in which they're reviewing available neuropathology specimens going
back in the past in the U.K. to restain them, and no case of variant CJD has
been found.
In
Europe, Herbert Budka coordinated a system to try and review all of the cases
they had in various brain banks in Europe to identify past cases of variant CJD
and nothing was found. So from the
perspective of neuropathology we think it's a new disease.
Secondly,
two studies have been done in the U.K. using death certificates to identify
cases that could have been miscertified as variant CJD in the past, one by Dr.
Majid (phonetic), which found no evidence of anything that could look like
variant CJD after review of case loads, and a study in Wales when they went
back in the past and obtained neuropathology tissue to restain in a small
minority, and again, there was no evidence of past cases of variant CJD.
So
I think the current evidence suggests that this is, indeed, a new disease that
developed in the U.K. in the mid-1990s.
Are
we missing cases through our surveillance system? Well, of course, we cannot be 100 percent certain that we are not
missing cases. However, we have a
number of levels of surveillance starting off with the direct referral
system. We have a very high postmortem
rate in suspects, in about 80 percent of suspects. There is a Neuropathological Network such that if any case of CJD
is identified in the U.K., it is referred to the Unit.
And
we obtained, again, death certificates mentioning CJD throughout the U.K., and
if we have not identified the cases, we go back and find out from the clinical
notes and, if available, neuropathology whether it was CJD.
And
I think I am confident that in the age range of individuals who would be seen
by a neurologist, we are confident we have very good ascertainment.
We
have a separate system for pediatrics called the PIN (phonetic) system, which
has identified six individuals under the age of 16 years at onset with variant
CJD. So we are confident that we are
identifying children.
The
issue that does arise, and I think it's an important issue which I suspect is
why you're asking the question, because of the age of this individual, is: Would we be good at identifying cases in the
elderly?
And
that is a question that is difficult to answer, and we are considering
mechanisms for trying to set up a pilot surveillance system in the elderly to
insure we're not missing variant cases in that age group.
DR.
BAILAR: Thank you.
CHAIRPERSON
PRIOLA: Mr. Bias.
MR.
BIAS: I was curious. Since the donor was of a younger age, how do
you handle their other medical care, let's say, surgery, dental care, if they
happened to like tattoos?
DR.
WILL: Well, in relation to the 17 individuals
who have been informed that they received a potentially contaminated blood
transfusion, one of the reasons for informing these individuals was to insure
that they did not act as blood or organ donors.
There
are a number of other potential mechanisms by which these individuals could
undergo invasive procedures during dentistry, as you mentioned, and of course,
a number of other procedures, and the CJD Incidence Panel from the Department
of Health in London has been set up specifically to discuss these particular
issues.
And
a document in relation to blood itself, I think, will be shortly released by
that group. My understanding, although
I'd have to confirm this, is that the general views of the risk from dentistry
are probably very low indeed.
We've
done some epidemiological work, limited as it is, because of relying on dental
histories from families, but we've not found any evidence of transmission of
variant CJD through dentistry, although the information is limited, and there
have been some studies of dental pulp, both in sporadic and variant CJD, which
do not show immunostaining for PrP.
But
it's a very important question, and there are a range of other issues that
could be discussed. One of them, just
to mention in passing, relates to the use of tonsillectomy instruments in the
U.K. because, of course, the tonsils contain quite significant amounts of PrP
in variant CJD, and the individuals who undergo tonsillectomy are often
children. And in the U.K. it was decided some years ago that they would try
introducing disposable tonsillectomy instruments in order to mean that they
were one-use and, therefore, no reused on subsequent patients.
But,
sadly, that resulted in complications with a higher risk of post operative
hemorrhage and possibly one death, and that policy was reversed. And I think this underlines the enormous
difficulty in dealing with public health issues in relation to variant CJD,
particularly in relation to medical issues like blood transfusion, because any
action that is taken can have a very negative effect on public health as well
as minimizing the risk.
CHAIRPERSON
PRIOLA: Dr. Bracey.
DR.
BRACEY: I may have missed this, but did
you provide any information on the interdiction efforts regarding the pools,
the pooled products that the plasma went into?
And
is there a study, an infectivity study in progress with any of that material?
DR.
WILL: As far as I'm aware there is not
an infectivity study specifically in relation to that material. However, I do believe that there are plans
to do, say, extensive studies using the BSE sheep transfusion model in relation
to looking at the plasma fractionation.
In
relation to the withdrawal of plasma fractionated products in which there was a
variant CJD donor, that, indeed, did happen very early on in variant CJD,
within two years of the first case. We
think there may be -- I can't remember exactly if it's two or three withdrawals
of plasma fractionated products.
Of
course, because of the time lag between the donation and the onset of variant
CJD, in many cases the products had already been used up. However, there have been at least two or
three occasions in which there was extant product potentially contaminated with
variant CJD, including, I think, Factor 8.
And
the clinicians who were informed about this usually took the decision to inform
the individuals to remove the potentially implicated Factor 8 and to get rid of
it.
Of
course, this does raise another issue which you raised before about what do you
tell people, and I think it's a very important issue.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Will.
You'll be around for most of the rest of today; is that right? All right.
So if the Committee has any more questions, he'll be available.
Thank
you very much.
Our
next speaker will be Dr. James Sejvar.
DR.
SEJVAR: Good morning. It's a pleasure to have the opportunity to
speak to the group this morning about the various surveillance activities that
we at CDC conduct for Creutzfeldt-Jakob Disease.
I
will mention that basically surveillance for CJD was enhanced back in 1996 due
to the emergence of variant CJD in the United Kingdom, and basically since that
time, CDC has undertaken a number of different measures to increase
surveillance ability for CJD, both classic and variant, in the United States.
And
so what I'd like to do in the next 15 minutes or so is to give you kind of a
quick overview of the surveillance mechanisms for CJD and to suggest to you
that the evidence from this surveillance indicates that we are not observing an
increasing rate of CJD in the United States, nor the emergence of variant CJD.
Next
slide, please.
One
thing that's probably important to keep in mind as I speak is that there's a
number of different features of CJD as a disease entity that make it somewhat
difficult to conduct surveillance for.
So basically in an attempt to circumvent some of these problems, CDC
takes basically a multi-pronged approach to the surveillance for CJD, and the
core mechanisms that we employ include periodic reviews of the National
Mortality Database, collaboration with state health departments to perform
active case review of CJD decedents age less than 55 years, and the
establishment and support of the National Prion Disease Pathology Surveillance
Center, which is headed by Dr. Pierluigi Gambetti at Case Western Reserve
University.
Now,
additionally, in association with several other organizations, including FDA,
we collaborate on special surveillance projects involving groups of persons
thought to be of particular public health concern, and this includes, for
instance, recipients of human growth hormone, and as I'll talk about a little
bit later, recipients of blood transfusions.
And
then finally, we respond to spontaneous reports provided to us by clinicians
and others.
Next
slide, please.
Now,
one of the cornerstones of our CJD surveillance entails review of the National
Mortality Database, and this has been ongoing for many years. Now, basically to perform this surveillance,
we utilize data provided by CDC's National Center for Health Statistics, which
basically keeps a very large database encoding death diagnoses for the entire
U.S.
And
there's actually several features of CJD that lend themselves very well to this
type of surveillance. Now, first of
all, this is a disease with essentially 100 percent fatality rate, and as a
result, once a diagnosis is made, it should make its way into this database,
and further a clinical diagnosis of CJD is actually much more accurate towards
the terminal stages of the illness, and so as a result death information on
this illness is actually fairly reliable.
Now,
our continued assessment of this data suggests several things. Now, first of all, it seems it's clear that
since the early 1980s, reported rates of CJD in the United States have remained
stable over time, and cases basically continue to occur at a rate of about one
per million population, and the median age at death in the United States
remains at about 68 years. And
basically neither this median age at death nor the rates have shown any
significant change over time.
Now,
additionally, nearly all decedents have been over the age of 45 years, and
basically we have had no reports of CJD among teenagers, nor have we seen rate
increases among younger age groups. And
basically this provides evidence that we are not witnessing the appearance of
variant CJD nor the emergence of CJD in basically atypical age groups.
Next
slide.
Now,
I'd like to show you a graph that I think is very illustrative, and basically
it displays the age distribution of cases of variant CJD in the United Kingdom
over in the yellow, compared with that of sporadic CJD in the United States.
And
I think that you can immediately appreciate that one of the distinctive
features of variant CJD in the United Kingdom and elsewhere is the young age at
death compared with that of CJD in the United States.
Basically
the vast majority of deaths from variant CJD occur in very younger age groups;
while for cases of CJD in the United States, cases younger than 45 are
extremely rare.
Next
slide, please.
And
so basically CDC has utilized this fact to pursue enhanced surveillance among
U.S. CJD cases aged less than 55 years in an effort to detect the emergence of
variant CJD.
Now,
in collaboration with state health departments, we obtain and review the
medical and neuropathologic records of CJD cases aged less than 55 years, and
to date, we have reviewed 165 such cases occurring since 1994. Now, 80, a little less than half, of these
cases have had either brain biopsy or more typically autopsy to confirm the
diagnosis of CJD. And, more
specifically, since the first detection of variant CJD in the United Kingdom,
basically all U.S. CJD cases under the age of 30 have been autopsied, and
basically to this point there has been no histopathologic or clinical evidence
that any of these cases has been attributable to variant CJD.
Next
slide.
Now,
another important piece to CDC's surveillance activities has been helping to
establish and support the activities of the National Prion Disease Pathology
Surveillance Center. This was done in
collaboration with the American Association of Neuropathologists back in '96
and '97. And basically the Center
offers advanced diagnostic testing for prion diseases and serves as a way of
confirming suspected diagnoses, as well as detecting emerging forms of prion
disease, including variant CJD by pathology.
Now,
clinicians are basically encouraged to provide brain tissue from biopsy or,
again, more typically autopsy from patients with suspected prion diseases, and
in this way basically one of the important aspects of the Center is that it
provides basically a free state-of-the-art diagnostic testing service for
referring clinicians.
Now,
one thing that's critical for the success of the Center is the performance of
autopsies in suspected cases of CJD, and so basically we're actively
collaborating with various sites to increase the generally declining rates of
autopsy performance in the United States.
But
what's clear at this point, however, is that with the exception of the one U.S.
case of variant CJD which epidemiologically is felt to have been acquired in
the United Kingdom, of the over 1,200 specimens reviewed by the Center to date,
there has been no evidence of variant CJD in these cases by
histopathology. And so basically this
data is reassuring.
Next
slide.
And
so I think basically you can appreciate that there are several lines of
epidemiologic and laboratory evidence from CDC's various surveillance
activities to suggest that we have not seen the emergence or the appearance of
domestically acquired variant CJD in the United States.
Next
slide.
Now,
one of the other things that I was asked to comment on this morning and
specifically address is the epidemiologic data regarding risk of acquisition of
CJD through blood transfusions. Now,
obviously this concern -- next slide, please -- this concern has been ratcheted
up quite a bit since the recent events in the U.K., which Dr. Will has just
explained in detail.
But
what we can say is that the epidemiologic evidence continues to suggest that
the risk of transmission of sporadic or classic CJD in the United States from
transfused blood is low or absent.
Next
slide.
And
there's actually several lines of epidemiologic evidence to suggest this, and
I'd like to sort of walk you through those at this time.
Now,
first of all, to this point there has been no case reports of a case of classic
or sporadic CJD related to transfused blood.
Now, in addition, several case control studies have been conducted among
patients with sporadic CJD. Now, in
addition to other potential risk factors, the risk of blood transfusions has
been repeatedly assessed by these studies, and really at this point none of the
current seven studies provides any evidence of a risk of transfusion in classic
CJD.
Now,
additional epidemiologic evidence is provided by CDC's data from the National
Mortality Database. Now, as I mentioned
before, we have not seen any significant changes in rates or demographics over
time of cases of CJD in the United States, and, again, no cases of CJD have
been observed in teenagers, a group likely to receive blood products as well as
albumin derivatives and immunizations, and importantly, among all of the CJD
decedents in the database, none has had a co-diagnosis code of hemophilia,
sickle cell disease, or thalassemia, basically groups who obviously receive
multiple and frequent blood transfusions and blood products.
Next
slide.
Now,
there's additional evidence provided from a study initiated jointly by the
American Red Cross, CDC, and the now inoperative National Blood Data Resource
Center, and this is a study that has basically been ongoing since 1995. And basically the study has identified 331
transfusion recipients of blood components from 25 known CJD-implicated donors,
16 of which have been pathologically confirmed.
Both
look-back studies and prospective data is available on this group, and of 236
deceased recipients, none has died from CJD.
Additionally,
about 116 long-term survivors, patients surviving greater than five years, have
been identified from this group, and this includes 84 who are currently still
alive, as well as 32 who are now deceased.
The
median survival time for these patients was nine and a half years post
transfusion. Now, additionally, 17 of
these patients had survival durations greater than 16 years, and three have had
survival durations of greater than 26 years.
Now,
given the fact that iatrogenic CJD generally has an incubation period of less
than 13 years, sometimes as short as one, one and a half, or two years, while
not definitive, the evidence from this study is certainly reassuring.
Now,
a similar, albeit much smaller assessment was conducted among 27 known
recipients from a single donor with sporadic CJD in Germany, and again, no
evidence of CJD detected among 18 deceased and nine living recipients.
Now,
finally, persons with hemophilia who would be expected of being at much higher
risk of the development of transfusion-related CJD have been closely assessed
by a study conducted by CDC's Hematologic Diseases Branch and the Hemophilia
Treatment Center's group. And
essentially there have been no cases of clinical diagnosis of CJD among over
12,000 patients with hemophilia who have been assessed since 1996.
Now,
additionally, 40 decedents that were identified from this group have undergone
brain autopsy, and among these 40 cases there has been no evidence of
spongiform changes on histopathology, suggesting that these patients were not
harboring subclinical or early stage CJD at the time of their death.
So,
again, more supportive evidence against blood transfusion as a route of
transmission of sporadic CJD.
Next
slide.
Now,
the reason that variant CJD has been able to make this jump is unclear. There are several hypotheses and perhaps
some of these will be touched upon during the course of this conference. It may have to do with the differing
physical chemical properties of the variant CJD agent. It may be that the oral route of
transmission of variant CJD is more likely to lead to a blood phase, so-called
"prionemia." Or the fact that
the agent is in such high concentration in lymphoid tissue.
But
basically what we can say is that the available epidemiologic evidence suggests
that the risk of transmission of sporadic or classic CJD through blood appears
to be extremely low, if it exists at all.
And
I will close my talk there and take questions.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
GAMBETTI: I think that the data that
you presented are very reassuring, but from the perspective of the Nation Prion
Disease Pathology Surveillance Center, we feel that really the final answer as
to the presence or absence and the actual number of cases of sporadic or
familial CJD will come out only if we can expand the number of cases that we
examine by tissue analysis.
And,
therefore, as you recommended, I would like to underline further the need
really to increase the number of autopsies in cases of suspected CJD and if the
autopsy is done, make sure that the complete examination is carried out so that
at least we should be able to examine about 70, maybe even 80 percent of the
cases, as is done in several European countries, and then be able to examine
very carefully the clinical data of the remaining cases in which autopsy for
various reasons cannot be performed.
I
think this really is what we should try to achieve here in the United States
following the example of the European countries.
CHAIRPERSON
PRIOLA: Dr. Linden.
DR.
LINDEN: Thank you very much for an
excellent presentation that touched on some very important points. I agree with my colleague about the
importance of tissue pathological diagnosis as a contributing factor, but I
also commend CDC for putting in resources to some very important epidemiologic
studies which I think are a very important contribution to this. And I would certainly encourage ongoing work
in that area.
I
also thought that many of your slides were very nice slides, with the exception
that thalassemia wasn't spelled correctly.
DR.
SEJVAR: Sorry about that.
DR.
LINDEN: But I did not see that they
were in our packet, unless I missed them.
Would it be possible for us to get a copy of those? That would be very helpful.
DR.
SEJVAR: Absolutely.
DR.
LINDEN: Thank you.
CHAIRPERSON
PRIOLA: Go ahead.
DR.
BRACEY: The question I have relates to
-- I had a telephone call, so sorry. I
may have missed this. Is there a system
in place that tracks ‑- obviously there has been no variant CJD, but
tries to link transfusions to cases?
Are we looking at CJD and previous transfusions?
DR.
SEJVAR: Basically, we are looking at --
when a case of CJD is identified, we do go back and look at transfusion
records.
DR.
BRACEY: I guess, then, perhaps a
comment. One of the things that we've,
I guess, found through our experience with HIV is that sometimes, based upon
the weaknesses of our system for tracking, that can be somewhat difficult. We're not a point right now where this
perhaps would be so critical, but I think one of the things that we may need to
look at in the future is the capability of our system to allow tracking,
complete tracking.
DR.
SEJVAR: And I think as Dr. Will alluded
to, sometimes that is not as easy an endeavor as it kind of appears on the
surface, but I agree with you that, in anticipation, that is something that we
are focusing on.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: How long does it take on
average after diagnosis or after death for a patient to get into your data
system?
DR.
SEJVAR: The lag time is probably within
a year.
DR.
BAILAR: Would a shorter time be
helpful? Obviously, it would be a
little help. Would it be significantly
helpful?
DR.
SEJVAR: Basically, since we're
following this data over time and given the nature of CJD as an illness, I
don't really think that decreasing that lag time significantly is going to make
a significant change in surveillance.
DR.
BRACEY: Thank you.
CHAIRPERSON
PRIOLA: Dr. Hogan.
DR.
HOGAN: Thank you for this great
presentation.
Of
course, all of us are concerned about the issue of under-reporting of cases of
CJD, not only cases of known CJD that are not reported or analyzed, but cases
that are misdiagnosed as perhaps dementia, and other problems in which CJD is
never brought up.
So
are there methods in place from CDC or the Prion Unit to address these issues
or any way that we can tighten up the reporting issues? Have you thought about this or is there
anything planned?
DR.
SEJVAR: Well, you know, again, as Dr.
Gambetti mentioned, you know, the key is the pathology. Do you know what I mean? There are going to be cases that are
misdiagnosed, and you know, the bottom line is to try and increase the
available pathologic data on these cases.
Certainly,
there are cases that are misdiagnosed.
On the other hand, as I mentioned, you know, by the time a patient with
CJD is in the terminal stages, the clinical diagnosis is actually fairly good. So I think the key is, as Dr. Gambetti
mentioned, pathology.
CHAIRPERSON
PRIOLA: Dr. Linden.
DR.
LINDEN: Yes. Following up on the question about reporting, I think you assumed
100 percent reporting into your death database. Since I work for a state health department, I am somewhat
familiar with vital statistics reporting.
Do
you feel that you get 100 percent death certificate reporting from all 50
states?
DR.
SEJVAR: We actually tried to address
that at the onset of enhanced surveillance, and basically we went back and basically
did a population-based assessment, basically seeing what results we are getting
from the National Mortality Database compared to active case finding within a
defined population, and we were finding that basically we were getting over 85
percent ascertainment through the National Mortality Database.
You
know, so again, we are confident that we are catching the majority of cases in
this manner.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: If I could partially answer
the question that Nick Hogan asked, one of the studies that was done by the CDC
was to look at hemophiliacs who had become demented so that the idea was to
sort out what was the cause of the dementia in those patients. These are young people who had received
transfusions for many, many years.
And
as I recall, 95, 98 percent had died of HIV-related problems, and then a couple
of the others ended up dying of hepatic encephalopathy, and no evidence by
prion protein analysis or by histopathology of CJD.
So
they were addressing the issue of dementia in this population also. It wasn't just patients who had received
lots of blood transfusions.
DR.
SEJVAR: Yes. Thank you for that.
CHAIRPERSON
PRIOLA: Dr. Nelson.
DR.
NELSON: Yes. There was one U.S. case of variant CJD that was apparently
acquired in the U.K. How was that case
detected?
DR.
SEJVAR: That case actually was detected
by a diagnosis in the U.K. This patient
sort of had frequent back-and-forth travel between the United States and the
United Kingdom and was pathologically diagnosed in the U.K.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Sejvar.
Our
next speaker is Dr. Steve Anderson.
DR.
ANDERSON: Good morning. My name is Steve Anderson. I'm in the Office of Biostatistics and
Epidemiology at the Center for Biologics Evaluation and Research, part of the
FDA.
Next
slide.
Actually,
the goal of my talk is a comparison. So
I'm going to take some of the prior information that you heard in Dr. Will's
talk and some of the prior information that we've heard in Dr. Sejvar's talk
and try to compare some of that information and then share with you some of the
conclusions or lack thereof that we can draw from some of this information.
I'm
a risk assessment person. I'm a data
analyst. I'm not an
epidemiologist. I'm not in
surveillance, but I rely a lot in my work on quantitative analysis and
assessing risk.
So
just to start off comparing CJD and variant CJD, the risk of transfusion via
blood, I think Dr. Will alluded to and the subsequent speakers in the next
session are going to be talking about transmission of TSEs via blood
transfusion in the animal experiments.
I think the implications in the human system are, first of all, for CJD,
the protein is not found in the lymphoreticular system or it has not been
identified at this point, but for variant CJD there is some evidence that
suggests it is found in the lymphoreticular systems.
And
it, I think, is somewhat thought that there might be a higher possibility for
or probability of transmission of variant CJD via blood products versus CJD.
Next
slide.
Now,
I'm basically just going to summarize this information because Dr. Will has
given us excellent information about this case. The December 17th announcement in the U.K. of this case, the
transfusion transmission, the recipient received red blood cells. I'm just going to skip through this onto our
next slide.
And
I apologize because there were too many different blood services and
organizations to put on this slide. He
had about 15 listed, and I ran out of space.
So I apologize to any of those involved, but the study in the U.K.
involved a large group of agencies that followed the donations, as he said,
from 15 donors that were later diagnosed with variant CJD.
The
critical thing when I look at this is it follows 48 individuals that receive
blood products from these 15 donors, and as Dr. Will alluded to, there were a
variety of different products, whole blood, RBCs, plasma, et cetera.
Next
slide.
And
he also alluded to this information as well, and actually it was -- I stand
corrected. He said 20 units of
plasma. So there were 18 units or 20
units in this case of plasma from variant CJD-infected donors included in fractionated
products prior to 1998. I look at this
and see that is a potential exposure route.
Again,
thousand of potential exposures. I
think the critical thing to remember here, though, is that you've got large
batches of product being made, large dilution going on. So this would probably be a relatively
low-risk pathway of exposure to variant CJD if the agent is, indeed,
transmitted through the blood or blood products.
And
I think it's important to emphasize, as he said, that so far variant CJD hasn't
been observed to date for these products.
Next
slide.
I'm
not going to go much through this.
Again, CJD, I'm going to move from variant CJD into CJD, talk a little
bit about more on the side of CJD. It's
a rare disease, again, that occurs in older individuals, long incubation
periods.
I
think the point that Dr. Sejvar made is that it's considered a low risk, CJD
transmission via transfusion, considered a low risk, and I think from my
standpoint if the risk was significant you might expect to see increases in the
CJD rate annually. And as Dr. Sejvar
said, at least in the United States the rate has remained stable for the last
20 or so years, and in many countries that are conducting surveillance that's
also true.
Next
slide.
I'm
not going to go much through this study because Dr. Sejvar has already walked
us through this study, the American Red Cross-CDC-NBDRC look-back study. I think the important thing here, I'm just
going to emphasize the numbers since I'm more interested on the quantitative
side.
Three
hundred thirty recipients were followed, and for my analysis, I'm interested in
these 116 recipients that lived longer than five years.
Again,
there were no observed CJD infections that have been observed to date in this
study.
So
the next slide.
Again,
Dr. Sejvar alluded to seven studies. I
present one paper that evaluated five case control studies in 2,400 CJD
patients. Again, there was no observed
association between CJD and transfusion.
Again,
these came from a variety of locations, Japan, U.K., Europe, and
Australia. Again, I'm just going to
move forward to the next slide.
He
also alluded to this, although I presented it slightly differently. Basically, CJD studies in hemophilia
populations. These you might expect to
be at high risk since they receive frequent and perhaps significant amounts of
blood products over a several year period.
So
CDC has done autopsy studies and antemortem studies, first starting with 30,
and I think that as Dr. Sejvar said, that has been expanded to 40.
Looking
at patients who died of CNS symptoms after 1983, again, looking at those, there
was no indication of CJD. They also looked at the more than 12,000
hemophilia patients assessed for CJD, again, and didn't find indications of the
disease.
So
in this high-risk population you don't see any indication of transmission
transfusion.
Next
slide.
And
a similar study in the U.K., although they just did an antemortem study of --
postmortem study of 33 hemophilia patients.
They had received concentrates over this period of time from '62 to 1995
from a range of 3 to 27 years.
Again,
this was also an evaluated for variant CJD, I believe, and CJD, and no
indication in this population of these diseases.
The
next slide.
Okay. So that brings us to the evaluation I did,
and it was a very simple analysis, given the information that is
available. I'm going to walk you
through an example comparison between the data for variant CJD and CJD, and
it's nothing extremely complex because the data really aren't there yet, and I
think one of our recommendations will be that further data are obviously
needed.
Again,
we looked at 48 recipients, the 48 recipients in the U.K. study for variant CJD
transfusion infection. Of those 48, we
really focused on these patients that had survived greater than five years post
transfusion, and the one presumptive variant CJD infection that came six and a
half years approximately after transfusion.
And
then there is the data that Dr. Sejvar presented from the NBDRC CJD look-back
study. Again, the interesting thing for
us to focus on is these 116 recipients that survived greater than five years. Again, zero infections to date from those
individuals, and let me just -- the next slide. I think I'm going to pass.
Next slide.
Okay. So we compared those two groups, the 15 out
of 48. We looked at those recipients,
the percentage of recipients in those overall relatively small groups and the
percentage surviving longer than five years post transfusion in the two groups,
and they looked very similar.
So
what we can say from this -- I did this because we're looking at U.K.
populations versus the U.S. populations, and we wanted to be sure there wasn't
any distinctions at this level of survival at the five-year point. Pretty much very similar, 31 percent, 32
percent, 35 percent for the CJD study.
So very similar on that level.
And
on to the next slide.
And
the quantitative and analyst person in me wanted to set this up as a two-by-two
table and see what I could glean from this information. I would say, you can do statistical analyses
on these, and I played around with doing that, and basically the thing that
just jumps out at you is zero and one.
So that's why I sort of wanted to present this.
And
what you've got from this basically, given the relatively small size of each
group, it's really difficult to say much about these two groups. You've got zero and one, and the conclusion
that you can draw from this is this could be a chance event. This could be due to a confounding
factor. It could be due to transfusion,
and I don't think we should eliminate the possibility that it's due to
transfusion. But just based on the
statistical analysis side of things, you can't really determine that just based
on the size of the groups in this analysis.
I
think it's important to say though that we're treating it as a presumptive case
and acting as if it is, indeed, a transfusion-transmitted case to err on the
side of caution.
And
I think the one strong conclusion that I can draw from this information is that
we really need additional data and research in this area to really determine
what the trend is in this situation.
You certainly would like to see a greater number of individuals enrolled
in these studies to look at possible trends.
And
the next slide.
There
are certain challenges to doing that though.
First of all, the size of the group so far has been small. The incubation period for these diseases is
long. So if you are transfused with
blood from an individual that was diagnosed with one of these TSE diseases, it
will take a very long time, perhaps four years, five years, or longer, to
actually develop disease.
And
one thing we note is post-transfusion survival. Many of the patients that receive transfusions are very sick or
have severe medical conditions. And
many of them don't survive ? a
significant percentage, let's say, don't survive beyond one or two years. So you've reduced your population that you
can analyze significantly, and that's an important limitation in these studies,
and I think I'll stop there.
CHAIRPERSON
PRIOLA: Any questions for Dr. Anderson?
Dr.
Bailar.
DR.
BAILAR: I don't understand what I've
been reading -- and now what you referred to very briefly -- about the possible
benefits of dilution. I understand how
the risk per person might go down, but it seems to me the total risk would go
up.
DR.
ANDERSON: You're correct. The benefits of dilution as far as -- can
you repeat that?
DR.
BAILAR: Well, if you had a blood
product with, say, ten infective units in it, and you give it all to one
person, you'll have one case. If you
give it to 50 people, you'll have ten cases, but the risk per person goes down
to 20 percent.
DR.
ANDERSON: You're just spreading that
risk.
DR.
BAILAR: You're spreading a larger risk.
Now,
the way around that would be to find that there is some minimal infective dose
such that you can dilute beyond that and a tiny bit of the prion isn't going to
cause a problem. But I don't know that
that has been established.
DR.
ANDERSON: Right. I mean, I think dilution is an issue and
pooling is something that we definitely grapple with, and we don't know what
the infectious does for a human for these agents are, and definitely, I think
the most valuable thing that's really difficult to generate is you need a good,
at least from a risk assessment person, is you need a good dose-response curve,
and that's just not available.
So
making the predictions when you start diluting down, down, down is very
difficult, and we don't know what the threshold is. If you go below a certain threshold or amount of infectivity,
whether infectivity is even possible.
So you are spreading that out among a significant number of people
potentially.
DR.
BAILAR: But that seems to me, on the
basis of very little knowledge, something that could be studied in animal
systems.
DR.
ANDERSON: Well, I think the issue here ?- and maybe one of the TSE experts might want to
comment on that ?- is the
more and more you dilute down, I think the longer it takes to develop
infection. So I think those studies
would just have to go on for very long periods of time, and then I'm not sure
that that's necessarily possible.
DR.
BAILAR: This apparent change in
incubation period with decreasing dose is another matter I have some trouble
with as a statistician, but I don't think we need to talk about it here.
DR.
ANDERSON: Well, maybe we can talk
offline.
CHAIRPERSON
PRIOLA: Dr. Linden.
DR.
LINDEN: Okay. So you're trying to use a statistical approach to see if there's
a difference between variant CJD and CJD based on one case versus no cases out
of 14 noninfection cases and 116 noninfection cases, and you're saying that the
n in the groups is too small, and I understand from a statistical standpoint
you'd like to see the groups be larger.
I
mean, I would argue from a clinical standpoint we don't want to see those
groups be any larger.
DR.
ANDERSON: Well, from a public health perspective we don't want ?- you know, we want to see all groups at zero
actually.
DR.
LINDEN: Right. But from a statistical standpoint, if you
continue to compare the one infection case and zero, I mean, we certainly hope
it continues to be zero for CJD.
Statistically, how many cases would you need to have in the noninfection
groups to see a difference between one and zero? I mean, isn't that going to have to be a very large number for
you to ever see a difference between one and zero statistically?
DR.
ANDERSON: I didn't do those
calculations, but you're correct. I
mean, this is a low probability, very rare event, even for blood transfusion
groups that we're evaluating, and we already narrowed things down. But I think it's such a rare event that, you
know, you would need -- I don't know -- thousands, just off the top of my head,
and that's obviously not realistic, given that you have to trace these people
and then do the follow-up analysis with them.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Just a comment. The dilution studies have been done in mice
starting with high titer prions from brain, and you can define down to what a
single infectious unit is, which I think includes like ten to the fifth prion
protein molecules. So that has been
done, but we have no concept about what it would be in blood. We don't even know if prion protein there is
infectious yet, at least in the typical CJD, not variant CJD, but in typical
CJD.
And
actually Rohwer, Dr. Rohwer wanted to make a comment, and I'd like to hear what
he has to say about that.
CHAIRPERSON
PRIOLA: He's going to present data in a
talk, so I thought we'd wait for that.
Dr.
Nelson.
DR.
NELSON: Yes. I think that this really isn't a statistical problem, as
such. I think the biology of, you know,
the proper incubation period and, you know, the fact that the cases were
related with a proper incubation period makes it more persuasive.
But
the one question I had was: Is the prion genotype the same, the distribution of
the MM genotype the same in the U.S. and U.K. populations? In other words, is susceptibility the same
in the two populations?
DR.
ANDERSON: Oh, I have no idea on that.
CHAIRPERSON
PRIOLA: Dr. Gambetti, do you want
to? You were going to ask a question
anyway.
DR.
GAMBETTI: The question is: Is the
susceptibility is the same?
DR.
NELSON: Is the genotype distribution
the same in the U.K. and the U.S.?
DR.
GAMBETTI: No. Whether the homozygous methionines at codon 129 have the same
risk of developing sporadic CJD in U.K. and in United States,. Is that the question?
DR.
NELSON: The question is --
DR.
GAMBETTI: And the answer is I don't
know.
DR.
NELSON: -- is is the distribution
within the population of the MM genotype the same in the U.K. population and
the U.S. population?
DR.
GAMBETTI: Yes, yes. I based ?- the only
elements to answer this question are the data from the National Prion Disease
Surveillance Center and the one in the publication by Collins, the regional
publication by Collins in which this risk was assessed, and, yes, it looks very
comparable. That is definitely --
DR.
NELSON: So about 35 percent of the
population is MM genotype; is that correct?
DR.
GAMBETTI: The population is 37, yes,
MM, and we see -- I have the exact figure, but off of my head, I would say we
see about 60, 70 percent of the case of prion -- no, actually higher, probably
75 percent of all the cases that we see of sporadic CJD are from patients that
are MM.
DR.
DeARMOND: I think the question had to
do with proportions in England and here.
DR.
NELSON: Yes.
DR.
DeARMOND: And in the United States and North America, they're essentially the
same as in Europe and in England. Japan
is different.
DR.
GAMBETTI: Yes, much more MM.
I
just wanted to point out that actually it looks like the differences that are
still conspicuous between variant CJD and sporadic CJD seem to kind of
decrease, after a report from Switzerland, in which I'm sure you know, the
scrapie prion protein was found in the spleen and muscle of about 20 to 30
percent of the cases with sporadic CJD, indicating that there must be, sometime
during the course of the disease or during the entire course of the disease,
some scrapie prion protein in the blood also of sporadic CJD patients, or at
least a portion of sporadic CJD patients.
CHAIRPERSON
PRIOLA: If there are no more questions
for Dr. Anderson, I think we'll take our break a little bit early because it
seems like a good place to break the two presentations, and we?ll reconvene at about quarter after.
(Whereupon, the foregoing matter
went off the record at 9:57 p.m. and went back on the record at 10:16 a.m.)
DR.
FREAS: Dr. Priola, I'd like to turn the
meeting back over to you.
CHAIRPERSON
PRIOLA: If all of the Committee members
could come up and take their seats, in the second part of this morning's
session we're going to hear from Dr.
Robert Rohwer, who is going to discuss experimental transfusion models for
TSEs.
DR.
ROHWER: Thank you very much for having
me here.
I'm
going to be focusing today on the experimental work that has been done looking
at the various issues associated with blood-borne TSE infectivity. I'll be mainly focusing on work from my
laboratory because that's what I'm most familiar with, but I will be mentioning
the work of others as we go along, and really the story is very consistent
across laboratories as it stands right now.
If
we could go to the first slide, to put this discussion in a proper perspective,
it is important for you to understand how the experiments are actually
done. There's hardly any infectivity in
blood. As you'll see in a moment, it's
about ten infectious doses per mL, which means that we cannot resort to the
conventional method of endpoint dilution titration, which is typically used for
assaying infectivity in the TSE agents.
In
a typical brain experiment, we'd start with a very high titer of infectivity,
and we'd go through a bunch of serial dilutions over here, and each dilution
would be inoculated into a cage or more of animals, hamsters in this case. This is the 263K model that we'll be
discussing here largely.
And
then these animals would be allowed to incubate for approximately a year. And after a year, we did assess which
animals became diseased and which didn't, and diseased animals are indicated in
gray here, and you'd find an endpoint where you were no longer getting
infections, where in fact there's less than one infectious dose per inoculum
because some of these animals survive the infections.
And
from that endpoint, using a couple of different statistical methods, you can
calculate a titer. Nevertheless, you
can kind of see what the titer is just by looking at the dilution. This isn't actually that big of an
improvement on just the eyeball estimate.
But
in the case of blood, the issue is that we're at this titer to begin with. The undiluted blood is already at what we
call limiting dilution, a dilution where some animals become ill and some
don't, and so what we devised early on was a strategy of instead of trying to
do an experiment like this, we invest the animals entirely in the undiluted
sample.
And
then we get a spectrum of infections.
Some get sick; some don't. And
we can calculate the titer by the Poisson.
I'll show you that in a minute.
But
there is one other detail that I need to point out here, which is that there is
a dose response associated with this infection. These animals that receive the highest dose come down in the
hamster model in about 60 days. At the
limiting dilution dose, they begin to get sick at about half a year and they
continue to get sick from there on out for a year and a half.
Next.
And
that's indicated here. This is a dose
response. This is titer on this axis,
logrithmically, and these are incubation times down here, and what you see is
you get a fairly broad spectrum of response, but nevertheless, when you put it
together it's a consistent dose response where the incubation takes longer the
lower you go.
But
once you get down to limiting dilution, the whole dose response goes away and
you get random infections all the way out here for a year and a half.
Next.
We
have a theory about why that happens, but we can discuss that later if you're
interested.
So
the model we've developed for these low titer inoculations is to create a donor
animal, and at some time later collect the blood by exsanguination, process the
blood or not, as we see fit, to make the various measurements we want to do,
and then we want to look at a statistically valid sample of that blood, and
we've standardized on a five mL whole blood equivalent for inoculation into
hamsters.
The
problem is to inoculate five mLs of blood by the intracerebral route into this
small animal requires a lot of hamsters because you can only inoculate about 50
microliters per animal by that route.
Why
are we using that route? Because it's
the most efficient route, and the question we're trying to answer is: Is there
infectivity there or not? And how much
infectivity is there?
This
is a quantitative assay. It's not necessarily a relevant route of inoculation
for the acquisition of the disease, but it is a way to make an accurate
measurement.
Next.
At
some time later, in this case a year and a half later, we have this spectrum of
infected versus uninfected animals, and this is actual data from the
leukoreduction experiment that I'm going to show you later in the talk.
So
in this case, in our whole blood inoculation we had 44 out of 100 animals
inoculated acquired the disease, and just roughly you can see what the titer
would be. It would be 44 divided by
five mLs, or about 8.8 infectious doses.
However,
the infectivity presumably assorts randomly into these animals. So, in fact, some of these animals that were
infected probably received two doses instead of one dose. Others received three, some four, at
diminishing levels as it goes up, and this is described very accurately by the
Poisson distribution, and you can apply a correction, a very precise correction
to this value, which jogs this number up to about 12 infectious doses per mL.
Associated
with this, presuming that we are getting random assortment into these animals,
there is also a very precise statistic associated with this, and the standard
deviation is plus or minus 3.4 in this case.
What
this tells us is that we can detect less than twofold differences in titer by
this method. This is a vastly more
precise method of measuring titer in the TSE agents than has ever been used by
any other method.
Next.
But
it is essential to what we have been able to do.
Next.
Now,
we have looked at several large blood pools, like the one I just showed you,
over the last seven or eight years by this method, and this is the range of
titers that we've seen looking at pooled blood, and we've also looked at
individuals -- next -- the individual titers.
In
this case we inoculate a full two mLs of blood obtained from the individuals,
and the titers range like this. So they
kind of reflect the same distribution.
Next.
There
are a set of control experiments that we did involving splenectomies that I'm
not going to discuss today, but those titers also fell right in this
group. If we look at the mean and the
median -- next; put them both on, next -- we end up with something that's right
around ten infectious doses per mL, and that's what we take as our kind of
benchmark titer for TSE infectivity in this rodent model.
Now,
we've made these measurements also in the BSE-adapted mouse model, where we
have had two measurements now from pools, one at about ten infectious doses and
another one at about 20, and Larisa Cervenakova has made some measurements
which also fall nicely in this range using her variant CJD mouse model.
Next.
One
of the first things you want to know is where is the infectivity in blood. How does it distribute? This is a component separation that was done
using the ultracentrifugal methods protocol that's used by the American Red
Cross. This was done on 250 mLs of
pooled hamster blood, and this is, again, inoculating a large cohort of animals
with each one of these fractions, and that's where these numbers are derived
from.
The
distribution of infectivity in this case went this way: 25 percent in plasma, 35 percent here, 20
here. That doesn't add up to 100
percent. If you re-normalize to 100
percent, you'd get this distribution over here.
This
is a very complex fraction. You have
everything in it, white blood cells, platelets, plasma, et cetera. There is also white blood cells and plasma
contaminating this fraction. This is
the cleanest fraction which contains pretty much plasma and some platelet
fragments.
We
were surprised to see this. Paul Brown
and I, in an original experiment that we did years ago, saw this in the mouse
Fukuoka strain. We weren't expecting
it. We were thinking that it would be
-- that everything would be associated with the white blood cells. That's clearly not the case. We have lots of evidence now that we've seen
this over and over again now. This is a
real effect though. We do not know what
the nature of the infectivity is in this plasma fraction.
This
is just a vastly more precise measurement of the same thing.
Next.
Because
platelets could be responsible for that plasma contamination, we are very
interested in knowing whether platelets themselves harbor the infectivity. Platelets in humans at least have quite a
lot of the prion protein in them or on them, and that association implied that
perhaps platelets could be involved in the blood-borne infectivity story.
I'd
like to remind you, however, that the prion protein, the normal form of the
prion protein is very widely distributed in the body. It is found, for example, in the heart at almost the same
concentration that it's found in the brain, and yet we find very, very little
infectivity in the heart.
So
the correlation with infectivity is not with the prion protein itself. It's with the abnormal form of the prion
protein, and the form that we find in platelets is the normal form, and what we
see here is that in 22 mLs of blood which titered out, again, right on the
money at ten infectious doses per mL in this case. Inoculating half of the entire Ficoll-purified platelet fraction,
we had one infection that worked back to a titer of about 3.5.
Our
feeling is that the platelets are not where the infectivity is in blood. However, I do want to make one warning about
this. These were highly purified
platelets. We did this in collaboration
with platelet experts at the FDA. They
were Ficoll-purified, washed exhaustively, et cetera, and as a consequence they
do not represent what you would get in a platelet concentrate, which is a
mixture of platelets, plasma and other components.
Next.
This
does not say that platelets themselves or a platelet concentrate would have no
infectivity in it.
We're
also interested in where the infectivity might be in plasma, and the plasma
industry was interested as well. With
sponsorship from the Red Cross for this experiment, we did a Cohn fractionation
using endogenously infected blood on 50 mLs of plasma from that component
separation that I showed you a few minutes ago.
This
is just showing you the volume distribution of the various fractions that come
out of the plasma in the course of fractionation. And what we did here is we inoculated as much of these pellets as
we could or often the entire thing, or if that was not possible, we inoculated
at least a five mL whole blood equivalent so that we could relate it back to
whole blood.
Next.
This
data is plotted in the following way.
This is incubation time down here on this axis, and these are the
various fractions we looked at, and each dot represents an animal that acquired
the disease at that point in time, the incubation time, and basically what I
wanted to show you here is these are the whole blood samples here. In yellow are the various plasma fractions,
and these are the various pellets of various sorts.
A
point I want to make is that even though the concentration is low in the plasma
fractions, the volume is high and the total amount of infectivity associated
with the plasma frequently is similar to that that's found in these pellets
where we are inoculating the entire pellets.
The
main point I want to make here is that we were able to track the infectivity
through the cone fractionation all the way to fraction IV but no further. We found nothing in fraction V or fraction V
supernatant or in fraction II or fraction II supernatant.
Next.
This
is the cone fractionation. We don't
have time to go through this, but this is showing both arms going to the
immunoglobulins over here and albumin over here. We saw infectivity to this point, but not beyond in this
fractionation.
Next.
Another
thing that we're all very interested in is when, in fact, does the infectivity
appear in blood during the infection.
This is something that can be addressed directly in the experimental
models, and this is an experiment in which we inoculated a large cohort of
animals in this particular case using the intracerebral route, but inoculating
a low dose. So the incubation time was
quite long by this route, somewhere between ten and 50 infectious doses.
And
then at three week intervals we sacrificed pools of 20 animals, exsanguinated
them, pooled all of the blood from that because what I wanted to get at here
was what is the average behavior during the course of the infection, and then
we would inoculate 100 animals. In this
case 85 to 95 hamsters were inoculated with whole blood directly to measure how
much infectivity was present at that point in the infection.
And
we can see that three weeks after inoculation we saw nothing, saw nothing
here. This was very reassuring to us
because it answered a long question that we had about a possible artifact that
could be associated with that, and that is that we were actually reisolating
inoculum in the case of these blood experiments.
Since
we saw none at these early times that rules that possibility out. This is also a very good control for us
because we had a lot of animals invested at this point in time. We saw no infections, which tells us that
our environmental controls are extremely good.
We're not picking this up in our colony adventitiously.
And
then the data are also very consistent.
Midway through the clinical disease, we start seeing infections. We see more as the disease progresses with
the highest titers at the time of clinical disease at 125 days. This is plotted in a graph in the next
slide, and again, we see these two points with nothing in them, and then we see
these very interesting kinetics.
What
I can tell you is that we have another experiment on at the moment that's about
a year out in its incubation where we inoculated the animals by the oral
route. This is a much more natural
route of infection, we believe, and we're seeing, to the extent that we can
talk about it at this time, we're seeing what looks to be a very, very similar
picture.
There
is something very peculiar about this data which we don't understand, and that
is that this is a linear axis over here.
These are infectious doses per mL in blood, and my original assumption
was that the blood-borne infectivity was probably coming from the brain. We have huge amounts of infectivity in the
brain, and the clinical stage of this animal, ten to the tenth infectious doses
per gram, and I could imagine that at a very low level it was spilling over
into the bloodstream just due to the necrosis that was taking place in the
brain.
But
if that were true, we would expect the same kind of exponential growth kinetics
that we see in the brain in the blood, and we're not seeing that here. This is absolutely linear, and it suggests
that there is some other source for the blood-borne infectivity, and we're very
curious to know what that is.
Next.
Of
course, it's also of interest to know whether this disease can be transmitted
even though there's infectivity in the blood.
Let's put it that way. It wasn't
clear to me when we began these experiments that it would be transmissible by
the blood route. My own prejudice was
that this stuff was probably associated with white blood cells, and it was on a
dead-end pathway to elimination.
And
these are central nervous system diseases.
They're not hematogenous diseases, in the usual sense of that word, like
HIV or HCV or something like that. And
so it wasn't clear to me that if you actually transfused this blood that you'd
actually also transmit the infection.
So
we set up a transfusion model which is rather extreme in some ways. What we did is we took our donor and would
exsanguinate them in clinical disease, and then transfuse the blood, which we
expect to have about ten infectious doses per mL in it. We transfused two mLs of that to a recipient
hamster. We would do a cannulation of
the carotid, remove two mLs and then replace it with two mLs of this donor
blood.
So
essentially we're moving the clinical infection from an infected animal to an
uninfected animal via the bloodstream at about a third of the blood volume of
the animal. This is, on the basis of
blood volume, this is a massive transfusion.
These
are difficult to do, and over the course of four or five years we did about 100
of them, which are summarized here in this figure.
Early
on, we had a transfusion transmission, but we only had one. We had the same problem that has occurred
with the variant CJD transmission. What
kind of statistic can you attach to that?
Is that one in a million or what?
And
that has encouraged us to go on and do additional transfusions. At the end of this study, this is where it
stands at this point. We've seen three
transfusion transmissions, but when we look back to see what we've done, we
have over this period of time transfused a total of over 200 mLs of hamster
blood by the transfusion route two mLs per hamster.
Well,
if this had been brain-derived infectivity at somewhere between four to 20
infectious doses per mL, we would have had these kinds of titers in this 200
mLs, this amount of infectivity total.
Even at a tenfold reduction in efficiency, which is probably more than
is warranted for blood ?- it's less
than brain, but it's actually quite an efficient route of transmission. It's quite an efficient route of
transmission of brain- derived infectivity -- we still would have had 80 to 400
infectious doses. We should have seen
most of these animals infected as opposed to what we actually saw.
So
there is something different about the transfusion route of transmission
compared to the IC route and compared to the introduction of brain-derived
infectivity by the IV route.
On
the other hand, had we been able to put the entire 200 mL volume into a single
hamster, sort of the question that came up earlier from Dr. Bailar, we would
have expected an infection for sure because an infectious dose is, by
definition, the amount needed to cause an infection, and we had three of them.
Next.
What
can we take from this? Well, it doesn't
seem to us that blood plays a very important role in the pathogenesis of the
disease in the hamster. We know that
transient exposures to blood-borne infectivity in the right context by this
transfusion route, at the highest titers that can be achieved naturally in
blood, i.e., during clinical disease, did not transmit the disease
efficiently. On a per animal basis, it
was rare.
At
earlier stages the titer would be even lower and the transmission would be even
less efficient. So if blood-borne
infectivity does play a role in the pathogenesis, it has to be because of
chronic exposure to the very low, early preclinical levels of infectivity.
Nevertheless,
it still may be a problem, a public health problem if, by transfusing large
volumes, you can actually transmit the disease.
Next.
And
this data contrasts sharply with the experience that has been obtained with
sheep. Nora Hunter and Fiona Houston
and their colleagues at the Institute for Animal Health in Great Britain or
Scotland have done a number of sheep transfusions now where they have
successfully transfused from experimentally infected sheep, experimentally
infected with BSE, bovine spongiform encephalopathy, and from sheep that are
naturally infected with sheep scrapie, showing that either by an experimental
route or natural infection they can get these transmissions.
They're
seeing them at a fairly high frequency in this flock, a higher frequency than
we saw in the hamster model, but the model differs in some important ways from
the one we're using. They're only
transfusing four to six percent of the blood volume, even though they're
transfusing large volumes, and they're seeing frequent transmissions.
By
comparison, we were transfusing 33 percent of the blood volume, but at a low
volume and rare transmissions. What
this is telling me is that it's the total amount of infectivity that's
transfused that's important. It has
nothing to do with blood volume.
Next.
Okay. I'm going to discuss now an experiment that
we've done and just very recently completed and are preparing at the moment for
publication, and this is an evaluation of leukoreduction using this same
endogenously infected blood model.
Next.
When
the first variant CJD cases emerged in Great Britain, there was immediate
concern for the blood supply, and that's because there did seem to be more
peripheral involvement in this disease, and a likely source of that peripheral
involvement was some sort of hematogenous spread of the infectivity, and so
measures were taken to mitigate the risks from this.
One,
the British stopped fractionating their own domestic plasma, but the other
measure that was take is leukoreduction, and there were good reasons for doing
this. A lot of laboratories besides our
own had identified buffy coat as a source of infectivity in blood. And PrP scrapie and infectivity had been
demonstrated in the lymphoid tissues of the variant CJD cases and in some other
TSE infections as well.
And
then at almost this same time, Aguzzi had published a paper showing that B
lymphocytes, using knockout transgenic mice deficient in B lymphocytes, he
showed that they were absolutely required for the propagation of the
infectivity from peripheral sites.
Now,
it was presumed that that was because B lymphocytes might either be replicating
or transporting the infectivity. It has
since been shown that their role is an indirect one. They are absolutely required, but indirectly, and so this isn't
necessarily a relevant reason anymore, but it's part of the reasoning that went
into the measure.
Next.
Once
this was implemented, we knew about our component separation and had presented
that several times and were concerned that leukoreduction might not be able to
do the job because we only saw about half of the infectivity in the buffy coat.
Some
other groups, Paul Brown and Larisa Cervenakova and their colleagues, and a
group at the Scottish National Blood Transfusion Service did some direct
experiments on leukoreduction. This
experiment involved endogenous infectivity and a filter, a scaled down filter
supplied by Paul, which showed no removal from plasma.
These
people used brain-derived infectivity
to spike all of the major manufacturers of leukoreduction filters and so
no loss of infectivity by passage through any of these filters.
Next.
We
decided that if we were going to contribute to this that we needed to do a
different type experiment. We would use
endogenous blood-borne infectivity. We
didn't want to scale down because there would always be issues about the
relevance of the scaledown, which meant using a full unit of blood, the
commercial filters at their rated capacity, and we had a partner in this
experiment in the Canadians.
Health
Canada was proposing to also implement a universal leukoreduction, and they
wanted to know whether this would have any effect on their risks to CJD.
So they supported us financially, and we used their protocols and
equipment to do the experiment and their personnel.
We
ended up testing two Pall filters, next, which you'll see in the next, and
logistically this is a difficult experiment.
We had to get a large cohort of animals at the same stage of disease on
the same day, collect the blood within a few hours, get it into a blood bag, do
the leukoreduction, take our samples, and get it into animals, and get the
infections underway.
We
had everyone in the lab involved, plus a number of people from Health Canada,
and it was a big party actually. But it
was very nicely orchestrated by Luisa Gregori in my lab, and we were able to do
this.
We
were interested in meeting the AABB specifications for leukoreduction. We did a bunch of prototype experiments with
normal blood to make sure that we could do this. We were within specs on everything except platelets, where our
platelet recoveries were a little low.
Next.
And
that's because the platelets enhancers are somewhat more dense than they are in
humans and a larger fraction of them ends up with the red blood cell fraction.
So
we collected this within two to four hours, did the whole experiment.
Next.
The
first experiment we did was with this whole blood filter right here, the
WBF2. We titered an aliquot of whole
blood, an aliquot of the leukoreduced blood.
We
then subsequently carried this through a hard spin to produce an RBC
concentrate and platelet-poor plasma.
We have these thing stored.
Next.
A
few days later, the rest of the cohort was at a stage where we could bleed it,
and so we collected another unit of whole blood and tested this plasma filter
and RC filter right here.
We
did not titer these. We did not have
the funds to do that, but what we did do is determine that the blood behaved
and met the AABB standards in this model, showing that this is an excellent
model for doing this type of experiment.
Next.
They
operated within specifications both with respect to white blood cell removal
and red blood cell and plasma recoveries.
Platelets were low.
Next.
This
is the actual data. These are the
recoveries over here, and these are the AABB specifications down here, and as
you can see, we're right on for all of these things.
Next.
This
was the second set of experiments and, again, a similar story.
Next.
This
is the titration data. The
prefiltration whole blood came out to about 12 infectious doses per mL; post
filtration, about six. This is actually
a little higher now because we've completed the Western blots on this data, and
we found a couple more infections in the post-filtration group.
But
what it's telling us is that we're only removing about 50 to 60 or 40 to 50 percent
of the infectivity by leukoreduction.
Next.
Interestingly
enough, this is exactly consistent with what we found earlier in our component
separation by ultracentrifugation.
Again, we saw about 45 percent of the infectivity in the white blood
cell fraction and the rest in plasma and red blood cells.
So
both of these experiments are highly consistent, and these are two completely
independent measurements.
Next.
What
would this mean for a unit of blood?
Well, in this particular unit, we would have had 5,500 IC infectious
doses in the in-going blood, by IV route at ten percent efficiency maybe 550,
and the red blood cell component, this is our estimate. We would have had about 138.
Post
filtration, we dropped both of these things by a little less than a half, but
we still end up with significant amounts of infectivity in those fractions.
Next.
The
implications here are leukoreduction is necessary, but not sufficient to
eliminate the risk. Whatever measures
we do take, I think, to get rid of the infectivity in these components,
leukoreduction will have to be part of that solution.778
The
infectivity in leukoreduced blood is in a different state. It appears to be in a more soluble state,
and as a consequence, it may be harder to get rid of; may or may not, depending
on the technology that's used.
And
we haven't titered the post-filtration components. We'd like to do that just to see, you know, how it distributes
farther down the line.
Next.
So
in summary for the entire presentation here, from the animal models of
blood-borne infectivity, I think we can say that we've had unequivocal
demonstrations of blood-borne infectivity in rodents, sheep, and possibly now
in monkeys. We've had diverse strains
of agent that have been looked at, and this effect has been seen with familial
Creutzfeldt-Jakob disease, the Fukuoka strain, variant CJD ?- this is Larisa Cervenakova's work ?- BSE, our work, and scrapie.
We've
seen it in natural TSE infections, as well as experimental infections, and this
is the Institute for Animal Health work with the sheep transfusions.
Next.
We've
seen unequivocal demonstrations of transfusion transmission in hamsters. Larisa has seen some of these transmissions
in her mouse system; and in sheep; diverse strains of agent, again; and in
natural infections.
Moreover,
there's a credible explanation for the difference in susceptibility to
transfusion transmission that we saw between the hamster and the sheep.
Next.
So
what we get down to is that all of the experimental data are consistent with
and predictive of transfusion transmissions of TSE diseases in humans.
Next.
So
in some ways we shouldn't have been surprised to see this though I, frankly,
have to tell you I was surprised. It
was quite a shock to hear this had happened just before Christmas.
But
this is the time line. Bob Will has
already gone over this, but I just want to reiterate it. This donation occurred three years before
the donor died. This is
preclinical. This is consistent with
what we see in the hamster. We see
infectivity, preclinically, halfway through the incubation period of the
disease and beyond.
That's
not to say it's not there earlier. It
just means it's at titers lower than our assay is sensitive enough to pick
up. My guess is it is probably there,
but you'd have to inoculate 10 mLs or 50 mLs of blood in order to pick it up.
So
it was a preclinical exposure, and we had a six-year incubation time, which is
actually quite short compared to the incubation times that we typically see for
iatrogenic cases due to dura mater or human growth hormone.
Next.
So
if we take the presumption, and the FDA has just told us that they will presume
that this was a transfusion transmission, then it fills in most of the missing
gaps in this story. There can be TSE
infectivity in human blood. It is
present preclinically, and it is transmissible by transfusion. It may even have a virulence greater than
might be expected from the incubation time in rodents, based on the incubation
time in this particular case.
Next.
The
only thing that's inconsistent with this story, and it is a major
inconsistency, is why we haven't seen transfusion transmissions from classical
cases of Creutzfeldt-Jakob disease.
That has been discussed by a number of people already today. I can't really add much to that. Is it that we?re missing them, our surveillance isn't right? Is there something really truly
different? We just don't know.
Next.
I
just want to acknowledge the members of my lab that helped produce this data,
in particular, Luisa Gregori and Claudia MacAuley ?- Claudia MacAuley is responsible for these
surgeries that are involved in the transfusion experiments ? our collaborators at Health Canada, and Pall
Corporation for the leukoreduction experiment.
Next? I think that's the end. Forget that. Go back. We're going to
stop here.
Thanks.
CHAIRPERSON
PRIOLA: Are there any questions for Dr.
Rohwer from the Committee? Dr. Wolfe.
DR.
WOLFE: Bob, now that it is clear or
even clearer that cell-free plasma has some infectivity, have there been any
efforts at filtering and things like that?
I mean, we keep hearing about filters that will filter this stuff
out. Have you looked at that or has
anyone else looked at that?
DR.
ROHWER: We have been working with
nanofiltration, but we have not done nanofiltration on plasma.
DR.
WOLFE: Are you planning to try that or
is someone else?
DR.
ROHWER: We've been working mostly with
the Asahi people, and they are interested in that experiment, and I think
getting it together logistically will be -- it's taken time, let?s put it that way. But it's something we're very interested in doing.
There
are other ways you can get at this.
We're very interested to know whether that infectivity is big or
small. Also, there's always the
possibility that it's there just because it's floating, and it's not being
brought down by centrifugation, and there are ways we can get to that, at that
directly by centrifugal methods, and those are more accessible to us, and we do
have that underway, yes.
CHAIRPERSON
PRIOLA: Dr. Hogan.
DR.
HOGAN: Bob, thanks.
I'm
very fascinated by the age issues with both variant CJD and sporadic CJD and
the fact that the index case for blood transfusion was older. Is there any data either from your studies
or others that age has anything to do with susceptibility relative to IV or IC
inoculation, for that matter?
And
it's also interesting that, of the 17 recipients in the U.K. that are still
living, only three are younger than 40.
DR.
ROHWER: Yes. That's hard information to generate in these rodent models
because we need the whole lifetime of the animal to detect the infectivity. So, you know, if we started inoculating
these animals in their adult, senior years, we don't have a hope in seeing it.
Personally,
I think that's probably true for the human population as well. I don't personally feel particularly
threatened by transfusion transmissions or any transmissions of TSEs,
considering that it would take, you know, 20 years or more to develop.
So,
yes, for technical reasons it's difficult.
I would have to say in the sheep model most of that work has also been
done with young animals, and you might have a little more flexibility there for
getting at that question, but I don't think we're going to get it out of the
rodent system.
CHAIRPERSON
PRIOLA: Dr. Bracey.
DR.
BRACEY: Yes. Thank you for the presentation.
Would
you attribute any of the residual infectivity in the red cell component to that
small amount of residual plasma that exists within the red cell? Could you speculate on that?
DR.
ROHWER: Yes. We presume that all of the infectivity in the red blood cell
concentrate is coming from plasma and residual white blood cell contamination. However, we have not proven that. Because of that, we put on an experiment I
guess it was last May where we have tried to do the same thing we did for
platelets. We've made a very highly
purified preparation of red blood cells just to ask the question directly: Is
there infectivity intrinsically associated with red blood cells?
I
highly doubt it, but we haven't actually made the measurement. You know, another eight months or so from
now we'll have an answer to that.
CHAIRPERSON
PRIOLA: Dr. Khabbaz.
DR.
KHABBAZ: Yes. First of all, thank you very much for a very elegant presentation
of fascinating data.
I
have two questions. One, in the
experiments where you measured the preclinical infectivity you alluded to some
experiments where you did oral inoculation and said it was the same pattern
that you observed in terms of days-preclinical-to-clinical.
Is
the absolute number of days the same or was it different?
The
oral inoculation is very inefficient compared to the intracerebral
inoculation. There's an interesting
aspect of this. In the case of the
intracerebral inoculation, we can reduce the titer down to ten to 50 infectious
doses and get a reliable infection of the animals knowing that we introduced a
very low titer.
To
get the infection to go at all by the oral route, we have to infect with
enormous amounts of infectivity. So we
infected these animals with -- I forget.
I think it's a milliliter of a ten percent brain homogenate, which means
that they're getting approximately ten to the ninth infectious doses by the
oral route.
We
titered this material at the same time.
We know that the efficiency of infection by that route looks like it's
going to be about ten to the minus six compared to brain. So the actual measurable titer by that route
is low. The incubation times are
long. So the experiment is strung out
for 150 days or something like that before we get to clinical disease going by
that route.
But
I just wanted to throw in that caveat.
The actual exposure, in a way, is higher. So you kind of need both experiments to get a clean
interpretation of the result. That was
our feeling.
But
in terms of percent of incubation time, they seem to be right on. About halfway through clinical disease,
we're seeing infections. It just needs
to go another, I think, four or five months before we can actually conclude the
experiment and do the actual, you know, substantive quantitation of it.
DR.
KHABBAZ: Thanks.
The
other one, when you summarized the animal experiments, you mentioned the
strains and I didn't see classic CJD there or did I?
DR.
ROHWER: You didn't. The reason for it is we don't have a good
animal model of it. It's not as readily
transmissible to mice. Moira Bruce has
some strains that she's trying to develop into a decent model. But it's a curious aspect of variant CJD,
for example, that it's idiosyncratically relatively easy to transmit this
disease to the R3 mouse and a couple of other readily available mice. It doesn't seem to transmit at all well to
humanized transgenic mice. Exactly the
opposite is true for sporadic cases, but we don't have those models in the
laboratory, and so we haven't actually looked at those yet.
DR.
KHABBAZ: Does that qualify the
conclusion of transmissibility to all TSEs?
DR.
ROHWER: Well, I tried to qualify that
in my last slide. There is a big
unanswered question here about why we don't see these things in sporadic
Creutzfeldt-Jakob disease, and personally, I think that needs to be done, and
we are developing the tools to do it actually.
But it is an unanswered question at this time.
My
own personal perspective on this is I'll be very, very surprised to see
anything different in variant CJD, and part of the reason for that is that
there's a very big difference between, for example, the hamster 263K model in
the hamster and the variant CJD model in the mouse.
Hamster
also has relatively limited peripheral involvement compared to some of the
mouse models, and yet we don't see any difference between them in terms of
their blood-borne infectivity.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: You made the comment that the
increasing amount of titer in the blood was probably not related to release
from the brain because it's an exponential increase in the brain and a linear
increase in the blood.
But
my feeling there is that a lot of the prion protein or the infectivity stays in
the brain and that the mechanism of exit from the brain into the vascular
system may be a linear system not related to the accumulation because a lot of
it stays with cells or as amyloid-like deposits around the ventricular system.
Any
comments?
DR.
ROHWER: Well, there has to be an
explanation, and I think we're going to have to invoke something like that, but
in terms of just a direct relationship between the two sources of infectivity,
there's a disconnect there, and so something like that is going to have to be
invoked in order to explain this.
And
that kind of thing is going to be difficult to access experimentally, I think,
and our own approach to this was to do these splenectomy experiments that I
alluded to earlier, and I'll just say something about that.
I
was concerned that another potential artifact in the rodent model is
extravasation of the blood when you handle these rodents, if they become
alarmed at the time that you're bleeding them or something like that.
So
we did a bunch of splenectomies, infected these animals by the oral route, the
IC route, the IP route, and then we looked for blood-borne infectivity. And we didn't see any effect on the titers
of blood-borne infectivity after splenectomy or by route or by any other of
those parameters, which makes me feel like probably we're looking in the wrong
place for the explanation.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
ROHWER: Just a minute. Steve, it may well be that we have to go
back to brain, you know.
DR.
GAMBETTI: I may have missed something,
but it is not clear to me how your model, which is extremely interesting,
actually applies to the sporadic CJD simply because if I understood correctly,
with the intracerebral inoculation, you essentially, by inoculating, disturb or
destroy the blood-brain barrier. So you
would expect that, at the time of the intracerebral inoculation, if you have a
certain amount of PrPsc of the inoculum, that it will go in the general
circulation, and therefore may start a very slow, general, systemic infection
or PrPc along with the one much more rapid, much more florid in the brain.
If
you do, of course, the intraoral administration and infection, you already are
out from the sporadic CJD. At least,
theoretically, you are not reproducing the sporadic CJD models.
So
I wonder how you see this, how one could translate your data that are very
interesting into the sporadic CJD that, of course, account for the largest
number of cases.
DR.
ROHWER: Well, we are very aware of that
caveat associated with the work, and that's why fairly early on we started
first going to low titer IC inoculations, because we didn't want to put very
much infectivity in, and I actually have some very nice data showing how the
infectivity is distributed after an IC inoculation, and a large proportion of
it goes directly into the bloodstream and is transported systemically, as you
say.
It's
also the reason why we've moved towards this oral inoculation model, but it has
also been rather reassuring to us that every time we've applied the oral model
now, both in these splenectomy experiments and these incubation-time
experiments, we're getting a consistent result. You know, it doesn't seem to have a big impact on the infection
in the hamster at least.
But
I agree with you. It's a practical
matter in terms of using the oral inoculation because it's just inefficient,
and it also makes me nervous applying this huge amount of infectivity to these
animals. You have to care for them very
carefully over the next month or so because they're shedding this stuff in
their feces and everything else as well.
So you have to do a lot of cage changes and you're relying on high-
level dilution just to get it out of the environment. They have to be handled very carefully, and so it's a difficult
model to work with.
On
the other hand -- and it takes much longer for the infection to develop -- on
the other hand, the benefit of eliminating these types of caveats is so strong
that we are moving more and more to that model just for the reasons that you've
mentioned.
On
the other hand, I'm not convinced that there's really any real difference, you
know.
DR.
GAMBETTI: Just a point of
clarification. You think it is
possible, or is it possible that at the time of the inoculation you have a wave
of PrPsc in the blood that may infect another organ and, therefore, there is an
expansion of that PrPsc locally. So you
have a fast-growing PrPsc formation in the brain, along with a very slow PrPsc
formation systemically.
DR.
ROHWER: Absolutely, and as far as I'm
concerned, that's the explanation for the loss of the dose response at limiting
dilution. In a limiting dilution case,
you have a high probability that the infection will originate in some
peripheral site instead of the brain because you're only inoculating one
infectious dose.
So
if that's the dose that ends up in your foot, the infection starts there. If it ends up in the brain, it starts in the
brain.
But
because you have a high preponderance of these peripheral sites dominating,
suddenly you see a loss of incubation time, and what you're looking at actually
are these very low-dose peripheral infections.
That's
a hypothesis. We haven't proven that in
any way whatsoever, but it seems to me like a very reasonable explanation for
what's going on there. And it's well known. I mean, it has been known from ‑- there is some
beautiful work in the '60s actually by Nims and Kearns (phonetic) looking at IC
inoculation of rodents with respect to the development of the polio vaccine,
where they show that the way it's typically done ends up with really an IC/IV
inoculation where the vast proportion of the infection is IV, not IC.
And
we've confirmed that actually with bacteriophages studies that I did, you know,
15 years ago or something like that.
You can see it just instantly.
It goes all over the place.
CHAIRPERSON
PRIOLA: Dr. Petteway.
DR.
PETTEWAY: Yes, thanks.
Just
a comment, getting back to Dr. Wolfe's question concerning filtration or
looking at filtration. A couple of
weeks ago at the EMEA TSE workshop in London, there was quite a bit of data
presented. A lot of labs are working on
removal by filtration, including nanofiltration, and depending on the type of
filter, depending on the process, it can be fairly efficient at removing PrPsc
and infectivity, but it is a process- dependent issue.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: I'd like to follow up on my
question and Pierluigi's because I think it's very important to identify the
source of the infectivity in the blood, and certainly in our own experiments
you inject into the brain, and the next day you see the spleen has a lot of
infectivity in it. So we know that the
inoculation does spread outside.
But
in this case, one way to look at it is from your data with the presenting
orally. Are the curves for the increase
of infectivity titer in the blood -- do they occur in the same time point if
you give it orally? That is ?- I can't remember. You start at about 60 ?- 51 days is
where the breakpoint occurs and you start having your linear increase.
If
you give it orally, do you get it at the same time point or is it delayed out
to 100 or 150 days? Does it correspond
to the then-exponential increase in the brain that results from oral, which
should also be displaced in time?
DR.
ROHWER: Well, I'm beginning to regret
bringing this up because this is work in progress. So I don't want to be held to a definitive statement. We haven't seen the final results of this
experiment.
But
all I'm saying is that from the data that we've seen to date, we're seeing
infectivity appear at the mid-clinical point.
Realize that the infection is over.
We've collected these pools. The
pools are now incubating in animals, but the pools are also staggered because
it took almost half a year for all of the infections to get to clinical disease
in this model.
So
the data is somewhat staggered, and we know what the incubation time was
because the incubation time of the primary disease is over. We're waiting to see what the blood titers
are.
As
we look at those pools, we're seeing infectivity appear, mid-clinical disease
just as it did before at very low titer, and then it looks like we're getting
more cases down as we go up later in the infection, which is consistent with
what we saw by the IC route, and that's by percentage of incubation time, not
actual day values because the incubation time by the oral route is longer. It was 155 days or something like that.
DR.
DeARMOND: So that would argue though --
so what you're saying is the blood titer looks like it's increasing at a later
time from the oral route compared to the IC route. So that it's not --
DR.
ROHWER: Yes.
DR.
DeARMOND: So it is not congruent with the oral route or the IC route. It's displaced away from it.
DR.
ROHWER: Yes. In absolute terms, that's true, yes.
DR.
DeARMOND: And the only question then is
--
DR.
ROHWER: Yes. The interpretation would be if you shorten the incubation time,
it will take -- whatever the incubation time happens to be -- it will take
about halfway through for us to pick up the infectivity by these methods, and
again, I emphasize that that's by these methods. That means we have to see at least one infection per five mLs of
blood inoculated.
DR.
DeARMOND: So the only question is what
its timing is with the exponential increase that is occurring in the brain with
the oral route.
DR.
ROHWER: Right.
DR.
DeARMOND: Whether it follows it or
precedes it.
DR.
ROHWER: And I have to say we don't have that data for the oral route.
CHAIRPERSON
PRIOLA: Dr. Bracey.
DR.
BRACEY: Currently, we are not
universally leukocyte-reduced in the U.S.
I don't know the exact figures, but it may be as many as 30, 40 percent
of units are routine units.
Given
the current state of information in your studies, I would present that you
would make a recommendation for use of universal leukocyte reduction.
DR.
ROHWER: I think that has to be modeled
pretty carefully. It's not clear to me
whether removing half the risk does anything.
CHAIRPERSON
PRIOLA: Dr. Nelson.
DR.
NELSON: Yes. I was very interested in your data on when, during the incubation
period, you could identify infectivity.
And it looked like for the hamsters it was about halfway through. I?m trying to
correlate that with the tonsil data where there was one out of 8,000. I wonder if we could use, you know -- they
are different data. Obviously, one is a
bioassay and the other is demonstrating the prion protein in tissue.
But
I wonder if we could use -- if we could merge those two data to predict the
theoretical risk, you know, over time.
I think the fact that you were able to show when infectivity occurred
during the incubation period is pretty important and probably transferrable to
the human case, but I wonder if you'd comment on that.
DR.
ROHWER: It would be good to get Bob
Will's comments on that as well, but my own perspective on this is the appendix
results are just like the transfusion results.
You know, one is not a good number to base a statistic on, and you can
do it, and the prevalence rate that comes out of that number ranges from one in
8,000 to hundreds in 8,000 depending on how you interpret it.
What's
really needed is another number, and so what needs to be done is to ramp up
these surveillance programs so that you get the data you need to actually make
a deduction.
There
is something that has bothered me about the appendix result, however, and that
is my guess is that the ascertainment rate for picking up variant CJD by this
route is probably less than one, and if you look at it that way, it makes it
even less reassuring.
And
the ascertainment rate for picking up the transfusions, I suspect, is a lot
better just because the program is in place for doing it.
But
in terms of actually doing that kind of modeling, I hope that people like Steve
Anderson and Cousins and people like that are doing that kind of modeling
because I think it's important, yes.
I
think Susie El-Saadany is here. She
works on that kind of thing, as well.
CHAIRPERSON
PRIOLA: Okay. I think we'll move on then to the next speaker. Thanks very much, Dr. Rohwer.
Our
next speaker is one of the former chairmen of this Committee, Dr. Paul Brown.
DR.
BROWN: Thank you, Chairman Priola. I feel a little bit like I'm coming home,
maybe for the last time, but it's a nice feeling.
I
was asked by David Asher to present the results of the study which several
years ago was undertaken by us with the funding of the Baxter Pharmaceutical
Company, and it has henceforth become known as the Baxter study.
Before
I do that, assuming I have my full complement of 15 minutes and I'm not down to
six and a half, I wanted just to make a comment or two about one or two of the
interesting questions that have been raised in the course of the morning.
The
difficulty of proving that sporadic CJD could be transfusion-linked I think is
probably only going to be solved by exactly the reverse of the situation that
is so compelling as evidence for variant CJD transmission; and that is, instead
of having a young, typical variant CJD donating blood to a person who is
elderly -- when I say "elderly,? that's my
age -- you're going to have to have a classic sporadic elderly patient
transmitting blood to an unusually young patient, and then you'll have the same
kind of certainty which is not totally certain, but you'll have some confidence
that that has happened. And that's not
going to be easy to find.
I
wanted also to say something about the 50 percent reduction of infectivity,
whether or not that's worthwhile. The
fact is we don't know obviously if it's worthwhile. My guess is that if I'm a recipient, anything is going to be
worthwhile even if it hasn't proven to be worthwhile practically speaking. But a 50 percent reduction does reduce the
risk by 50 percent, presumably, and that I mention in the context of this issue
that came up in a very interesting way earlier in the morning about dilution.
Is
there a point where you can dilute infectivity to the point of extinction? The question is not whether a dose that is
measured by intracerebral inoculation is sufficient to transmit disease by some
peripheral route like blood or orally.
We already know that. That's a
done deed.
Just
to give you one example, BSE, for example, is 10,000 times less efficiently
transmitted by the oral route than by direct IC inoculation. So by definition we know in terms of the
route of infection that we can extinguish transmissibility.
The
question is whether all things being equal and giving the infective material by
a given route, shall we say, IC or IV, whether you can extinguish that by
dilution, and that is a question that comes up time and time again. It's an experiment that actually I've been trying to do for some time, but
nobody wants to do it, and yet it's an important question to answer, and it
bear son the question as to whether or not a 50 percent reduction is enough to
get below the threshold of transmissibility.
So
that's an experiment that really cries out to be done, and I hope that someone
will do it.
Now,
it's always a mystery whether this technology is going to work or not. I use a Mac, and not only do I use a
Mac. I use a Keynote program, which
doesn't seamlessly transfer to anything.
(Laughter.)
DR.
BROWN: I think we are probably going to
be okay. The previous trial gave us a
bilious green color for everything.
Bravo.
I
was asked by David -- and with the kind permission of Corinne Lasmezas ? to also give you a summary of her studies, the
studies of her group, directed by her now on what the French are up to with
respect to primates.
But
the first thing is our own study, and as I mentioned, it's a Baxter primate
study, and those are the major participants.
And the goal was twofold, and here is the first one: to see whether CJD, either sporadic or
familial -- actually it turns out to be the familial CJD is incorrect. It really should be the Fukuoka strain of
Gerstmann-Straussler-Scheinker disease.
So it's really GSS instead of familial CJD ‑- when passaged
through chimps into squirrel monkeys using purified blood components, very pure
blood components.
So
this addresses the question that was raised just recently about whether or not
red cell infectivity that's been found in rodents is really in the red cells or
is it contaminated.
We
prepared these samples with exquisite care, and they are ultra-ultra-ultra
purified. There's virtually no
contamination of any of the components that we looked at ? platelets, red cells, plasma, white cells -- with any other component.
These
are a sort of new set of slides, and what I've tried to do is make them less
complicated and more clear, but I'm afraid I haven't included the build. So you'll just have to try and follow what I
explain with this little red pointer.
There
were three initial patients. Two of
them had sporadic CJD. One of them had
Gerstmann-Straussler-Scheinker syndrome.
Brain tissue from each individual patient was inoculated intracerebrally
into a pair of chimpanzees. All right?
From
those chimps, either plasma or ultra purified -- in fact, everything is
ultra-purified. I'll just talk about
purified plasma, purified white cells -- were inoculated intracerebrally and
intravenously to get the maximum amount of infective load into a pair of
squirrel monkeys.
The
same thing was done for each of these three sets. This monkey died from non-CJD causes at 34 months post
inoculation.
Let
me go back for a second. I didn't point
out the fact that these were not sacrificed at this point. These chimpanzees were apheresed at 27 weeks
when they were still asymptomatic. In
this instance, we apheresed them terminally when they were symptomatic.
And
before I forget, I want to mention just a little sidelight of this. Chimpanzees in our experience -- and I think
we may be the only people that have ever inoculated chimpanzees, and that's no
longer a possibility, so this was 20, 30 years ago -- the shortest incubation
period of any chimpanzee that we have ever seen with direct intracerebral
inoculation is 13 months.
So
we chose 27 weeks, which is about seven months, and incidentally typically the
incubation period is more like 16 or 18 months. The shortest was 13 months.
We chose the 27th week, which is about six and a half months, thinking
that this would be about halfway through the incubation period, which we wanted
to check for the presence or absence of infectivity.
But
within four weeks after the apheresis, which was conducted under general
anesthesia for three or four hours apiece, every single one of the six
chimpanzees became symptomatic. That is
another experiment that I would love to conclude, perhaps because this is simply
not heard of, and it very much smells like we triggered clinical illness. We didn't trigger the disease, but it
certainly looks like we triggered symptomatic disease at a point that was much
earlier than one would have possibly expected.
Maybe
it will never be done because it would probably open the floodgates of
litigation. There's no end of little
things that you can find out from CJD patients after the fact. For example, the neighbor's dog comes over,
barks at a patient, makes him fall down, and three weeks later he gets
CJD. So you have a lawsuit against the
neighbor.
I
mean, this is not an unheard of matter, but I do think that physical stress in
the form of anesthesia and four hours of whatever goes on with anesthesia, low
blood pressure, sometimes a little hypoxemia looks like it's a bad thing.
So
here we have the 31st week. All of the
chimps are symptomatic, and here what we did was in order to make the most use
of the fewest monkeys, which is always a problem in primate research, we took
these same three patients and these six chimps. Only now we pooled these components; that is to say, we pooled
the plasma from all six chimps. We
pooled ultra-purified white cells from all six chimps because here we wanted to
see whether or not we could distinguish a difference between intracerebral
route of infection and intravenous route of infection.
With
respect to platelets and red blood cells, we did not follow that. We inoculated both intracerebral and
intravenously, as we had done earlier because nobody has any information on
whether or not platelets and red cells are infectious, and so we wanted again
to get the maximum.
This
is an IV versus IC goal. This one,
again, is just getting the maximum load in to see whether there is, in fact,
any infectivity in pure platelets, in pure red cells.
And
of all of the above, the only transmission of disease related to the
inoculation was in a squirrel monkey that received pure leukocytes from the
presymptomatic apheresis. So that goes
some way to address the question as to whether or not it's a matter of
contamination. To date the red cells
have not been -- the monkeys that receive red cells have not been observed for
more than a year because that was a later experiment.
So
we still can't say about red cells, but we're about four and a half years down
the road now, and we have a single transmission from purified leukocytes,
nothing from plasma and nothing from platelets.
That
was the first part of the experiment.
The second part was undertaken with the cooperation of Bob Will and
others supplying material to us. These
were a couple of human, sporadic cases of CJD and three variant cases of CJD
from which we obtained buffy coat and plasma separated in a normal way. That is, these are not purified components.
The
two cases of sporadic CJD, the plasma was pooled from both patients. The buffy coat was pooled from both
patients, and then inoculated intracerebrally and intravenously into three
squirrel monkeys each. This is a
non-CJD death five years after inoculation.
The other animals are still alive.
For
variant CJD we decided not to pool. It
was more important to eliminate the possibility that there was just a little
bit of infectivity in one patient that would have been diluted to extinction,
if you like, by mixing them if it were to so occur with two patients, for
example, who did not have infectivity.
So each one of these was done individually, but the principle was the
same: plasma and buffy coat for each
patient was inoculated into either two or three squirrel monkeys. This is, again, a non-CJD related death.
In
addition to that, we inoculated rain as a positive control from the two
sporadic disease cases of human -- from the two human sporadic cases at ten to
the minus one and ten to the minus three dilutions. We have done this many, many times in the past with other
sporadic patients. So we knew what to
expect, and we got exactly what we did expect, namely, after an incubation
period not quite two years, all four monkeys developed disease at this dilution
and at the minus three dilution, not a whole lot of difference between the two.
Now,
these are the crucial monkeys because each one of these monkeys every three to
four months was bled and the blood transfused into a new healthy monkey, but
the same monkey all the time. So this
monkey, for example, would have received in the course of 21 months about six
different transfusions of blood from this monkey into this monkey, similarly
with this pair, this pair, and this pair.
So you can call these buddies.
This is sort of the term that was used.
These monkeys are still alive.
In
the same way, the three human variant CJD specimens, brain, were inoculated
into four monkeys, and again, each one of these monkeys has been repeatedly
bled at three to four month intervals and that blood transfused into a squirrel
monkey, the same one each time. Ideally
we would love to have taken bleeding at three months and inoculated a monkey
and then let him go, watch him, and then done the same thing at six
months. It would have increased the
number of monkeys eightfold and just unacceptably expensive. So we did the best we could.
That,
again, is a non-CJD death, as is this.
This
was of interest mainly to show that the titer of infectivity in brain from
variant CJD is just about the same as it from sporadic. We didn't do a minus five and a minus seven
in sporadic because we have an enormous experience already with sporadic
disease in squirrel monkeys, and we know that this is exactly what happens. It disappears at about ten to the minus
five. So the brain titer in monkeys
receiving human vCJD is identical to the brain titer in monkeys that have been
inoculated with sporadic CJD.
That's
the experiment. All of the monkeys in
aqua are still alive. They are approaching a five-year observation period,
and I think the termination of this experiment will now need to be discussed
very seriously in view of a probable six-year incubation period in the U.K.
case. The original plan was to
terminate the experiment after five years of observation with the understanding
that ideally you would keep these animals for their entire life span, which is
what we used to do when had unlimited space, money, and facilities. We can't do that anymore.
It's
not cheap, but I think in view of the U.K. case, it will be very important to
think very seriously about allowing at least these buddies and the buddies from
the sporadic CJD to go on for several more years because although you might
think that the U.K. case has made experimental work redundant, in point of
fact, anything that bears on the risk of this disease in humans is worthwhile
knowing, and one of the things we don't know is frequency of infection. We don't know whether this case in the U.K.
is going to be unique and never happen again or whether all 13 or 14 patients
have received blood components are ultimately going to die. Let's hope not.
The
French primate study is primarily directed now by Corinne Lasmezas. As you know, the late Dominique Dromont was
the original, originally initiated this work, and they have very active primate
laboratory in France, and I'm only going to show two very simple slides to
summarize what they did.
The
first one is simply to show you the basis of their statement that the IV route
of infection looks to be pretty efficient because we all know that the
intracerebral route of infection is the most efficient, and if you look at this
where they inoculated the same infective load either intracerebrally or
intravenously, the incubation periods were not substantially different, which
suggests but doesn't prove, but doesn't prove that the route of infection is
pretty efficient.
Lower
doses of brain material given IV did extend the incubation period and
presumably it's because of the usual dose response phenomenon that you see in
any infectious disease.
With
a whopping dose of brain orally, the incubation period was even lower. Again, just one more example of inefficiency
of the route of infection and the necessity to use more infective material to
get transmissions.
And
they also have blood inoculated IV which is on test, and the final slide or at
least the penultimate slide shows you what they have on test and the time of
observation, that taken human vCJD and like us inoculated buffy coat, they've
also inoculated whole blood which we did not do.
So
to a great extent their studies are complementary to ours and makes it all
worthwhile.
We
have about -- oh, I don't know -- a one to two-year lead time on the French,
but they're still getting into pretty good observation periods. Here's three-plus years.
They
have variant CJD adapted to the macaque.
That is to say this one was passaged in macaque monkeys, the cynomolgus,
and they did the same thing. Again,
we're talking about a study here in which like ours there are no
transmissions. I mean, we have that one
transmission from leukocytes, and that's it.
Here
is a BSE adapted to the macaque. Whole
blood, and then they chose to inoculate leukodepleted whole blood, in both
instances IV. Here they are out to five
years without a transmission.
And
then finally oral dosing of the macaque, which had been infected with -- which was infected with BSE, but a
macaque passaged BSE, whole blood buffy coat and plasma, all by the IC route,
and they're out to three years.
So
with the single exception of the leukocyte transmission from our chimp that was
inoculated with a sporadic case of CJD or -- excuse me -- with a GSS,
Gerstmann-Straussler, in neither our study nor the French study, which are not
yet completed have we yet seen a transmission.
And
I will just close with a little cartoon that appeared in the Washington Post
that I modified slightly lest you get too wound up with these questions of the
risk from blood. This should be a
"corrective."
(Laughter.)
DR.
BROWN: Thanks.
Questions?
CHAIRPERSON
PRIOLA: Yes. Any questions for Dr. Brown?
Dr. Linden.
DR.
LINDEN: I just want to make sure I
understand your study design correctly.
When you mention the monkeys that have the IV and IC inoculations, the
individual monkeys had both or --
DR.
BROWN: Yes, yes, yes. That's exactly right.
DR.
LINDEN: So an individual monkey had
both of those as opposed to some monkeys had one and some had the other?
DR.
BROWN: Correct, correct. Where IC and IV are put down together was IC
plus IV into a given monkey.
DR.
LINDEN: Into a given monkey. Okay.
And
the IC inoculations, where were those given?
DR.
BROWN: Right parietal cortex, Southern
Alabama.
(Laughter.)
DR.
BROWN: Oh, it can't be that clear. Yeah, here, Pierluigi.
CHAIRPERSON
PRIOLA: Dr. Epstein.
DR.
BROWN: Pierluigi always damns me with
feint praise. He always says that's a
very interesting study, but. I'm
waiting for that, Pierluigi.
I
think Jay Epstein --
DR.
GAMBETTI: I will say that there's an
interesting study and will say, but I just --
(Laughter.)
DR.
GAMBETTI: -- I just point of
review. You talk about a point of
information. You say that ‑-
you mention GSS, I guess, and the what, Fukuowa (phonetic) ‑-
DR.
BROWN: Yes, Fukuoka 1.
DR.
GAMBETTI: Fukuowa, and is that from the
102, if I remember correctly, of the --
DR.
BROWN: Yes, that is correct.
DR.
GAMBETTI: Because that is the only one
that also --
DR.
BROWN: No, it's not 102. It's 101.
It's the standard. It's a
classical GSS. Oh, excuse me. You're right. One, oh, two is classical GSS.
It's been so long since I've done genetics. You're right.
DR.
GAMBETTI: Because that is the only one
I know, I think, that I can remember that has both the seven kv fragment that
is characteristic of GSS, but also the PrPsc 2730. So in a sense, it can be stretching a little bit compared to the
sporadic CJD.
DR.
BROWN: Yeah, I think that's right. That's why I want to be sure that I made you
aware on the very first slide that that was not accurate, that it truly was
GSS.
There's
a GSS strain that has been adapted to mice, and it's a hot strain, and
therefore, it may not be translatable to sporadic disease, correct. All we can say for sure is that it is a
human TSE, and it is not variant. I
think that's about it.
DR.
GAMBETTI: I agree, but this is also not
perhaps the best --
DR.
BROWN: No, it is not the best. We understand --
DR.
GAMBETTI: -- of GSS either.
DR.
BROWN: Yeah. If we had to do it over again, we'd look around for a -- well, I
don't know. We'd probably do it the
same way because we have two sporadics already on test they haven't
transmitted, and so you can take your pick of what you want to pay attention
to.
Jay?
DR.
EPSTEIN: Yes, Paul. Could you just comment? If I understood you correctly, when you did
the pooled apheresis plasma from the six chimps when they were symptomatic at
31 weeks, you also put leukocytes into squirrel monkeys in that case separately
IV and IC, but in that instance you have not seen an infection come down in
squirrel monkey, and the question is whether it's puzzling that you got
transmission from the 27-week asymptomatic sampling, whereas you did not see
transmission from the 31-week sampling in symptomatic animals.
DR.
BROWN: Yes, I think there are two or
three possible explanations, and I don't know if any of them are
important. The pre-symptomatic animal
was almost symptomatic as it turned out so that we were pretty close to the
period at which symptoms would being, and whether you can, you know, make much
money on saying one was incubation period and the other was symptomatic in this
particular case because both bleedings were so close together. That's one possibility.
The
other possibility is we're dealing with a very irregular phenomenon and you're
not surprised at all by surprises, so to speak so that a single animal, you
could see it almost anywhere.
The
third is that we, in fact, did just what I suggested we didn't want to do for
the preclinical, namely, by pooling we got under the threshold. See?
You
can again take that for what it's worth.
It is a possible explanation, and again, until we know what the levels
of infectivity are and whether by pooling we get under the threshold of
transmission, we simply cannot make pronouncements.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Yeah, it was very interesting
data, but the --
(Laughter.)
DR.
BROWN: I just love it. Go ahead.
DR.
DeARMOND: Two comments. The first one was that the GSS cases, as I
remember from reading your publications -- I think Gibbs was involved with them
-- when you transmitted the GSS into animals, into monkeys, perhaps I think it
was chimps, the transmission was more typical of CJD rather than GSS. There were no amyloid plaques. It was vacuolar degeneration so that you may
be transmitting a peculiar form, as I criticized once in Bali and then you
jumped all over me about.
DR.
BROWN: I may do it again.
DR.
DeARMOND: Calling me a bigot and some other
few things like that.
(Laughter.)
DR.
BROWN: Surely not. I wouldn't have said that.
DR.
DeARMOND: So there could be something
strange about that particular --
DR.
BROWN: Yeah. I think you and Pierluigi are on the same page here. This may be an unusual strain from a number
of points of view.
DR.
DeARMOND: The other question though has
to do with species barrier because the data you're showing is kind of very
reassuring to us that it's hard to transmit from blood, but the data from the sheep
and from the hamsters and some of the work, I think, that has been done by
others, that it's easy in some other animals to transmit, hamster to hamster,
mouse to mouse.
Could
you comment on the --
DR.
BROWN: That's exactly why we went to
primates. That's exactly it, because a
primate is closer to a human than a mouse is, and that's just common sense.
And
so to try and get a little closer to the human situation and not totally depend
on rodents for transferrable data, that is why you would use a primate. Otherwise you wouldn't use them. They're too expensive and they cause grief
to animal care study people and protocol makers and the whole thing.
Primate
studies are a real pain.
DR.
DeARMOND: But right now it's
inconclusive and you need more time on it.
DR.
BROWN: I believe that's true. I think if we cut it off at six years you
could still say it was inconclusive, and cutting it off at all will be to some
degree inconclusive, and that's just the way it is.
DR.
DeARMOND: So what has to be done? Who do you have to convince, or who do we
all have to convince to keep that going?
DR.
BROWN: Thomas?
Without
trying to be flip at all, the people that would be the first people to try to
convince would be the funders of the original study. If that fails, and it might for purely practical reasons of
finance, then we will have to look elsewhere because I really don't want to see
those animals sacrificed, not those eight buddies. Those are crucial animals, and they don't cost a whole lot to
maintain. You can maintain eight --
well, they cost a lot from my point of view, but 15 to $20,000 a year would
keep them going year after year.
CHAIRPERSON
PRIOLA: Dr. Johnson.
DR.
JOHNSON: Yeah, Paul, I'm intrigued as
you are by the shortening of the incubation period. Have you in all of the other years of handling these animals when
they were transfused, when they were flown out to Louisiana at night -- a lot
of the stressful things have happened to some of these chimps. Have you ever noticed that before or is this
a new observation?
DR.
BROWN: Brand new.
MR.
JOHNSON: Brand new. Okay.
CHAIRPERSON
PRIOLA: Bob, did you want to say
something? Dr. Rohwer.
DR.
ROHWER: The Frederick fire, wasn't that
correlated with a lot of --
DR.
BROWN: Not that I k now of, but you may
--
DR.
ROHWER: Well, that occurred shortly
after I came to NIH, and what I remember is that there were a whole bunch of
conversions that occurred within the few months following the fire. That was
fire that occurred adjacent to the NINDS facility, but in order to
protect it, they moved the monkeys out onto the tarmac because they weren't
sure it wouldn't burn as well.
DR.
BROWN: Well, if you're right, then it's
not brand new, but I mean, I'm not sure how we'll ever know because if I call
Carlton and ask him, I'm not sure but what I would trust the answer that he
gives me, short of records.
You
know, Carlot is a very enthusiastic person, and he might say, "Oh, yeah,
my God, the whole floor died within three days," but I would want to
verify that.
On
the other hand, it may be verifiable.
There possibly are records that are still extant.
DR.
ROHWER: Actually I thought I heard the
story from you.
(Laughter.)
DR.
BROWN: You didn't because it's brand
new for me. I mean, either that or I'm
on the way
(Laughter.)
CHAIRPERSON
PRIOLA: Dr. Bracey.
DR.
BRACEY: I was wondering if some of the
variability in terms of the intravenous infection route may be related to
intraspecies barriers, that is, the genetic differences, the way the cells, the
white leukocytes are processed, whether or not microchimerism is established,
et cetera.
DR.
BROWN: I don't think that processing is
at fault, but the question, the point that you raise is a very good one, and
needless to say, we have material with which we can analyze genetically all of
the animals, and should it turn out that we get, for example, -- I don't know
-- a transmission in one variant monkey and no transmissions in another and a
transmission in three sporadic monkeys, we will at that point genetically
analyze every single animal that has been used in this study, but we wanted to
wait until we could see what would be most useful to analyze.
but
the material is there, and if need be, we'll do it.
CHAIRPERSON
PRIOLA: Okay. Thank you very much, Dr. Brown.
I
think we'll move on to the open public hearing section of the morning.
DR.
FREAS: As part of the advisory
committee process, we have open public hearings to allow members of the public
to address the committees on any issues pending before the committee. There will be three such open public
hearings at this meeting, two today and one tomorrow.
At
this time I've received two requests to address the committee at this morning's
meeting. These presentations will be
limited to six minutes. The Chair has
been required to read a statement regarding conflicts of interest at these open
public hearings.
S,
Prior Priola, would you read the public statement?
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 believe 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 or oral statement to advise the committee of any financial
relationship that you may have with the sponsor, its production, and if known
its direct competitors. For example,
this financial information may include the sponsor'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: Thank you.
Our
first speaker this morning is Dr. Michael Fitzpatrick. He's the Chief Policy Officer, America's
Blood Centers.
DR.
FITZPATRICK: Good morning. I want to thank you for the opportunity to
speak, and as Bill said, I'm the Chief Policy Officer for America's Blood
Centers, which represents 75 community based, independent collecting agencies
in the U.S. and Hema-Quebec in Canada.
So my salary is related to blood collection, and I think for disclosure
that probably covers it.
We
wanted to take this opportunity not to provide written comment, but just to
remind the committee of a few things, and make a couple of comments on the
morning.
One,
that the impact of deferrals for vCJD can't be lessened. We lost eight to ten percent of our donors
based on the precautionary principle and were able to compensate for that
through recruiting efforts, but at best the inventory today in the U.S. is
tenuous. We have a two to three-day
supply of blood as opposed to at least a five-day supply of blood that we would
like to be.
No
one wants to sacrifice safety for supply, however. So we would ask that the committee take into consideration the
safety of the patient, which of course is the paramount issue.
We
don't have a way to measure the resiliency of the population at this
point. How many more donors can we
defer before we hit a recruitment plateau that we can't go beyond?
Dr.
Epstein and other speakers have given you an excellent overview of the
implications in sentinel populations of transfusion transmission of variant
CJD, and those populations would be the hemophilia group, the sickle cell
group, and the thalassemia group.
That
dovetails very well with Dr. Brown's presentation, I believe, on his animal
experiments. Those animals who received
chronic transfusion and have not developed a disease would appear to mirror
what's going on in the population. A
single purported transmission in the U.K. is just that, a single purported
transmission. At this point one
positive is one positive, and it may or may not be positive. That patient was subject to the same living
conditions as all the other individuals in the U.K. and could be a coincidental
event, although statistically it looks unlikely, but we don't know that for
sure because there isn't enough data.
So
as you go through these considerations, we would ask that you consider first,
of course, the safety of the patients, as we do. We would ask that you consider the data that you have seen and
the data that you will see. Having been
involved with this for a long time, I can only say that it appears we have more
data. I'm not sure we have conclusive
data yet.
The
actions we have taken have resulted in no provable transmission, and we have
yet to see a human case in the United States.
So
I would ask that as you consider these things, that you consider all of those
implications.
And
can I ask Paul a question?
CHAIRPERSON
PRIOLA: Sure, go ahead.
DR.
FITZPATRICK: Dr. Brown. Did he leave?
CHAIRPERSON
PRIOLA: Well, you could have. Dr. Brown, are you still in the room?
DR.
FITZPATRICK: Oh, there he is.
CHAIRPERSON
PRIOLA: Oh, there he is.
(Laughter.)
DR.
FITZPATRICK: Paul, the animals that
died of natural causes or on autopsy, were there any clinical sign of brain
involvement at all?
DR.
BROWN: They have not all yet been done,
but those that have have no signs of infection.
DR.
FREAS: Thank you very much.
Our
next speaker this morning is Dr. Hatte Blejer.
Forgive me if I'm mispronouncing your last name.
DR.
BLEJER: Yeah, it's Blejer, Blejer or
Blejer.
I
represent myself. So I pay my own
salary and I don't owe anybody anything.
I'm
going to read my statement.
My
husband died about a month ago of CJD.
He was 52 years old, and he had numerous neurosurgeries in the late
1970s. Possibly he became infected at
that time, possibly from a dura mater graft.
He had shunt surgeries and revisions in the '70s in two states and a
pineal tumor resection in Boston,
Massachusetts. The CDC is investigating
Daniel's case on their initiative.
I
became concerned about the safety of blood products and medical devices when he
was diagnosed in September of 2003.
Daniel was B negative, and he donated blood three times a year for 25
years beginning in the 1970s.
I
became more concerned in December of 2003 as he lay dying when I read of the
suspected case of vCJD via blood transfusion.
Now,
CDC has talked about the fact that they're getting these cases reported, and I
want to give you some personal information.
When I heard the diagnosis, which is supposedly 90 percent probable, I
asked the hospital to contact various organizations, the Red Cross, the CDC,
and the Virginia Department of Public Health.
They told me I should report it.
So I started trying to report it while driving 120 miles round trip to
my dying husband's bedside.
So
I did get the Red Cross. It took me
four phone calls, and they were very helpful, and they contacted other
organizations that have received blood or plasma from Daniel, and I believe there
was a recall of albumin, I believe.
If
I had not contacted the Red Cross, they would have never known that a frequent
blood donor had CJD, and it's not optimal for the family member to be having to
contact the public health officials.
Okay. My husband was in Maryland when he had a
somewhat definitive diagnosis. That's
not reportable in Maryland. He died in D.C.
It's not reportable in D.C.
Okay? But he's a resident of
Virginia.
So
more concerning to me actually than the blood is the neurosurgeries. I know that's not the topic, but because
it's FDA and CBER and we're talking about biological devices, dura mater
grafts, and we're talking about neurosurgical instruments, Daniel had seven
neurosurgeries this year, in 2003, while his CJD was active, and the reason
that was he had aqueductal stenosis.
So
he had a shunt, and when he went into a coma in January of 2003, from the time
he went into a coma they thought it was due to the shunt. When he didn't retain and his mental and
gait status started deteriorating, they presumed that his shunt needed
adjusting.
So
various parts were replaced. It was
internalized, externalized, in seven surgeries, and as far as I know, there's
no indication that the surgical instruments were destroyed. So when you talk about that kind of a
process, you ought to talk about at least being able to track surgical
instruments so that when you have a case like my husband, you can get rid of
those surgical instruments afterwards.
I
did report Daniel's case myself to Virginia, to the Department of Health,
Epidemiology. They did not contact
me. CDC tells me they are aware, and
again, he died in D.C. So Virginia is
not aware that a Virginia resident has had CJD.
Anyway,
in conclusion, his complex case illustrates that our public health system may
endanger the public, and I realize that it does depend upon whether it's
transmissible via blood products and medical devices, but since he might have
been infected by a biological and medical device over two decades ago, when our
knowledge and our safeguards were less than today, but when we suspected the
cadaver material was not risk free, it is my hope that the U.S. government and
the FDA are taking the utmost precautions in light of recent research and the
recent possible case -- and I'm talking about the kind of animal models that
we've heard about -- and the recent possible case of variant CJD transmitted
via blood to safeguard against future infections.
It's
a long incubation period. We have
little numbers, and we don't know. So
with deference to the blood supply issue, I know there's an issue, but we need
to do everything we can because unless you have seen someone die over 12 months
like I have, you don't know what the human impact is.
Okay. So one of the ideas I had was that people
who have had neurosurgery. So you don't
let people from Great Britain come in and donate if they've lived in Great
Britain for more than six months, but someone who had neurosurgery in the '70s
may, in fact, be higher risk. So that
is one of the suggestions I have that's very concrete.
People
don't know whether they got dura mater grafts.
They have no idea. The doctor
barely mentions it in the 1970s. The
records are destroyed likely. So you
have some high risk patients who are donating blood 70-plus times over 25
years, probably 35-plus times in the ten-year possible infectivity stage.
So
that's all I have. Thanks for letting
me talk.
DR.
FREAS: Thank you very much.
I
believe we have --
(Applause.)
DR.
FREAS: -- a couple of questions for
you.
CHAIRPERSON
PRIOLA: Dr. Wolfe.
DR.
WOLFE: Thank you very much with the
difficulty you must have had presenting what has happened to you.
You
may know we have been attempting for five or six years to get the FDA to ban
cadaveric dura mater from grafts.
Britain banned it, Bob, 15 years ago, right?
DR.
WILL: A long time ago.
DR.
WOLFE: More than 15 years ago. Japan has banned it. Canada has banned it. It doesn't make any sense.
That
does not steep backwards to the time when your husband may have gotten a graft,
but certainly it does not make any sense knowing what we know now to allow in
this country, unlike the other four mentioned ones, these grafts to occur.
You
certainly raise a number of logistical questions about reporting and what
happens where instead of having one National Health Service, as in Britain, we
have a number of state sort of non-organized health services, and so what has
happened to you is entirely predictable, unfortunately and sadly.
DR.
BLEJER: I have heard it from 50 other
families.
DR.
FREAS: I'm sorry. We can't record you unless you're at a
microphone, and we would like to record your --
DR.
BLEJER: I wanted to just mention that
I'm in contact with 50 to 100 families who have lost family members. So the things I said about frequent blood
donation and about difficulty of reporting, I've heard this over and over
again.
I
mean, I had to fight to get a diagnosis.
I had to drag my husband to about five different places, and that's in
Washington, D.C. So think what it must
be like out in the hinterlands.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: I find this story very
disturbing. Is there anybody here who
will defend the difficulty of getting this thing reported?
I'm
not the one to look into it, but I think somebody really should. It may be a job for a tenacious
investigative journalist or somebody, but somebody ought to be looking into
this to find out what the problem is in getting a simple report in and fix that
problem.
DR.
GAMBETTI: May I?
CHAIRPERSON
PRIOLA: Yes, Dr. Gambetti.
DR.
GAMBETTI: What do you mean by
"reporting," that it has been referred to, for example, the center
like the National Prion Disease Pathology Surveillance Center? Is that what you mean by reporting?
DR.
BAILAR: Well, that, plus the state
authorities, plus the CDC.
DR.
GAMBETTI: Yeah.
DR.
BAILAR: These things, every one of
them, should be widely known and widely investigated, and that did not happen
DR.
GAMBETTI: I can tell you for the
National Prion Disease Pathology Surveillance Center essentially probably 60,
70 percent of our time is spent in trying to get these cases referred to us,
and it is extremely difficult. It is difficult
because many institutions are reluctant to perform an autopsy on these cases.
So
the center has to struggle to find other institutions around to have the
autopsy performed for a fee. So there
is constantly a search for other locations to do the autopsies. There is constantly trying to raise
awareness in neurologists and pathologists to submit cases to us.
So
it is really an uphill battle. It looks
like we are making some inroads in the number of cases reported as compared to
the number of cases expected. It is
increasing. We are 50 percent about and
now it looks like we are going up to maybe 60 percent, but still it is very
difficult.
So
this is the point of view of the surveillance center, but I don't know about
other issues that you raised.
DR.
BLEJER: Yes, Dr. Gambetti is right. I failed to mention that the hospital told
me that there was no need for a biopsy or autopsy, and this is a regional
teaching center in Baltimore.
I'm
Jewish. I didn't want to have an
autopsy on my husband, and I had an autopsy only because there are family
members out there who through the E-mail told me that this was really, really
important.
When
you have a family member dying, you need those neurologists, neurosurgeons
counselors to help you because this is a painful situation altogether. To have them tell you not to get an autopsy
and then to actually have to figure out how to get the autopsy yourself is
ridiculous.
CHAIRPERSON
PRIOLA: Okay. For just one moment we'd like to make sure there's no one else
who wants to speak at the open public hearing, and then we'll move on to the
discussion.
DR.
SCHOENBERGER: This was just to help
answer some of the issues.
CHAIRPERSON
PRIOLA: Okay. Dr. Gambetti and then Dr. Schoenberger if you want to.
DR.
GAMBETTI: I really sympathize with your
case because unfortunately I have heard similar stories over and over. I have a simple question. Was an autopsy finally performed in your
late husband and was sent to the surveillance center or not?
DR.
BLEJER: I directly contacted --
DR.
FREAS: I'm sorry. You're going to have to come to a
microphone. Otherwise we won't be able
to put your word on the transcript.
DR.
BLEJER: I personally contacted the
National Prion Disease Pathology Surveillance Center on my own. I contacted the office manager because the
family network of CJD families, CJD Voice, helped me come to that
decision. So I arranged for the autopsy
myself, and I had lots of help from your office manager, yes.
DR.
GAMBETTI: So he eventually was
examined. The case was sent.
DR.
BLEJER: He only died recently. It's only about five weeks since he died at
the age of 52, yes.
DR.
GAMBETTI: It was sent. It was sent. That's my question.
DR.
BLEJER: Yes, yes, yes. All the medical records, too.
CHAIRPERSON
PRIOLA: Dr. Schoenberger, did you want
to clarify something?
DR.
SCHOENBERGER: No, I just wanted to
mention that CDC is very much aware of this type of problem and is the basis
for our, in fact, funding Dr. Gambetti's group to promote increased autopsies
so that they can get these cases documented quickly.
We
also have recently provided some funds to the CJD foundation and the president
of that foundation is here today, Florence Kranitz, and they run a telephone
hot line for families, and they can call and get guidance as to how to proceed
when somebody in their family gets this disease, and they can do that in a very
sensitive way and at the same time encourage such an autopsy to be done.
I
think it's important for people who are making policy to understand that what
Mr. Blejer has experienced is not totally uncommon, and I have found myself in
meetings where people will get up and have said, "You know, there has
never been a case transmitted by surgical instruments," and then the type
of case that Mr. Blejer represents comes to my mind, and I'll say, "How
can we know that for sure?"
I
mean our data comes to us, and in fact, Mr. Bleger will come to us through many
mechanisms. First, the doctor is going
to put CJD on the death certificate.
That makes it reportable in a sense to CJD, but as you pointed out, that
will come later.
We
also got a report from the American Red Cross on Mr. Blejer. We got a report from FDA on Mr. Bleger. That is probably due in part to many of the people that Ms.
Blejer has contacted.
So
we are getting these reports from multiple groups. The State of Virginia, the State of Texas, the State of
Massachusetts have all gone to try to find records on this particular patient,
and as Ms. Blejer indicated, they're having difficulty finding a lot of the
records, although I can say that the operation, as I understand it, was done in
Boston, removal of a pineal tumor, and that surgical records that you can get
does not indicate that a dura mater was used at that instance.
Now,
that's 1979. The death is relatively
recent. Most of the dura mater cases
indicate an incubation period that would be a little bit sooner than that. I think the longest on record is 23 years. So 24 years would be the longest ever. So it may well be that based on interval
that the 1979 surgery was not really responsible for the illness in this case.
We've
talked to the American Red Cross and have many of the blood donations that Ms.
Blejer has reported in their records.
They are going out and identifying them. They don't have all 70 of them yet, but we have enrolled Mr.
Blejer into the study that I think Dr. Sejvar described before, and so we
should get a lot of benefit from the fact that Ms. Blejer has reported this to
us and we're very grateful to her and to the rabbis that permitted this
individual to undergo the autopsy to confirm it one way or the other.
I
know that the secretary at the National Prion Disease Pathology Surveillance
Center has worked -- Eileen was involved in making lots of calls, trying to arrange
for the transfer of the body. There's
been problems with ice and tissue mix-ups, but it's ultimately going to get to
Dr. Gambetti, and Dr. Gambetti's analysis may shed some more light onto what
the etiology is here, whether it's a typical sporadic case or whether there are
some other issues going on here.
DR.
BLEJER: I want to make sure you
know. This is not about my husband or
his case. This is not. When I was talking about the reportability,
I want to make you understand that I'm a fighter and I fought to get it
reported, but that actually it's really difficult to get it reported.
If
you want to fund somebody, you fund something national. First of all, you make reporting mandatory
in all 50 states and the District of Columbia.
Number
two, you educate the neurologists and neurosurgeons. Don't leave it up to the CJD Foundation or all the other family
foundations. You have to do this as a
government because it doesn't make any sense to be relying upon the individuals
who are suffering to do the reporting.
This
wasn't about my husband, and I don't actually care about what comes out of it,
other than to save a life by telling you what you have to do so that you
actually don't have under reporting and so that Dr. Gambetti does have
autopsies because otherwise you're not going to find out what's happening with
the transfusions, with the BSE or
anything else because if you don't autopsy them, you don't know.
DR.
FREAS: Again, thank you very much for
bringing your comments.
We
would like to see if there's anyone else in the audience at this time who would
like to address the committee.
(No
response.)
DR.
FREAS: If not, Dr. Priola, I turn it
over to you.
CHAIRPERSON
PRIOLA: Dr. Linden? No?
Would you like to make a comment?
DR.
LINDEN: I'd like to clarify the issue
about reporting of communicable diseases.
CHAIRPERSON
PRIOLA: Oh, please. Go on.
This is open committee discussion.
DR.
LINDEN: I have some passing familiarity
with reporting of communicable diseases, and I'd just like to comment.
Well,
for one thing, as with many, many other issues in life, it is partially a
resource issue, and I'm not defending the current situation by any means, but I
can just provide some explanation as to why we have the patchwork situation
that we do.
For
one thing, reportability of communicable diseases basically is a state-by-state
issue so that we're going to have 50-plus, you know, different jurisdictions as
to what is reportable as a communicable disease, and it is based on where the
patient lives, not where the patient is treated.
So
if somebody is treated in New York City but they live in New Jersey, that
disease is going to be reportable to the New Jersey Health Department, not to
the New York State Health Department, and likewise if they live in Nassau
County and, you know, they're treating in New York City, it's going to be reportable in Nassau County Health
Department, which will then come to the New York State Health Department. So it's really confusing as to where it
goes, and if somebody is very far from home, it may not get back to their home
health department.
And
likewise in this case, I assume the same thing would apply. If somebody is treated in Washington, D.C.,
if they live in Virginia, it's reportable in Virginia, and those reports may
not get always back to the jurisdiction of residence of the patients. So that can be really confusing. Different jurisdictions may have different
types of cases be reportable, and the different jurisdictions may have
different amounts of resources available to follow up on cases.
And
I would also say the reporting to the CDC is voluntary. I'm not aware of anything that's mandatory
to be reported to CDC, with the exception that we heard about the death
certificate reporting earlier, and I believe we heard that there's not 100
percent reporting with that either, but I'm talking about just communicable
disease reporting, morbidity cases, you know, as separate from deaths.
So
I just wanted to explain a little bit more how communicable disease reporting
works, and that, indeed, it's a real patchwork and it's not well
understood. We get questions about it
all the time.
CHAIRPERSON
PRIOLA: Dr. Bailar. Oh, are you finished? I'm sorry.
Dr.
Bailar.
DR.
BAILAR: This is a problem that has to
be fixed. Ms. Blejer's presentation and
the discussion that has followed here show that the system is just broken. It isn't working.
It
brings me straight back to my earlier question about the completeness of
reporting. The bottom line is we don't
know nearly as much about this disease, its frequency, its distribution as we
think we do.
CHAIRPERSON
PRIOLA: Dr. Nelson.
DR.
NELSON: Yeah, I picked up on another
issue that Ms. Blejer raised, and that was the issue of that her husband's
neurosurgical history and possible dura graft, although it's unclear, but in
terms of screening of blood donors, there is no question about past
neurosurgical history. The only thing
that is asked is do you have a family
member with CJD, and they ask about dura mater grafts or growth hormone.
But
possibly, I mean, the committee has spent the last two or three years, I think
on revising and hopefully improving the donor history questionnaire, which has,
you know, over 50 questions already, but it seems to me that somehow this
should have been picked up at some point, you know, Mr. Blejer's history as a
frequent blood donor.
And
I think that our donor screening questionnaire, though long an cumbersome, is
still not perfect, far from it. And I
think we could ask a question about neurosurgery during a given period. Most people aren't awake when they have
neurosurgery and, therefore, don't know what went into them or what didn't, but
you know, it's not everybody that has had neurosurgery. I don't know what number, but I would
suspect the number of donors with a history of neurosurgery during a certain
interval is probably pretty small.
But
nonetheless, and the risk of transmission of classical CJD is probably small,
too, but from what we've heard today, I think we could improve the selection or
deferral of donors with regard to this risk.
CHAIRPERSON
PRIOLA: Dr. Wolfe.
DR.
WOLFE: I know we're not supposed to
have votes or questions, but I would just like to ask the question and maybe
even subject it to a vote as to why, in the wake of this incredibly
irrationally disparate reporting of this disease and the importance of the
reporting, why by regulation or, if necessary, by law this country couldn't
decide that there is mandatory reporting all over the country for this disease.
CHAIRPERSON
PRIOLA: Dr. Sejvar, you had been
waiting. Would you like to go ahead?
DR.
SEJVAR: Maybe just to make a very quick
comment on the issue of reportability, and this is frankly something that we
hear quite often from families of people with Creutzfeldt-Jakob disease. You know, I mean, a couple of issues, one of
which was raised a little bit earlier, that the reportability basically is a
state domain.
I
think the other issue is to have a condition be reportable is one thing. To have the physician come and make the
diagnosis and then, you know, follow through and make the report is another,
and so, you know, unless the diagnosis is made and then unless that person who
has made the diagnosis actually follows through with the reporting, you can
make a condition reportable all you want.
You
know, I think that's one of the reasons that we have focused on several
additional mechanisms for surveillance, in addition to, you know, making the
condition reportable, but I think that it's important to keep in mind that
simply making a condition reportable is one thing. Actually having the diagnosis made and then followed through is
quite another.
CHAIRPERSON
PRIOLA: Dr. Khabbaz.
DR.
KHABBAZ: Yes, let me just add that I
agree. I think Dr. Sejvar has
articulated it well. Let me just add on
that CDC is on record encouraging states to make reporting mandatory if based
on their data they feel that that improves reporting.
There
are some states where it is mandatory, and there's some experience with states
where it's mandatory. Looking at the
data, and Jim or Larry might correct me, where because of what Dr. Sejvar has
told you, the reporting based on mandatory reporting is not as complete as in
other instances where it is not, and it has very much to d o with diagnosis and
other factors.
CHAIRPERSON
PRIOLA: Go ahead.
DR.
GAMBETTI: Again, I can give you the
perspective of the center. I think that
what Dr. Sejvar said is correct. I
think we need a double approach, and this is the one that we have tried in
collaboration with the advisor of CDC, but we have largely tried on our own to
obtain, one, to raise awareness in the neurologists and pathologists of
America, and that we have, therefore, sent a letter through the professional
organizations, both pathologists, and we use five of these organizations, and
the American Academy of Neurology.
Essentially
should the membership of this association -- should essentially cover a large
proportion of the pathologist and neurologist in the United States, emphasizing the need to report very early in the
course of the disease as soon as the diagnosis is made, to report it to the
state's health department and to us so that always through the caring physician
we can follow the patient.
And
if unfortunately the diagnosis is correct and the family concerned, we can
arrange for an autopsy.
On
the other hand, we have tried to contact the health department of all the
states, believe it or not. We started
with some states like Ohio, New York, now Washington, and California, and
Oklahoma, I believe, and all agree, all agree to send the letter on behalf of
the -- well, again, the states in which the disease is reportable, 26 states
out of 50, agreed to send out a letter to the physicians of the state,
especially to the neurologist, recommending on their own that as state health
departments, that the disease or that the cases be reported to the state health
department and to the surveillance center as soon as diagnosed so that it then
can be followed.
This
other state in which the disease is not reportable have been more kind of
careful and, therefore, they have allowed us to send a letter on our own to the
physician of the states, which we have done in some states.
And
we are now in the process. Essentially
we have covered about six states so far in which essentially we have an
agreement that the letter will be sent and in another state it has been sent
out already.
For
the other states, we are working with the President of the state and
territorial epidemiologist to send a letter or to ask the state to send the
letter to all the physicians of the state.
So we are working, trying to have this in all of the states.
However,
my experience is that whether the disease is reportable or not, that is,
whether we are dealing with the state and with the diseases are reportable or
with the state in which the disease is not reportable, it makes a difference.
If
the disease is reportable, the state will feel more motivated to really support
the initiative of the National Prion Disease Pathology Surveillance Center,
actually to endorse it.
In
states in which the disease is not reportable, there is more caution because,
of course, this is not something that can be easily endorsed if the disease is
not reportable. My personal opinion is
if there were a way, and I would really think I would support if there is a way
to do it and perhaps there is a way.
The disease should be reportable in all the states, and that would help,
along with raising the awareness of the physician.
CHAIRPERSON
PRIOLA: Dr. Wolfe.
DR.
WOLFE: This is an interesting
discussion, but I go back to what I'm saying.
I think we really need to propose that either by regulation or by law it
be reportable, and as everyone has said, and I agree, it isn't enough just to
have it reportable. There need to be
sanctions against these institutions.
These
people die generally in hospitals, and there is no reason why as part of a
reporting requirement there couldn't be some sanction that encouraged people to
report.
I
think this country has tried too many times to do important things on a
voluntary basis and has shied away from making them mandatory, and this is an
excellent example. If you think about
all of the money, time, resources, brilliant people involved in this, and yet a
very fundamental piece of it, namely, raising from 50 to 60 to 95 or 100
percent, which you know, who knows what sort of selection bias there is in the
cases that are not getting reported.
They may yield more information.
I
mean, I don't want to dwell on this, but I really would proposed that we
suggest that there be either by regulation or, if necessary, by law, mandatory
reporting with sanctions for those that don't report.
CHAIRPERSON
PRIOLA: Before we go too much further
with this, I have to remind everybody that this is not something that's
regulated by the FDA. So we can't
really --
DR.
WOLFE: We can make recommendations
though.
CHAIRPERSON
PRIOLA: Well, there are people
listening who are hearing this conversation, but we can't do that, what you
just suggested.
Dr.
Schoenberger and then Dr. Linden.
DR.
SCHOENBERGER: Let me just make a couple
of comments. One is that CJD, because
of the nature of CJD, is one of the better reportable diseases to CDC, and I
say that because 100 percent of these cases die, and it's unusual in this
country for people who die not to have a physician put down on a death
certificate that they died of CJD.
We
don't get them all, but as Dr. Sejvar pointed out, probably 85 percent plus
come to CDC's attention, and there is the delay.
The
other issues you should know about CJD, and it's illustrated by, I think, Ms.
Blejer's experience, is she had trouble getting a diagnosis, and that is, in
part, the nature of the clinical disease.
When these patients come to the neurologists initially, they don't make
the diagnosis of CJD right away. In
fact, CJD, since it is 100 percent fatal, they often wait until they have a
chance to see the entire picture of the illness, and the CJD disease and
diagnosis is probably best made at the time of death.
And
even then, after death, if you'd ask Dr. Gambetti how many of the cases that
are submitted to him on autopsy of suspected cases actually get confirmed as
prion disease, and I'll bet you he'll say, what, 40 percent or so?
DR.
GAMBETTI: Sixty.
DR.
SCHOENBERGER: Sixty percent do what,
get diagnosed?
DR.
GAMBETTI: Are confirmed.
DR.
SCHOENBERGER: Are confirmed. So 60 percent are confirmed, 40 percent are
not confirmed. So given that situation,
to have this reportable in the same way that people, say, report measles or
hepatitis, it sort of requires a different system, and the important thing is
not whether it's reportable or not, but whether the state has the resources to
follow up on cases to make sure it gets the full kind of work-up that it needs,
and you need an extra bit of work-up in these particular cases.
And
so we encourage states who are at least willing to put that extra energy into
it to make it reportable if that will help them get the autopsies done and get
the tissues in and so on.
In
general, whether we get cases or not get cases is often a relationship issue
between Gambetti and the various networks of pathologists and the states and
their relationships with many of the states.
The
proof of the pudding is, I guess, that many of the states where it's reportable
don't do a whole lot better than those that it's not reportable in terms of the
total number of cases that we get.
DR.
WOLFE: There are no sanctions.
DR.
SCHOENBERGER: Okay, and that may deal
with a whole other issue of whether there are sanctions or not.
One
of the real problems that I'm struck with is the whole problem of autopsies in
this country. I know that when I went
to medical school, you know, in training and so on, I'd say half of the cases
that died would get an autopsy and we'd learn about, you know mistakes and what
happened, and my sense is that today in the average hospital the number of
people who die and get autopsied is well below ten percent, you know, maybe
well below five percent, and I think that's a quality of care issue.
And
so I'm dealing with a disease where autopsies are right now the only real way
to definitively make the diagnosis and to confirm the case, and so in a sense,
I feel like we're fighting a secular trend trying to go opposite, and I'm in a
sense very pleased that we've been able to raise the number of cases that Dr.
Gambetti has been able to see. If you
look at his charts, they've been going up very nicely, and we want to continue
that trend.
But,
again, we've left it to the states to tell us whether making it reportable will help get the kind of information that
we need, and we've been telling the kind of information that you need in this
particular disease. And we've gotten
funding for Gambetti. We've gotten
funding for the CJD Foundation and all of these other ways to try to encourage
this increased surveillance and the getting of this kind of information.
CHAIRPERSON
PRIOLA: Dr. Linden and then Mr. Bias.
DR.
LINDEN: In my experience, the
compliance with reporting by hospitals is excellent. That's not where the problem is.
The problem is with the local physicians in the community not reporting
communicable diseases in ambulatory patients.
So I don't think going after hospitals would be beneficial at all.
And
I basically agree with what Dr. Schoenberger has said, that the reporting and
finding the cases for this particular disease, actually we're doing a very good
job, and I don't think the authority is remotely within the realm of this
committee or FDA to be looking at a nationwide type of reporting. So I don't think it would be fruitful for us
to really even get into that type of issue.
But
I do agree that it might be fruitful to, you know, somehow recommend further
efforts in the area of trying to get more tissues from these types of
patients. You know, it seems like that
has been a very fruitful type of effort and to do more of these epidemiologic
investigations because we've been getting some very valuable information. If we can try to continue those efforts with
the cooperation of the states, that's something that we could continue to
encourage, you know, and recommend.
MR.
BIAS: This is a little off the topic of
reporting, but I wanted to bring it to the group's attention. Two of the presentations earlier spoke about
how we hadn't seen any cases in the hemophilia or bleeding disorders population
related to CJD, and I wouldn't expect to with the manufacturing processes
today.
What
I would suggest to the CDC is that you look at the group prior to the current
fractionation processes. The
individuals with bleeding disorders who received components prior to the
current level of intermission is for the first time in the bleed disorders
community that we're not the canaries in the coal mine, so to speak; that the
rest of the blood supply is, and if you're going to find clues, you're not
going to find it in the group of children and young adults who have been raised
and using recombinant or monoclonal products.
You're going to find it in those of us who are using component prior to
that.
So
I would suggest seeing some figures on that the next time the CDC presents
what's going on with that group. It has
got to be a small group because most of us haven't survived HIV and Hepatitis C
and so forth, and it should be easily taken out of the data based on that.
And
then in terms of the reporting issue, I'd like to remind everyone that the best
way to encourage accurate reporting, it's a partnership between public health
agencies and private family or nonprofit groups. You can't impose reporting.
That won't work. You have to
work at both sides of it and do it through collaboration, and that's what the
CDC tires to do by supporting these various foundations.
So
it's a partnership between family and public.
If you simply levy sanctions and try and force people to report, they'll
simply retreat. It just won't work.
CHAIRPERSON
PRIOLA: Okay. Thank you.
I
want to try to refocus this discussion back on the blood and blood products
issue since we can't do anything about the reporting issue with this committee,
but we can discuss it and bring up the problems, and I think where it perhaps
overlaps a bit with FDA interests is in communication between blood suppliers
and the various public health agencies enabling you to track any danger to the
blood supply.
So
maybe Dr. Epstein has some things he wants to clarify for us.
DR.
EPSTEIN: Well, yes. I wanted to make a comment in that narrower
context. Ms. Blejer pointed out the
difficulty of identifying the case where an individual who later develops CJD
had been previously a blood donor.
Almost
always that information is learned from the family. We simply don't have a system in which there is any automatic
tracing of records from the hospital back to donor centers. So that's not at all unusual.
We
do, however, have required reporting.
If a blood establishment becomes aware that a previous donor later
develops CJD, the previous collected units are regarded as subject to what we
call biological product deviation reporting, meaning that they did not meet a
standard. Had the information been
known at the time of donation, the unit would have been on unsuitable.
In
that circumstance the blood establishment must report the fact of those units
to the FDA. Additionally, when units
are taken off the shelf, if donation was more recent, as has in some cases
occurred, then they also are obliged to report these product withdrawals to the
FDA.
We
routinely will make that information known to the Centers for Disease
Control. When the information comes by
the other route, when the Centers for Disease Control becomes aware of a case
of CJD, the CDC is well aware of the need for investigations to include the
question whether the individual previously had been a blood donor, and that
triggers an investigation of donation records.
So
we do at least have a handle on that element of the reporting system, and we do
have communciations that are needed so that the different components of the
health system become aware of at risk units and of the need to enroll such
index cases in the ongoing studies that we call "look-back" to try to
find out outcomes in recipients, and those studies were already described by
Dr. Sejvar and Dr. Schoenberger.
And
then just one additional point. Ms.
Blejer again mentioned the issue of screening donors for a history of
neurosurgery. There was over the last
three or four years a major effort to reexamine the standard donor
questionnaire. The American Association
of Blood Banks has sponsored what's called a uniform donor history
questionnaire that has been submitted to the FDA for review and which we have
accepted that can now be adopted by any blood collecting establishment.
The
specific question whether to modify a current donor screen which asks if you
have ever had a dura mater or brain covering graft was not modified in the
recent update to the proposed uniform donor history questionnaire, and that was
an outcome of an effort to determine whether it was practical to ask a more
broadly stated catchment question about surgeries.
And
it should be noted that brain surgery is not the only surgery where dura mater
has been used. It is also used in
tympanoplasty and various other neurovascular procedures.
But
it was looked at, and unfortunately those who were doing the studies concluded
that it was not going to help our system.
I don't know the exact reason that was found. It may have been that it just yielded a very high false positive
rate of reporting. So I can't clarify
that except to say that that issue was examined, and we do remain today with a
donor question specific to dura mater.
CHAIRPERSON
PRIOLA: Dr. Nelson.
DR.
NELSON: Which in this case failed.
DR.
EPSTEIN: Well, we understand that it
has low sensitivity. Not everyone will
recognize or even know that they had a dura mater graft, but the flip side is
whether a more general question about neurosurgery would be sufficiently accurate
to be used on 14 million donors a year, and it has to do with, you know,
sensitivity and specificity of questioning.
So
I don't have the data in front of me.
We can reexamine that, but that's how you'd have to frame the issue.
DR.
NELSON: Yeah, I think it should be
looked at again, you know, as to how sensitive and specific a broader question
as a lead-in might be.
DR.
EPSTEIN: Right. My only point here was that we haven't
ignored the potential utility, but we could examine the reasoning that led to
no current change.
CHAIRPERSON
PRIOLA: Are there any other questions
or comments from the committee?
I
think all of this speaks to the importance of -- Bob, would you like to say
something?
DR.
ROHWER: This is back to an earlier
topic, but I did want to clarify one point, and that is we discussed the issue
of dilution at several points during the session, and I just want to point out
that this method of limiting dilution titration does get at that question.
Some
of these samples have one or two infections per hundred animals
inoculated. This method absolutely
could not work if we could dilute the infectivity away because, in fact, that's
what we're doing here. We have less
than -- in that particular case you have something like a tenth of an
infectious dose per inoculum, and yet we're still picking it up.
You
could take it a step farther, and we have always wanted to do the experiment
and make another tenfold dilution and see if you could pick up the same titer
again. This time you'd have to
inoculate 1,000 animals to see it.
But
my guess is you would see it because none of these titration methods, even the
endpoint dilution titration method would work if you could dilute the stuff
away.
CHAIRPERSON
PRIOLA: Okay. All right. I think that
we'll get ready to break for lunch here until about 1:30, unless anyone else
has any other comments or questions.
(No
response.)
CHAIRPERSON
PRIOLA: Okay. So 1:30 we'll reconvene.
(Whereupon,
at 12:48 p.m., the meeting was recessed for lunch, to reconvene at 1:30 p.m.,
the same day.)
A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
(1:41
p.m.)
CHAIRPERSON
PRIOLA: If I could ask the committee
members to take their seats please, we'll get started.
Our
first speaker for the afternoon session is a very busy person even though she's
retiring. She's on the committee and
now she's giving a talk. Dr. Lisa
Ferguson.
DR.
FERGUSON: Good afternoon. I'm assuming this is on.
Okay. I was asked to sort of summarize our
investigation and at least APHIS' part of the response to the finding of a case
of BSE in the State of Washington just before Christmas, as we call it,
"the cow that stole Christmas" because there were several of us who
really did not have a holiday.
Anyway,
so I'll go through some of our response, and then I believe my colleagues with
FSIS and FDA are also going to address their part of the issue.
So
next slide, please.
This
is a very brief time line sort of of the whole event, and all of this actually
started on the 9th of December 2003, when a Holstein cow arrived at a slaughter
plant in the State of Washington, and we obtained a sample from this animal
because she presented a non-ambulatory animal or as a downer.
That
sample proceeded to our National Veterinary Services Lab, and on the 23rd of
December we announced that we had a presumptive positive case of BSE.
We
immediately began our epi investigation even though we were calling that
presumptive at that point in time, but we sent the samples with one of our
pathologists to the U.K. to one of the reference labs in Weybridge, and they
graciously agreed to meet us on Christmas morning and looked at the samples and
confirmed that, yes, we did have BSE.
On
the 30th of December, our Secretary, USDA Secretary Veneman, announced a series
of additional preventive measures that we and the department would take.
On
the 12th of January, we actually declared an extraordinary emergency. For those of you who aren't familiar with
out regulatory process that's really not quite as drastic as it sounds. That's really a mechanism for us to obtain
some additional authorities and some additional funding that we had needed.
And
then this, for the committee. You don't
actually have this on your handout, this last bullet point I would change right
before lunch because actually on Monday of this week we did announce that we
have closed out our active field investigation in the State of Washington.
Next
slide.
So
let's talk a bit about the investigation and what animals and what we did. The index case, we based our presumptive
positive diagnosis at NVSL on both immunohistochemistry and histopath, and my
colleague Al Jenny, I believe, has copies of those slides, and he's up next. So we won't go into great detail there.
And
as I said, this was confirmed in the U.K.
Next
slide.
This
animal was a Holstein dairy cow, about six and a half years old; was sent to
slaughter due to calving complications.
She calved towards the end of November and then was having some
difficulty. She would fall down and she
couldn't get up. She had some posterior
weakness.
Actually
in talking with the folks on site, it really does sound like in many ways sort
of truly what you would expect for BSE with the way that she presented, but she
actually presented at the slaughter plant as non-ambulatory, and as part of our
routine surveillance, she was sampled due to the non-ambulatory status.
Our
trace-back investigation determined that she was actually born in Alberta,
Canada, moved into the U.S. as part of a disbursal sale from this herd in
2001. The herd in Canada was disbursed
due to health issues of the owner there.
He just wanted to completely get out of the business; so did a complete
herd dispersal sale, and many of those animals did actually come to the U.S.,
and that's what we've been investigating since then.
She
initially went into a dairy finishing herd there in the State of Washington and
then moved shortly thereafter into the dairy herd in Mabton.
Next
slide.
She
had had four offspring over her lifetime both in Canada and in the U.S. that we
know of, one a heifer calf born in Canada, but we were concerned about what had
happened, what she had had after she had entered the U.S., and she had a
stillborn calf in 2001 shortly after she entered. She had a heifer calf in 2002.
That heifer was till in the index herd, and then she had a bull calf in
2003. This was the calf that she had
right before she went down and before she was slaughtered.
And
this calf had gone to a bull calf raiser close by there in Sunnyside,
Washington.
Now,
this next slide is a very busy chart, but this just shows you -- I don't know
if I have a pointer or not -- shows the investigation actually on both sides of
the border. So the big, black line
there is the 49th parallel with north of it being Canada and south of it being
the U.S.
The
red is the investigation in Canada, and the blue is our side of the
investigation, but as you can see -- I don't think this one is working. Okay?
Okay.
This
is the index herd in Calmar, Alberta with the dispersal sale in 2001. There were actually 81 cattle that we know
came across on one certificate in September 2001, and these were the ones that
we were primarily trying to track down.
I
won't go through all of this detail.
You can read a lot of this on our Website of the various different towns
and where we found animals, but these were primarily the ones that we were
tracking down.
There
were some other animals dispersed from this herd, specifically up here in
blue. There were 17 heifers that went
through some of these dealers, and we weren't specifically looking for these
heifers because we did not have specific information that said all of these
animals came into the U.S.
The
Canadians never really -- we're still working on some of that, but as we did
our investigations and were doing herd inventories and different things, we did
find some of these animals through the traces.
So
when you see a little note in blue here that says "heifers found,"
that's part of these 17 heifers, and these were fairly young animals when they
came into the U.S.
Next
slide.
This
just, so that you don't have to look at the busy chart, tells you exactly what
animals we found and where. There were
81 animals in this shipment, and we found 29 of them, including the index
animal.
This
number tells you how many of the 81 that we found in each facility, but then
this tells you the total number that we euthanized on each of those premises.
Now,
this has gotten rather confusing.
Everybody says, "Well, if you found this one, why did you euthanize
15?"
This
was part of our epi investigation where sometimes it was a challenge to find
these specific animals. We were dealing
with different types of identification and different types of records. We were dealing with cattle dealers who
sometimes -- they're not the top notch operators one would hope to see. So we were dealing with some real sketchy
traces at times, and we would have sale yard records that said, "Yep, I
sold, you know, eight animals over here, and I think she was one of
them." That would cause us then
to go to that herd, look at every animal in the herd, record all of the
identification and then go back.
So
in many instances we could say, "Yes, we know that that one is one of the
81 we're looking for." In some
instances we could say, "Well, I know she's one of those three. So we're going to take all three."
So
that's why you get these differences in numbers.
Next
slide.
So
out of the 81 in that index herd, 29 accounted for, as I said. We tried to do some estimates based on the
age of these animals and normal culling practices in dairies, how many would we
expect to find, and we tried to use that to help us decide when it essentially
was not worth our time to continue the investigation.
So
based on normal culling practices, we estimated that between 17 to 36 of these
81 animals might still be alive, and we found 29 of them. So we felt like that was doing very well.
The
OIE, which is the World Animal Health Organization, actually identifies the
animals born within one year, either before or after an infected animal, are
considered to be at higher risk. These
are the birth cohorts, pretty wide definition.
But
in this 81, there were 25 animals that would fall into that OIE definition of
birth cohorts, and we accounted for 14 of those 25 higher risk birth cohorts,
including the index cow.
Again,
based on normal culling practices, we estimated that 11 of those 25 higher risk
animals might still be alive.
Next
slide.
So just total numbers of animals that we
depopulated, we did take out a total of 704 animals that we euthanized. We paid indemnity for the owner, and we
disposed of them appropriately. Four
hundred and 49 of those were on the bull calf premises. You remember that I said that the bull calf
born to this animal had been sent over there, and 255 were what we called
animals of interest. So these are the
specific animals out of the 81 and then those others that could have been part
where we couldn't narrow it down, and seven were part of that additional group
of 17 heifers that I referred to.
Next
slide.
In
line with just tracking down the animals, we actually did some other parts of
the investigation. Our colleagues in
FSIS on Christmas Eve announced that they would do a Class II voluntary recall
of meat. This included meat from all
ten animals slaughtered on the same day as the index cow.
And
our colleagues in FDA did a very extensive investigation for rendered product
and feed. This animal when she was
slaughtered, obviously, the meat from this animal went into the human food
chain. The rendered product was picked
up and rendered. FDA did find all of
the rendered product that could have remotely contained any of the parts of
this animal. Over 2,000 tons of
rendered protein were disposed of, and they also did an investigation with the
dairy farm and the rendering and feed facilities and found that they were all
in compliance with the feed regulations.
Next
slide.
As
part of our investigation, we followed the lead of our colleagues in Canada,
and we did invite an international review team to come in. We asked the team to review what we had done
with our epi investigation and also to give us recommendations on policies that
we perhaps should consider.
That's
a very brief explanation of what their literal remit was. I believe a lot of that is still on our
Website also if you want to read the actual remit to the committee.
So
they were chartered as part of the Secretary's Advisory Committee for Foreign
Animal and Poultry Diseases. So they
delivered their report to the Secretary's Advisory Committee on February 4th,
and what they said in this report, first of all, they commended us for the open
and transparent manner in which the investigation was conducted and commended
us on the way that we had handled some of the communication aspects of it.
But
they did essentially say that both this case and the Canadian case from A-2003
are indigenous BSE in North America.
Next
slide.
As
I said, we had asked them to specifically look at our epi investigation and
what we had done, and they did that and gave us these recommendations. Essentially they said we had conducted a
very comprehensive epidemiological investigation that conforms to international
standards, and they suggested that really all of the relevant information that
we could get from that investigation we had already gotten, and they
recommended that we stop all of our active tracing efforts, which we were
already in the process of reaching that same conclusion. So we took their recommendation there and
concluded our investigation.
They
did commend us for the tracing and the recall of the meta and bone meal or the
tendered product, and they also said that the trading and recall of the meat
was consistent with WHO recommendations.
Next
slide.
Then
we got into policy recommendations, and they looked at various aspects of
policy. Start off with specified risk
materials, and they recommended that SRMs be removed from human and animal feed.
They
did recognize that the interim rule that our colleagues in FSIS had already put
out there removes the highest risk tissues.
However, they did recommend extending that definition and essentially
bringing that down in age. FSIS' regs.
refer primarily to tissues from cattle greater than 30 months of age. The committee recommended we look at cattle
greater than 12 months of age.
They
commented on our non-ambulatory cattle issues and actions, and essentially what
they said there, they strongly recommended that we maintain access, that that's
a crucial population in our surveillance and encouraged us to maintain access
to that population for surveillance.
Next
slide.
Which
leads into surveillance. They did
confirm that targeted surveillance, looking in the high risk population, is the
most efficient way to find disease if it is present, and they recommended that
we make an attempt to test all cattle greater than 30 months in the targeted
high risk population for a one-year period; so make an all out, intensive
effort.
They
did say that testing of all cattle slaughtered for human consumption was
unjustified. However, they did say that
random sampling of slaughter cattle greater than 30 months could be considered
primarily to encourage disease reporting at the farm level. They also recommended that we adopt rapid
screening tests and decentralize some of our laboratory facilities.
Next
slide.
They
looked at feed restrictions. They did
recognize that we have had a feed ban in place in the U.S. since 1997, but they
recommended that all SRMs be excluded from all animal feed including pet food,
and they also recommended that all mammalian and poultry protein be excluded
from ruminant feed.
Traceability,
they recognized as we have that we need to improve our animal identification
system, and the department has already made a commitment to do that.
And
then last but not least, they recommended that a strong educational effort
needs to be maintained essentially. We
have done very strong educational efforts since 1990, but they felt like that
needed to be strengthened and maintained.
Next
slide.
So
now I'm going to summarize a bit of what we have done in surveillance over the
past several years and kind of what we're looking at or perhaps looking
at.
Our
surveillance has been targeted surveillance where we have tried to focus on
adult animals in the highest risk population.
Specifically, this is where we think the disease would be most likely to
be found if it was here.
So
that's where we have focused our efforts, and this has been done with
non-ambulatory animals or downers, dead stock, those animals that are out in
the field that have central nervous system signs or on farm suspects.
We
work with various state veterinary diagnostic labs as they examine neurological
cases. We also work with public health
laboratories. If they're testing an
animal for rabies and it's negative, they can forward that sample on to us.
And
then we work with our colleagues in Food Safety Inspection Service, and if they
condemn an animal that is presented for slaughter on an antemortem inspection
for central nervous system signs, they will call us, and we will get samples
from that animal.
Next
slide.
Our
surveillance goals. We've attempted to
do our surveillance and set those goals at a level sufficient that we would
find one case per one million adult cattle at a 95 percent confidence level. Now, we've done these calculations based on
estimates of our targeted high risk population, and previously we were using an
estimate primarily of the non-ambulatory cattle population.
We
worked with the American Association of Bovine Practitioners several years ago
to try and get an estimate of the non-ambulatory cattle population in the U.S.
at any given time, and what came out of that survey was 195,000. So we were using that as our targeted high
risk population for these calculations.
Last
fall, in response to the finding of the case in May in Canada, we decided to
broaden that definition and to try and do a wider estimate and tried to come up
with numbers of animals that die on the farms, other animals that are
condemned, and came up with an estimate of 600,000 animals that would be in
that targeted high risk population.
It's
really somewhat of a challenge to try to come up with those estimates, and we
feel like that figure probably has a lot of overlap in it, but we wanted to be
somewhat broader rather than too narrow.
And
just as a reminder, we estimate that the adult cattle population in the U.S. is
about 45 million.
Next
slide.
So
based on sort of those assumptions that I just gave you, we calculated our
goals, and when we did that calculation based on the non-ambulatory animal
estimate with 195,000, the goal -- and we used this for our goal in FY '02 and
'03 -- was 12,500 samples.
When
we used that broader estimate of the targeted population, and we did that to
try to set our goals for FY '04 before disaster struck, and we came up with a
goal of at least 40,000, because if you run that same calculation with this
higher estimate, the actual statistical calculation is 38,462 samples, and we
just rounded that up to be 40,000.
Next
slide.
So
these are our surveillance numbers for the past several years. We have been doing active surveillance since
1990. In '02 and '03, once you put
those numbers on this slide, it really skews the slide. So you lose a lot of this detail down
here. But in fiscal year '02 we had
19,990 samples; in '03, 20,543 samples.
Now,
this bar for 2004 is actually the start of fiscal year 2004. For those of you who are not in a regulatory
agency, the fiscal year starts in October.
So this is essentially the first quarter of fiscal year 2004, and we had
8,150 samples.
Next
slide.
We
have tried to focus our surveillance and set our goals based on regional
estimations. Early on when we started
surveillance, we were reporting things out on a state-by-state basis. We recognized that was somewhat misleading
because many times if you're obtaining a sample from a slaughter plant or from
a rendering facility in a given state, it's reported as coming from that state,
but the animal had actually moved in from the state next door or the state two
states over.
So
we tried to work with our field people to define regions based on what we knew
of adult cattle movements and then set goals for each of these regions based on
the adult cattle population in the region.
Next
slide.
Very
busy slide, and I won't go through all of the numbers, but this just shows you
what the goals here in the darker were for each of the regions in fiscal year
'01 through fiscal year '04, and then the samples that we had obtained to meet
those goals.
And
in most regions, we exceeded our goals, with one exception that I know
everybody always points out if I don't do it beforehand. In fiscal year '03, our northwest region
goal was 1,200, and we got about 781 samples.
Next
slide.
So
let's look at the different populations that those samples are obtained from,
and a significant proportion of our samples have been obtained from the
non-ambulatory cattle population. So
this purple bar are the non-ambulatory or the downer animals.
And
as you can see, in fiscal year '02, out of about 20,000 samples total, about
15,000 of those were non-ambulatory animals.
About 2,700 of them were dead stock.
A
similar type thing in '03. Out of
approximately 20,000 samples, a little bit more than 16,500 were non-ambulatory
animals, and a little bit more than 3,000 were dead stock.
Let
me make one point here, however, that I think has gotten somewhat confused in a
lot of the discussion over the past several months. Not all of those non-ambulatory animals are those at slaughter,
and there has been a lot of concern about how we will maintain access to that
population.
Now,
we recognize that a significant proportion of them have been obtained at
slaughter because that's a convenient way to do that. You have a captive population right there, but there are other
outlets for those animals with salvage type plants and rendering facilities,
and we have been obtaining samples at those facilities also.
So
we are committed to maintaining access to that population, and as we develop
our plans for the future, we'll build on that experience that we already have
in working with those alternative outlets for those animals.
Next
slide, please.
Future
policy changes. We continue to evaluate
the international review subcommittee recommendations, and we are working with
our colleagues in Harvard, with the models that they have done to compare the
conclusions of the two different groups, I guess.
We're
also considering a range of options on surveillance. We recognize that there's lots of different things that we could
do. We have made no final decisions
yet, but we are looking at a wide range of those.
In
the meantime, our field folks are still continuing to get samples, especially
from deads and downs as they can find them.
And
we're also, as I said, continuing to
work with the states, industry, and others to maintain access to our targeted
population, and we recognize that all of those affiliated industries and our
colleagues in the states will really be crucial in helping us maintain
surveillance at whatever level we finally decide will be our final goal.
I
believe that will wrap it up for me for now.
CHAIRPERSON
PRIOLA: Thank you, Dr. Ferguson.
Are
there any questions from the committee?
Dr. Bailar.
DR.
BAILAR: Over the period of a lot of
years there have been many suggestions that the U.S. have a system for identifying
individual animals. As far as I know,
nothing has been done along those lines.
Would
such a system have helped here?
DR.
FERGUSON: Well, in some ways that's a
difficult question to answer, and actually I wouldn't characterize it that
nothing has been done. I mean, we've
been making efforts towards a national identification system. Those efforts have now been significantly
speeded up.
DR.
BAILAR: As a result of this, yes, and
you know, having a national ID system and having computerized databases with,
you know, 100 percent recording of each and every piece of ID that was on an
animal, yes, that would have helped.
You know, that's not something that's going to happen overnight.
I
want to make a point. These animals did
have identification. It's just that
they had a metal ear tag. They had a
bangle tag. You know, they had
different other numbers, and sometimes one number got recorded on one piece of
paper and another number got recorded on another piece of paper.
DR.
BAILAR: As far as I know, there is no
national system for tracking these things, and showing when they move out of
the population as slaughter or dead.
DR.
FERGUSON: Well, that's what we're
working on with the national animal ID program.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
GAMBETTI: Lisa, is it fair or not to
say that you examined essentially ten percent of the downers or you were
examining ten percent of the downers at the time that the BSE case was
discovered? Do I understand correctly
the data? It looks to me that the
downers are estimated to be 200,000, and you were examining about close to
20,000, 16,000 or so.
So
is it fair to say or not that if you had examined all of them, now we would
have ten cases rather than one or BSE?
DR.
FERGUSON: I don't believe that would be
necessarily fair to say. Actually I
think about all we can say about our surveillance and the calculations that we
have done is we believe we are doing surveillance and continue to do
surveillance at a level sufficient that if there were one case per one million
adult animals, we would find the disease.
We're not saying we're trying to identify true prevalence or even any
prevalence. All we're saying is if it
was out there at that level, we're pretty confident we would have found it, and
we did find it.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: I don't know how to ask
questions with regard to this because it's very complicated, and I talk to a
lot of people, both cowboys, guys who run ranches, people who have computerized
microchip systems that they can subcutaneously put into animals, consumers, the
whole group, and they're all frustrated.
Certainly
the pharmaceutical industry continually calls and asks, "Well, we got our
tallow," or, "we got our collagen from a certain place." They can't even identify the place usually. They're worried that it's contaminating
their products, and they've already invested huge amounts of money into
it. The public are aware of this, and
they're upset about it.
Those
of us who still eat beef are upset that we are never sure of whether the beef
is BSE free or not. It goes on.
There's
lots of concern, and no one is confident that they can be assured that the
products even in the United States are free at this stage because of this one
event, nor is it clear what the difference is between sporadic BSE and acquired
BSE, and how we're ever sort that out, we don't even know what the incidence,
unless you can tell me the incidence of sporadic BSE in the cattle population
is and how we would even identify it, and even if we could identify it, is it
transmissible to humans or is it like sheep scrapie? It just doesn't seem to go across.
So
as I say, it's more a frustration that I'm sort of venting, but I don't
know. There are lots of questions, and
there are lots of ways of solving this.
For instance, are there certified ranches and processing plants in
existence in the United States where people could be assured that they have BSE
free cattle, where cattle are universally tested so that the pharmaceutical
company could go to them and get whatever parts they wanted, that even a
Mexican restaurant in San Francisco could get brain and serve it in a tortilla,
whatever they serve it in?
Is
there anything like that? And how could
we get to that stage, and shouldn't we get to that? Should there be tax benefits to ranches that do this and to
processing plants that go the extra mile to assure the public that their
product is free of BSE?
So
I'm just asking for a simple --
(Laughter.)
DR.
FERGUSON: Yeah, right.
DR.
DeARMOND: But is your answer yes?
DR.
FERGUSON: That's about the least simple
question I've ever heard.
DR.
DeARMOND: But it is the frustration of
the public.
DR.
FERGUSON: Well, no, trust me. I recognize that, you know. I mean, we've been dealing with this since
December 23rd with the public, and actually I do have to make one point though,
that you know, really consumer confidence in the U.S. has not dropped
significantly, which is very encouraging.
And
in the Canadian situation, a similar type thing. Consumer confidence really did not drop, and I believe that
reflects on, you know, control measures that had either already been in place,
educational efforts that have been in place for many years, and then subsequent
actions that we have taken.
I
think your question about, you know, defining free herds, defining free
whatever, actually I think some of that gets into the next topic, Topic No.
3. I think some of that about risk
based sourcing.
I
guess while I have the microphone, I'd just caution everybody to be very
careful about what do we mean when we say BSE free. That's a very difficult distinction to make with any of the TSE
diseases. That's a very difficult point
to make.
And,
you know, it will be interesting to see how a discussion goes.
Your
question about sporadic BSE, that's still an unanswered question out there, you
know, in the whole TSE community. On
the one hand, you can make the argument, well, wait a minute. If there were spontaneous cases of BSE in
the U.S., we had all of the appropriate conditions to really propagate an
epidemic and see a similar type thing that happened in the U.K., yet we didn't.
You
know, does that mean that spontaneous BSE doesn't occur? No, I don't think anybody can say that. You could say spontaneous BSE is something
different than the agent that they had in the U.K., and it's not transmissible
in this same way. That's one of those
unanswered questions that will either be out there for a while or will depend
on the researchers to answer it for us.
DR.
DeARMOND: But the public wants us to
answer those questions, which means, I think, increased testing to try to sort
out these questions.
CHAIRPERSON
PRIOLA: Okay. One more question from Mr. Bias.
DR.
GAMBETTI: Just echoing what Dr.
DeArmond was saying, there is also another issue that is not only the American
consumer, but also the country that imports from United States, which may
really at a certain point require a kind of reciprocity in the level of testing
that they do in order to import American beef.
And
I don't know what your ideas are about this issue.
DR.
FERGUSON: Well, we are also well aware
of that. I mean, we've been dealing
with the trade issues actually even before the 23rd. We had some of the fallout from the Canadian case.
I
guess the way we have looked at it in our department, our surveillance has been
an animal health measure, and it has been geared to identify the presence of
the disease in the U.S. at a certain level, and that's really all our
surveillance program is set up to do.
I
would caution everybody at leaping to the assumption that testing equals food
safety. I think that's really a bit of
a challenge to make that leap. There
are other measures that are really more accurate in assuring public health
safety, and that such things as the feed ban to prevent spread of the disease,
removing specified risk materials, those are relief of things that are
primarily assuring public health and food safety.
Mr.
Bias.
MR.
BIAS: I'm not surprised consumer
confidence hasn't dropped considering the amount of McDonald's, Wendy's,
BurgerKing, and the beef commercials that are running extra specials now on TV. So that doesn't surprise me at all.
But
I'm wondering -- my question is a little bit simpler. Sometimes industries that provide blood or food for the American
public sometimes benefit from a little extra scrutiny with the beef industry
benefit from a little extra regulation, scrutiny, attention from the federal
government in the next three to five years in terms of surveillance of cows.
DR.
FERGUSON: Oh, man. That question probably should be asked to
the beef industry, and I'm looking out there to see who my industry colleagues
are in the audience, and I think they're hiding.
(Laughter.)
DR.
FERGUSON: I think what we've recognized
with this case and with the case in Canada is that sort of the livestock
industry in general and all of our TSE management practices can stand a bit
more scrutiny, and we need to look at what our policies have been, what we
think the real risk is, and what policies we need to change, and we're in the
process of doing that.
I
think as you've seen, you know, with the announcements that we made on the
30th, with additional measures on the FSIS side, with measures done at the
slaughterhouse, those are some of the policies that are being changed.
Has
that increased scrutiny? I don't know,
but it's adjusting the policies to address the problem as we need to do.
CHAIRPERSON
PRIOLA: Okay. I think we're going to have a period of discussion after all of
the speakers. So let's go ahead and
move on to Dr. Al Jenny and keep your questions in mind for the general
discussion part.
DR.
JENNY: Okay. I went to a planning meeting to plan a new building and came
back, and the pathologist that reads the day-to-day immuno said, "Hey,
I've got a slide for you to look at," and he had already had the H&E
made for the histopath. The IHC slide
was very positive on this animal, and there definitely was spongiform change
present when we looked at the H&E.
So
my nightmare has been for the last ten years that because we do both deer and
sheep and elk and cattle all in the same place, that we'd get a deer or a sheep
that somebody called a cow, and so my first question was: is this really a cow?
And
we do have totally separate cutting areas.
So the cattle are done one place and the other species are done
someplace else, and we have color coded cassettes. So if it's a yellow cassette, it's supposed to be a bovine. If it's an orange cassette, it should be a
sheep.
So
next slide.
And
this is the immuno slide from this animal, and where you see red staining is
where we have the PrPsc. So this is
basically white matter here. This is
gray matter here. You can almost just
by where the staining is, you can pick out the gray from the white, and that's
with the TSE. It's like real
estate: location, location, location,
and so you're looking at you want to make sure that your lesions or your
staining are in the gray matter and with specific nuclei within the gray
matter.
So
next slide.
So
the first thing we did, we went back and recut from that initial block. We also cut in additional tissue from the
bottle for both tests, and then we didn't have the frozen tissue. A lot of times frozen tissue is retained by
the submitter and only sent in if we ask for it. So we called the submitter and asked for that frozen tissue to
come in.
Next
slide.
So
both the recuts and the additional tissue process were positive by
immunohistochemistry, and we had good spongiform change by histopathology.
So
the next slide.
So
when we say it's a transmissible spongiform encephalopathy, spongiform says
sponge-like. So you're looking for
basically holes, but not all holes are created equally, and not all holes are a
disease. So you have to be careful, and
you have to know that the hole you're looking at are holes associated with
disease in the right area of the brain, and in this case we also have gliosis. So that is another feature that we see with
the TSCs.
So
the next slide.
Again,
very nice holes, very nice spongiform change in this brain.
Next
slide.
And
when again you go back to location and you're looking at specific nuclei within
the brain at a given level for these lesions and so every nuclei that you go to
you could find some of the spongiform change.
Next
slide.
This
is artifact, and again, not all spongiform, not all holes are real spongiform
change associated with disease. So you
have to know what you're looking at and something about the tissue.
So
next slide.
And
now we're back to the immunohistochemistry.
We've been using immunohistochemistry to do our screening for quite some
time. We started out doing histopath
only. Then we switched to where we do
both histopath and immunohistochemistry, and then we basically screen mostly
with immunohistochemistry, now with histopath on the ones that CNS or nervous
system signs are reported.
So
routinely we're just doing the immuno, and again, this is the gray matter. This is the vessel. This is gray matter. This is white with some gray mixed, and
very, very, very distinct staining. No
question that this is positive.
Next
slide.
These
are neurons, and you can see we have staining around neurons and throughout the
gray matter.
Next
slide.
More
of the same.
Go
ahead.
And
this is the dorsal motor nucleus of the vagus, just about as intense staining
as you'd ever hope to have.
So
next slide.
Again,
this is a white matter track. So it's not
staining. The red is the gray matter
where you see the staining.
So
that's it.
Oh,
okay. We did get the frozen
tissue. We did have Dr. Dr. Richt at
the National Animal Disease Center do the Western blot. It was positive, and we are doing one of the
rapid tests just on a developmental basis at NVSL. So we did it on the biorad rapid test, and it was positive on
that test. I think that was it.
Okay. So according to our plan the BSE response
plan, the initial case was going to be confirmed in England by pathologists
that look at BSE routinely. So the
immuno and histo slides were taken to Weybridge, to that lab, agency lab there,
and their pathologists agreed to come in on
Christmas day. They spent about
ten minutes looking at the slide and said, "That's it."
And
the phone call came back here that they agreed, and so that converted it from a
presumptive to a confirm.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Jenny.
Are
there any questions? Dr. Bracey.
DR.
BRACEY: I was just interested in what
is the cost of performing the screening test per cow, per animal?
DR.
JENNY: The cost of the testing?
DR.
BRACEY: Yes.
DR.
JENNY: The testing itself is around $20
per animal, but you have all of the other associated cost of getting the
sample, getting it there and those types of things.
DR.
BRACEY: Oh, okay. Thank you.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: If I understand the dates
correctly, it took you about two weeks to do the preliminary testing before you
sent the stuff to England. If you were
doing this again, would you send it earlier in the process?
DR.
JENNY: It wasn't two weeks. We actually didn't do the sample, didn't
actually run the sample until the 22nd.
The 22nd was the first day we saw that slide.
The
next day we saw the tissue that came out of the bottle, and we were sure that
we had the right animal. So that was
the 23rd.
The
sample went to England on essentially Christmas Eve, the 24th, and England gave
us a positive on the 25th.
DR.
BAILAR: Well, then I should change my
question to ask about the long delay before you got it. Is there reason to try to shorten that a
great deal?
DR.
JENNY: Definitely, definitely.
DR.
BAILAR: And are you taking steps to do
that?
DR.
JENNY: Yes, yes.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Those are very nice slides,
but why couldn't you be convinced that they were correct? Why did you have to send them to England?
And
there are people all over the United States that would look at that and say
they're correct.
DR.
JENNY: Because the plan, which has been
in place since early in the '90s, had the first case going to England. So we followed the response plan that had
been developed for BSE, but we didn't wait for England to say it's positive
before we did the -- we started doing the follow-up tracing on the animals.
CHAIRPERSON
PRIOLA: Dr. Ferguson.
DR.
FERGUSON: Actually I think Al just said
some of it. I wanted to make the point
that we didn't wait for the U.K. confirmation.
We were extremely confident in what NVSL had reported to us, but in
addition to it was in our plan, that's actually also sort of the precedent that
has been established by other countries.
It's general when you find that first case, you have it confirmed at one
of the world reference labs. So we just
followed that precedent also.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Jenny.
Our
next speaker will be Dr. Mary Porretta.
MS.
PORRETTA: Good afternoon and thank
you.
I'll
just make one correction. I'm not a
doctor. I'm actually an attorney, and
I work in the Policy Group at FSIS, and I'm going to give an overview of some
of the new regulations and policies that FSIS implemented to further enhance
our safeguards against BSE.
Okay. Can I have the first slide, please?
The
mission of the Food Safety Inspection Service is to insure that meat, poultry,
and processed egg products are wholesome, not adulterated, and properly marked,
labeled, and packaged.
The
provisions in our regulations issued in response to the detection of the BSE
case on December 23rd are intended to prevent human exposure to the BSE agent
through consumption of meat and meat food products.
The
next slide, please.
On
January 12th, 2004, we published three interim final rules and a notice in the Federal
Register. All of the regulations
were issued as emergency interim final rules, and they were effective
immediately upon publication. So these
regulations have been in effect since January 12th.
Next
slide, please.
The
interim final rules have a 90-day comment period, and it closed on April 12th,
2004. After the comment period closes,
and this is standard procedure for any regulations, FSIS will analyze all of
the comments received in response to the regulations, and we will later publish
another document in the Federal Register that would include a discussion
of the comments received and any amendments that we would make to the
regulations in response to those comments.
The
three regulations in the policy documents, the first one is entitled "The
Prohibition on the Use of Specified Risk Materials for Human Food and
Requirements for the Disposition of Non-ambulatory Disabled Cattle."
The
next regulation is meat produced by advanced meat recovery, bone separation
machinery, and meat recovery systems.
That's regulations related to the advanced meat recovery process.
Next
slide, please.
The
third regulation is a prohibition on the use of certain stunning devices used
to immobilize cattle during slaughter.
And
then the fourth document is actually a policy, a notice that we issued on
informing the public of our change in policy on animals or cattle that are
tested for BSE under APHIS' surveillance program that are being tested at the
slaughter establishment.
Okay. So the first rule deals with specified risk
materials and non-ambulatory disabled cattle.
So I'm going to deal with those two aspects separately.
The
prohibition on these SRMs for human food, it designates certain materials from
cattle as specified risk materials, declares that those materials are inedible
and prohibits their use for human food.
Next
slide, please.
The
materials that we designated as SRMs include the brain, skull, eyes, trigeminal
ganglia, spinal cord, vertebral column, excluding the vertebrae, the tail,
transverse processes of the thoracic and lumbar vertebrae and the wings of the
sacrum, the dorsal root ganglia often cattle 30 months in age or older, and the
tonsil and distal ileum of the small intestine of all cattle.
To
insure complete removal though of the distal ileum, we are requiring that
establishments remove and disposed of as inedible the entire small intestine.
Establishments
that slaughter cattle or that process the carcasses or parts of cattle are
required to develop, implement, and maintain written procedures for the
removal, segregation, and disposition of specified risk materials, and they are
to address these procedures either in a HACCP plan, a sanitation program, or
another prerequisite program.
The
slaughter establishments and processing establishments, we operate under a
HACCP inspection system where the industry comes up with plans to insure that
food safety hazards do not get into meat food products as it verifies their
programs, and that's just what that last bullet is about.
Next
slide please.
Establishments
are required to maintain daily records that document the implementation of
monitoring of their procedures, and then FSIS verifies the adequacy and
effectiveness of their procedures, and that would be through reviewing their
records and looking at the procedures, observing the establishment, how they
are implementing the procedures, observing carcasses to make sure that
specified risk materials have been removed.
Next
slide, please.
Under
the regulations, materials are deemed to be from cattle 30 months of age and
older unless the establishment can demonstrate that the materials are from an
animal that was less than 30 months at the time of slaughter. So, you know, they can choose to treat all
animals as if they're 30 months of age and older and remove specified risk
materials.
If
they choose to segregate, they have to demonstrate to our inspectors that,
either through documentation or dentition, that they can determine the age of
the cattle. And, again, we would verify
that they're doing that appropriately, and if they're not, they would have to
take corrective actions.
All
of these regulations are codified at 9 CFR 310.22.
Okay. Next slide.
Now,
the second part of this regulation deals with the disposition of what we call
non-ambulatory disabled cattle. In this
regulation we defined non-ambulatory disabled livestock as livestock that
cannot rise from a recumbent position or that cannot walk, including, but not
limited, to those with broken appendages, severed tendons or ligaments, nerve
paralysis, fractured vertebral columns, or metabolic conditions.
So
it's really regardless of the reason for the non-ambulatory status. Non-ambulatory disabled cattle cannot go for
human food.
Next
slide, please.
As
I said, the carcasses of non-ambulatory disabled cattle are prohibited for
human food. Non-ambulatory disabled
cattle that are presented for slaughter will be condemned, and under our
regulations condemned cattle cannot be taken into an establishment and cannot
be slaughtered or dressed in the establishment.
The
other regulations that we issued are with regard to advanced meat recovery and
another product called mechanically separated beef.
AMR
Technology is the technology that enables processors to remove detached
skeletal muscle, tissue from livestock bones without incorporating significant
amounts of bone and bone products into the final product.
When
properly produced, under the regulations product derived from AMR systems is
comparable to hand deboned meat, and it can be labeled as meat.
Under
our former and new regulations, spinal cord, which is the high risk tissue, is
not considered a component of boneless meat, but under the former regulations,
beef AMR product that was found to contain spinal cord was not permitted to be
labeled as meat, but it could be used for human food if it was relabeled as
mechanically separated beef, which is considered as a meat food product. It's not considered meat, provided other
requirements for MS beef format.
Next
slide.
The
new regulations just declare MS beef inedible and it's prohibited for human
food.
Other
requirements that we issued for meat produced by advanced meat recovery systems
is vertebral columns and skulls, which are SRMs of cattle 30 months of age and
older, cannot be used in the production of AMR product.
AMR
product that's identified as meat cannot contain any brain, trigenital ganglia,
spinal cord, or DRG. That's for all
livestock and cattle under 30 months of age.
Meat
produced using AMR systems cannot contain unacceptable levels of bony solids
and narrows, and that's more because that's not consistent with hand deboned
meat.
Next
slide, please.
Again,
as in SRMs, establishments are responsible for developing, implementing, and
maintaining procedures to insure that the AMR process is in control, and those
procedures must include observation of bones entering the system and testing of
the product that exits the system.
And
FSIS, we conduct regulatory verification testing of the end product for spinal
cord and DRG, and if we find spinal cord or DRG in AMR product, that has to go
for inedible purposes.
The
third regulation that we issued was just a prohibition of the use of stunning
devices, captive bolt stunning devices that would inject, deliberately inject
air into the cranial cavity of cattle, and those were prohibited because the
studies have shown that they can force pieces of brain into the circulatory
system of the stunned cattle, which it could become lodged, and edible tissues
such as liver or heart.
So
although we're not aware of any establishments that are currently using it,
that's prohibited.
And
then the fourth, the policy statement that we issued, it's called our test and
hold policy, and basically it states that FSIS will not pass and apply the mark
of inspection to the carcasses or parts of cattle that are selected for testing
for BSE by APHIS until the sample is determined to be negative.
We
have issued a series of notices to provide additional clarification on the
rules to our inspection personnel. Our
policies and rules are available on our Website at those locations.
That's
really it.
CHAIRPERSON
PRIOLA: Okay. Thank you, Ms. Porretta.
Are
there any questions? Dr. Nemo
DR.
NEMO: How difficult would it be or how
easy would it be for an unscrupulous owner of a slaughterhouse to circumvent
these regulations? Do you normally have
people on site that inspect?
MS.
PORRETTA: Yeah, right, specially at the
slaughter establishments there's an inspector on site at all times. So it would be difficult.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: So as I was walking around
the cowboy antique show in Phoenix about three weeks ago, I heard the people
talking, the cowboys talking about that looks like it's forbidden for us now to
eat T-bone steaks because there's often a little spinal cord.
MS.
PORRETTA: Right.
DR.
DeARMOND: So what would stop a person
at the slaughterhouse from chopping off the spinal cord and giving the rest of
the steak? And so wouldn't the danger
still be there?
MS.
PORRETTA: You could get T-bone steaks
from cattle younger than 30 months of age, which is where most of that product
comes from anyway. The vertebral column
for the animals older than 30 months are prohibited, and bone in beef from
those older animals, they have to debone it.
DR.
DeARMOND: So in reality, as I
understand, cattle for food are usually slaughtered at 18 months of age in the
United States, 18 to 20 months?
They're
younger, in general, yes.
DR.
DeARMOND: So as a general rule then
these rules would not apply to them, except for distal ileum?
MS.
PORRETTA: Right, the distal ileum for
the animals younger than 30 months.
DR.
DeARMOND: So the rule is pretty
general. I didn't see an age
discrimination in it so that in theory then the rule only applies to older
cattle over 30 months of age, these new regulations?
MS.
PORRETTA: Well, the definition of
specified risk materials, certain materials except for the distal ileum are
specified risk materials if they're from cattle 30 months of age and older.
DR.
DeARMOND: So this shouldn't have a very
profound effect on the beef industry then if they slaughter their cattle in the
20-month time period?
MS.
PORRETTA: Depending on, right, what
their practices are for younger animals, but it does have an impact in that
they have to demonstrate to us that those animals are younger than 30 months of
age, and that they don't have to remove the serums.
CHAIRPERSON
PRIOLA: Okay. Mr. Bias.
Sorry,
Linda. Do you want to add to that?
DR.
FERGUSON: Yes, actually I would like to
add to that because I don't want to leave the impression here that animals
greater than 30 months of age are not slaughtered in the U.S. They are.
There
are about 35 million animals slaughtered annually. Probably about 20 percent of that, between seven and eight
million, are animals that are greater than 30 months of age.
DR.
DeARMOND: So 90 percent of the living
cattle are slaughtered each year? You
said there were 45 million cattle in the U.S.?
DR.
FERGUSON: I said there were 45 million
adult cattle.
DR.
DeARMOND: Adult, adult cattle. Of those 35 million are slaughtered?
DR.
FERGUSON: No. There are probably about
100 million cattle total in the U.S., and of those, 35 million are
slaughtered in a year, and of that 35 million slaughtered in a year, probably
about 20 percent of that or seven to eight million are adult animals
slaughtered greater than 30 months.
DR.
JOHNSON: Two quick questions. One was the comment was made last year that
there was a concern about fewer downer cows appearing, and the concern was that
ranchers were burying the cattle on the land to keep from being detected. Is that still a concern, that is, the dead
stock out on the ranch?
MS.
PORRETTA: Yeah, I think actually Lisa
can address that one better than I can.
DR.
FERGUSON: Well, let's not equate, you
know, downer animals and dead stock.
DR.
JOHNSON: Yes.
DR.
FERGUSON: There are some differences,
and there are sort of two points to that.
From a disease control standpoint for BSE, do we care if an animal out
on the range is buried? No, we probably
don't because that's not going back into the feed supply, and so the disease
isn't going to be spread.
From
a surveillance standpoint, yeah, we are interested, and that's the point that I
was trying to make where we're working with various industries, and we're
trying to revise our surveillance and really look at all of our options so that
we maintain access to those targeted high risk populations, be they, you know,
dead stock on a farm or downers that are now going elsewhere. We're trying to keep track of that.
DR.
JOHNSON: The other question is that in
Japan where they decided that all animals should be checked, they found several
positive animals under age 30 months.
Does that concern you?
MS.
PORRETTA: Yes, and we did acknowledge
that in what you call the preamble to the rules. We had a discussion on that.
We did request comments on, as I mentioned, these are interim rules, and
we are going to have comments on them, and we requested comments on that and
would consider that.
DR.
JOHNSON: Because one of them was only
21 months, right?
MS.
PORRETTA: Right.
DR.
JOHNSON: That would be a tremendous
change if you lowered it to 20 months, wouldn't it? That would be impossible.
CHAIRPERSON
PRIOLA: Mr. Bias?
MR.
BIAS: I'm just a little concerned about
the inspection process. It just seems
I'm not inspired with confidence here about the inspection process.
I
know that industries that are regularly inspected by the same series of
inspectors become collegial in some ways in compliance, and I know in the blood
industry when the FDA began to scrutinize the inspection process a little bit more
effectively, that's when we really began to see changes in how the industry
conducted their business, where they got out in front of potential problems as
opposed to waiting for them to happen.
So
I don't know if I have a question as much as a comment, that you know, if we're
not levying fines, if there's no repercussion from having a cow show up on your
facility that has BSE, if we are going to the herd and they are saying,
"Hey, I think it's one of those five cows," and then we're
reimbursing them for euthanizing the five cows, I'm not exactly sure we're
doing anything to facilitate their cooperation or them getting out in front as
an industry of the problem.
So
I don't know. I don't think that's a
question. It's just sort of the
inspection process is not inspiring me to go out and buy a burger tonight.
MS.
PORRETTA: I guess I don't under -- is
your concern that the animals -- they're sending downer animals to slaughter or
the inspection procedures that are inside the establishment to remove specified
risk materials?
MR.
BIAS: My concern is that the inspection
process may have some lapses in it, and my concern is that the industry may not
have the incentive to get out in front of these problems that we're continuing
to talk about.
This
could be a major health crisis for the United States. It's going to cause many lives potentially and certainly cost us
a lot of money and to our health care system.
And I'm just not inspired by the way the inspection process has been
laid out here today that the industry is motivated to make the changes that I
hear a lot of the committee members around the table asking about.
And
I'm wondering if it's something inherent in our relationship to that industry
that maybe needs to change.
MS.
PORRETTA: Well, I know, I mean, in the
plant if our inspectors don't believe that the establishments and effectively
complying with these regulations, I mean, they have the authority to withhold
the mark-up inspection, which means that that product can't be released for
commerce.
MR.
BIAS: Does that happen? Are there fines, things levied?
If
I have a BSE cow, what happens at my farm?
MS.
PORRETTA: Well, we are only at the
processing establishments. FSIS does
not go back to the farm. We regulate
the plants, the processing plants, the slaughter and processing plants. We don't have authority on the farm.
MR.
BIAS: And the USDA has authority on the
farm, and you have authority in the plant, and where do the two groups meet?
MS.
PORRETTA: Well, every animal that shows
up for slaughter at our plants are inspected by an FSIS veterinarian and
observed for any diseases. Those that
have obvious diseases are condemned and don't go into the establishment and
aren't slaughtered for human food.
CHAIRPERSON
PRIOLA: Dr. Khabbaz.
DR.
KHABBAZ: Yes, I'm just curious with
regard to the regulations that you highlighted and the additional policy
recommendations from the International Review Subcommittee. What are the Canadians doing? Are they doing the same, more, less?
MS.
PORRETTA: Yes. We tried to make our regulations consistent
with what Canada had implemented, and the list of SRMs are consistent with the
Canadian list.
DR.
KHABBAZ: So they're the same. Thank you.
CHAIRPERSON
PRIOLA: Dr. Egan, would you like to
make a comment?
DR.
EGAN: Yes. From the Office of Vaccines at FDA, I was going to ask a similar
question whether with the exception of the distal ileum, SRMs are defined only
for cattle greater than 30 months of age.
Is this the same definition that's used by Canada and other countries,
that SRMs are only defined among the cattle greater than 30 months of age, or
is it for other ages?
MS.
PORRETTA: No, for the materials that we
are designating as SRMs for cattle over 30 months of age, they are the same
ones that Canada has designated. In
Europe they use 12 months for most of the countries as the cutoff, and the
Advisory Committee recommended that we consider that, and we said that's
something we will be analyzing.
CHAIRPERSON
PRIOLA: Dr. DeArmond
DR.
DeARMOND: It's a question for Dr.
Ferguson. Following up on Dick
Johnson's question, there were these young cows in Japan, and I think there
were some other unusual cases, but I haven't seen the data or looked at any
reports on them, but I understand that the pathology and the distribution of
protein was different than standard BSE; is that correct, or can you enlighten
us on any of the pathology on those?
Is
it U.S. BSE or something else?
DR.
FERGUSON: I can tell you sort of. Well, I can tell you the information that we
have, which is extremely limited, and I would like to make that point, that
it's extremely limited, and there are a lot of unanswered questions about those
cases. Probably the Japanese need to be
the ones to answer that question.
What
we had seen are essentially electronic digital images of histopath slides, and
actually Al has seen these also. You
really can't even quit tell exactly where they're from, you know. What section of the brain are you looking
at?
And
then again, digital images of the Western blot test that they had run. You know, just looking at those images of
the blots, yep, there could be something there, but we also don't have
information on what type of process did they go through to perform that
blot. What exactly is going on?
So
there are a lot of unanswered questions, and I think there are a lot of
unanswered questions in the international community about those. You know, you compare that to what the
Italians have recently done in the papers that they have published, you know,
in regards to a new strain of BSE where they have lots of information, and they
have sectioned the entire brain and, you know, look at all of this, and it's a
very valid case.
But
there are still questions about the Japanese situation.
CHAIRPERSON
PRIOLA: One last question from Dr.
Bracey.
DR.
BRACEY: This question is more or less
for my own peace of mind. Knowing the
situation with the Japanese and the findings that they have, knowing that if
you slaughter 35 million cattle a year that, indeed, the cost would be
prohibitive, I guess I wonder is it truly impossible to test animals, thinking
about economies of scale. As you
increase the testing the cost will come down.
The Europeans have said, "No, you needn't do this," but it
sounds like there's a lot of uncertainty, and I'm just wondering. What is the determination that we've made
that says that we cannot possibly test all animals? Is it cost? Is it
inability to have a throughput? I mean,
has this been carefully analyzed?
DR.
FERGUSON: Well, I don't think anybody
has said we cannot do anything. What we
have said is there are lots of options out there, and we are evaluating those
options.
However,
talking about, you know, testing every animal, I think what you need to do is
determine what you want your testing scheme to accomplish. What are you trying to do with that scheme?
Once
you set that goal, then you build your surveillance scheme around that goal,
and the points that need to be considered in going into that goal are: what do you honestly think the risk is in
the U.S.? You know, where, based on
science, where do you think you're going to find that risk?
And
you know, the point there is in younger animals what the science tells us is to
have disease, you know, sufficient either to have clinical disease or to get a
positive test result in an animal less than 30 months of age, you have to have
a pretty hefty dose given to that animal at a very young age. Do we honestly think that that happens in
the U.S.? You know, and if so, what are
we doing differently if we're going out and testing animals?
Those
are all of the types of things that need to go into that decision about this is
what we want our surveillance program to do.
Once you make that decision, this is what we want it to do.
Then
you look at the logistics of how you do it and, you know, how you set it up.
You know, whatever can be done, I mean, it might take significant
dollars; it might take significant restructuring of our infrastructure. Again, it depends on what do you want it to
do.
CHAIRPERSON
PRIOLA: I'll tell you what. Let's again save some of the questions for
the general discussion so that we don't go too far, much more over time.
Thank
you, Ms. Porretta.
Again,
keep your questions in mind and we'll get to you.
Our
next speaker is Dr. Stephen Sundlof.
DR.
SUNDLOF: Thank you.
I
want to express my appreciation for the opportunity to speak here today and
talk a little bit about what the FDA's responsibilities are on the animal side
on this issue. You have heard from the
USDA, and there is an FDA component, and I want to talk a little bit about
that.
We
should move through this fairly quickly.
I only have four slides. So if
we can go to the first slide, please.
We've
had a ban in effect since 1997 on the feeding of certain mammalian proteins to
cattle as a measure to present the spread and amplification of BSE. We consider this to be one of our firewalls,
the third of three firewalls, the first one being preventing the importation of
any materials or live animals that may possibly harbor the infectious agent
into the United States.
The
second one that you've heard about from USDA/APHIS and Lisa Ferguson, in
particular, is the surveillance program to detect the presence of the disease
in cattle should it occur in the United States.
And
the third firewall is to prevent the spread and amplification through the
prohibition of any infectious or potentially infectious material that may get
into animal feeds.
Now,
since this disease is only spread among cattle through contaminated feed, we're
fortunate that, in fact, we have one choke point where we can really gain
control over this.
So
in 1997 we promulgated a rule that said that no mammalian protein can be used
in the feed of ruminants, which include cattle, sheep, goats, and certain other
animals. There were some exceptions to
the rule. Milk and milk products were
exempted from the rule because the data had indicated they were not capable of
transmitting the disease. Blood and
blood products, gelatin.
We
also said that if a rendering firm, for instance, only renders swine or horses
and no other animals, then since there have never been any TSEs reported in
those animals, then those products could go into ruminant feed, but if there
was any mixture of any other animals, then that couldn't happen.
So
that, and then the final exemption was plate waste, and that consists of
salvage from the restaurant, food that was presented for human use had been
cooked, presented for human use, and then not eaten. There are firms that come and collect that material, reprocess
it, and part of that can go into animal feed.
We exempted that practice as well.
Next.
I
will tell you a little bit about what we are proposing, but just to talk
somewhat about our inspection program, one of the things about having
regulations is they're only as good as your enforcement strategy, and we spent
a lot of our resources, about $20 million a year in programs that are designed
to inspect all of the firms that handle this prohibited material. That would include renderers, feed mills,
protein blenders, and a few other industries.
Every
one of them in the United States that handles those materials gets inspected on
an annual basis.
We
also inspect a large number of other firms, some of which don't handle the
prohibited materials and others, such as on the farm cattle feeders. There are approximately a million cattle
feeders in the United States, and so it's impossible to get down to that
level. So we concentrate our
enforcement efforts at the top of the pyramid, the rendering industry being at
the very top of the pyramid, and then from there on down it is the feed mills.
This
is the total number of inspections to date, 26,000 inspections, which consist
of more than 13,000 firms or facilities that were inspected. The reason that that's a different number
from the total inspection is because we go back to firms on a regular basis.
Of
those, all of those firms that were inspected of the 13,000, approximately
2,000 actually handle the prohibited material, and as of January 20th, there
were only five firms in the United States that are currently out of compliance
on their last investigation or in their last inspection.
And
so we have been talking about a 99 percent compliance rate, and those are the
numbers that lead us to that conclusion.
Next.
We
also announced the Secretary of Health and Human Services, Secretary Thompson
announced on January 26th that, in addition to the feed rule that was passed in
1997, that we will remove some of the exemptions that currently existed.
One
of those would be blood products. We
are proposing to prohibit the use of basically it's ruminant blood products in
the feed of ruminants. It says
mammalian, but if you read the definition of mammalian in the Federal
Register, we have redefined pure swine and pure horses as no longer
mammals.
(Laughter.)
DR.
SUNDLOF: So it gets a little bit
confusing, especially if you're a biologist.
We've
also moved to prohibit the use of poultry litter in cattle feed. This is a practice that occurs mainly in the
southeastern United States and not many other places in the United States, but
it is a relatively common practice.
The
problem there is that prohibited protein can be used in poultry feed and the
poultry feed gets spilled in the litter and the litter gets fed back to
cattle. That is a potential hole in the
firewall.
We
also have removed the plate waste exemption.
Once again, that was an area of potential vulnerability, and the final
announcement, the final measure is to require dedicated facilities if, for
instance, renderers or feed mills handle both ruminant protein and non-ruminant
protein in the manufacture of feeds.
There
is always some amount of cross contamination that can't really adequately be
prevented in our view without requiring either dedicated facilities or
dedicated production lines, plus some barriers to prevent any
cross-contamination or carryover.
And
so those are my remarks. Thank you.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Sundlof.
Dr.
Linden.
DR.
LINDEN: Could you please elaborate on
the rationale for removing the plate waste exemption and how we have food
that's suitable for human consumption that would then not be suitable for
animal feed?
DR.
SUNDLOF: Okay. Yeah, we get that question a lot, and thank
you for asking it because it seems to be a big source of confusion. I can tell you we also get the question on
blood and blood products.
Remember
that cattle are exquisitely sensitive to the infectious prion protein, much
more so than other animal species, including humans. The recent information that we've gleaned from the expert
committee is that as little as ten milligrams, an oral dose of ten milligrams,
can cause a disease in cattle. So
there's a very large species
difference. We also don't allow cattle
to eat anything that is muscle-related.
So we don't allow cattle to eat the same products that go into the
making of hamburger and get rendered into cattle feed. We don't allow that either.
So
there are clear scientific reasons why we prohibit certain products from cattle
but yet allow those products to be used in human food.
CHAIRPERSON
PRIOLA: Dr. Wolfe.
DR.
WOLFE: At the risk of sounding like
someone who's talking about the part empty glass instead of the part full
glass, given that the vector for this whole mess in Britain was recycled cow
parts or recycled animal parts, we and others have said and agree that the main
focal point in terms of prevention has to be the ruminant feed ban, and you
list on your slide there five places that were significantly in violation, and
you know, whereas that looks fine, 99 percent okay, any one of those -- I mean,
right now we do not have indigenous U.S. BSE cows. The one here is from another country, but one of those could
easily have caused, because it was found in violation after it had been
violated, could easily have caused in the right circumstances some cases of
BSE.
But
my question is simply what kind of sanctions are there against those five and
(b) what further is being done. I mean,
the GAO put out this report two years ago criticizing the ruminant feed ban
enforcement. I'm just wondering what is
being done to sort of get that number down and to really terrorize, which is
what it should be, violators out of doing that by becoming one of the five,
well, too bad. I mean, the damage that
could be done by that is just extraordinary.
DR.
SUNDLOF: Well, those are very good
questions, and just to let you know that since the GAO report has come out,
those numbers have really gone down. We
were at about 25 percent of the industry that was not in compliance, and we're
down to less than one percent, and just for a little bit further clarification
and then I'll get right to your point, it is that of those five firms that are
out of compliance, none of the material from any of those plants went into
cattle feed. They were producing their
product under conditions which could have allowed it to go into ruminant
feed. Fortunately, I think four of the
five were producing poultry feed, and they weren't labeling their product
appropriately. So that it could have
gotten diverted somehow. It could
have. I mean they were selling to
poultry producers.
But
your point is well taken. We have taken
a number of enforcement actions. We get
the question a lot: why aren't you
taking more enforcement actions? And my
answer is, we have five firms so that there's not a whole lot, you know, that
we can take because we're only dealing with five firms.
We
have one firm that is under a court-ordered injunction right now. We have done 47 recalls of animal feed which
constitute over 280 products. These are
at the expense of the feed mills that produce them.
Those
recalls are not isolated to small geographic areas. We've recalled all the way from the Middle East because these
products move in commerce very quickly, and they move all over the world. The United States produces 60 percent of the
animal protein in the whole world. So
it is a marketable commodity, and to the extent that we have the authority, we
prosecute.
You
know, again, we have a graded enforcement policy in which there's first a
warning letter followed up by more serious sanctions. Again, we do have one under court-ordered injunction, but I think
the real disincentive, the real disincentive to the industry is not so much the
FDA, but the fact that nobody buys their products anymore. We have had some examples where a feedlot
accidentally fed some meat and bone meal.
Not only could they not -- The feed company ended up buying the 20,000
animals, but it got worse from there.
Nobody, no renderer would take the animals. It cost them millions and millions of dollars in the long
run. So there are some built in
incentives as well, but the point is well taken.
CHAIRPERSON
PRIOLA: Dr. Hogan.
DR.
HOGAN: You may have said this. I might have missed it. Are those 13-some odd firms all of the firms
in the United States or is there a percentage?
And are the inspections surprise or not surprise, that is,
scheduled? And does that matter?
DR.
SUNDLOF: They are surprise
inspections. Is it the 13,000? The 13,000 represent -- they don't represent
everybody in the United States. They
represent everybody that is either a renderer or a feed mill that handles the
prohibited material. So in that sense
it is everybody.
It
doesn't get down to the individual farmers, which are a million or so, but
yeah, firms, absolutely, every one of them.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Well, so meat and bone meal
pellets or whatever are still being manufactured. What are they sold for now?
What is kind of the range of what they're sold for?
DR.
SUNDLOF: Most of the meat and bone meal
that is produced does go into animal feed, and it goes into poultry feeds,
swine feed, and pet food.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Sundlof.
Our
next speaker will be Dr. David Asher.
DR.
ASHER: Thank you, Sue.
In
previous sessions, we have just heard about a presumptive transfusion
transmitted case of variant CJD in the U.K. and a U.S. cow with BSE. The next sessions are mainly devoted to the
second event and its possible implications for the safety of FDA-regulated
medical products.
We
have asked two speakers this afternoon to present general BSE related risk
assessments, and then tomorrow for the staff from several or our FDA centers to
address the potential risk of BSE agents to specific classes of regulated
products in responses of the agency in attempting to manage those risks.
Next
slide, please.
We
need no further convincing that exposure to the TSE agents in contaminated
products poses a demonstrated risk to both humans and animals. Assessing the magnitude of the risk
associated with the different products in situation is, therefore, very
important.
Next
slide.
Human
blood risk associated with donors potentially committing CJD and of greater
recent concern, variant CJD were discussed this morning and many times
previously at meetings of this committee.
Now
we turn to the risk posed by CJD, bovine spongiform encephalopathy, for animals
and humans in the USA, taking into account the recognition last year of BSE in
two indigenous North American cows originating from different Canadian herds.
First,
Josh Cohen will review the assessment that he and his colleagues performed for
the USDA to model risk for U.S. cattle, and it is infected cattle that pose the
major risk for humans because of the ubiquity of bovine materials not only in the
food supply, but also as ingredients in and reagents used to prepare drugs,
biologics, and medical devices.
Next
slide, please.
Steve
Anderson of our Center for Biologics will then discuss the risk for humans in
the USA posed by potential exposure to the BSE agent. Although he will address the possible risk to the general
population, the implications for the safety of human blood and blood products,
other human cell and tissue-derived products are clear.
Since
1987, the FDA has acknowledged that, based on an increasing number of studies
showing infectivity in the blood of animals with TSE, there was a theoretical
risk that blood of humans incubating CJD might contain the transmissible agent
as well.
Aided
by the advice of this committee, the FDA has recommended deferral of certain
donors thought to be at increased risk for CJD, and since 1999, of donors who
might be at risk of variant CJD because of substantial time spent in BSE
countries.
The
report of variant CJD in a transfusion recipient will not cause a dramatic
change in thinking by the FDA because we've taken the theoretical risk of
blood-borne infection very serious for years.
It has increased concern about maintaining the safest possible human blood
and similar products while assuring an adequate supply.
In
view of the recent TSE-related events, we have asked Steve to reevaluate the
risk of potential human exposures to the BSE agent.
Next
slide, please.
And
I'd like to thank Moira Ricketts and the WHO for this slide.
Until
recently, the FDA has had the luxury of addressing and managing the second
risk, the risk of exposure to the BSE agent through contaminated bovine
materials in medical products by recommending that most such materials be
attained from cattle in countries identified by the USDA as BSE-free.
The
FDA did that through a series of letters and guidances starting in 1993 and
informally for a couple of years before that, but now, without attempting to
judge the BSE status of any particular country, I believe it's fair to say that
there remain in the world only a very few countries with absolutely impeccable
BSE-free status that have both general high levels of human health, including
BSE surveyance programs, plus a capacity to provide the substantial amounts of
superior quality bovine materials needed to support the manufacture of medical
products acceptable in the United States.
So
what now? Now we must at least consider
the possibility of obtaining safe bovine materials from countries like ours,
where the national risk of BSE in cattle, while estimated to be extremely low,
possibly even negligible, is no longer universally accepted as being
nonexistent, and that, after all, was the conclusion reached by the outside
expert committee that was invited to review the situation by the USDA.
Our
own FDA Advisory Committee, this committee, has previously discussed a similar
situation. In 1999, you suggested that
it should be possible to obtain material from U.S. sheep and goats safe enough
to use for manufacturing injectable products even though our country is not
scrapie free.
Next
slide, please.
The
first step in rational risk management should be risk assessment. For those of you here today who are, like
me, consumers of risk assessments rather than professional risk analysts, I was
asked to explain briefly in more or less ordinary English what quantitative or
probabilistic risk assessments are with their advantages and limitations, and
I'll try to do that.
After
doing that, I'll review possible ways to reduce the risk of transmitting TSE
agents through medical products, including a reminder of the general safeguards
against BSE exposures provided by regulations and policies of the USDA and
FDA. FDA has called those the BSE
firewalls, the safeguards already in place to protect humans and animals and,
of course, protecting animals from infection is arguably the single most
important step in protecting humans from exposure to the BSE agent.
And
there have been enhancements recently announced. Our previous speakers have just done that, but perhaps it doesn't
hurt to repeat.
I
oppose the talk by offering for the purpose of stimulating later discussion
only, not as a proposed policy of the Food and Drug Administration, some
possible additional safeguards that might be considered for bovine materials
used in or to manufacturer medical products.
If
additional safeguards are indicated for medical products, those should be
considered seriously only if they are likely to be both necessary and effective
for significantly improving product safety and practically feasible for
implementation because many of the medical products involved are clinically
very important so that continued adequate supplies must be available.
Next
slide, please.
Risk
assessment is often thought of as comprising three elements: assessment, management, and
communication. Our two speakers this
afternoon will assess, and tomorrow FDA staff will discuss regulatory efforts
to manage risk. We won't directly
address risk communication at this meeting, although perhaps we should.
Risk
assessment has been described generally as including four steps: identification of potential hazards,
characterization of the hazard, that is, attempting to understand the
quantitative relationship between the magnitude of the exposure, and the
frequency, possibly the severity of the adverse events caused, the so-called
dose response.
Then
estimation of the probable exposures to the hazard that might be expected in
the population, and finally for information generated by the last two steps, a
probable overall risk can be characterized or estimated.
Next
slide please.
In
assessing the risk of exposure to infectious agents in products, three elements
are generally considered. The first of
these is the source material or raw material, the risk that the material might
be contaminated with an agent, and of course, materials from cattle that have
never been exposed to the BSE agent should, absent some opportunity for later
contamination, carry no risk at all for containing the agent.
The
second element of risk is the manufacturing process, which may or may not have
the potential to eliminate accidental contaminating agents either by
inactivation or by physical removal of the agent, which then must be disposed
of.
Some
injectable products -- gelatin might be an example. You reviewed that the last meeting -- are highly processed, that
is, exposed to chemicals like calcium hydroxide and heating that remove a
substantial amount of TSE agents. Many
plasma derivatives -- Dot Scott will review those tomorrow -- are highly
processed by chemical and physical treatments that have a validated capacity to
eliminate TSE agents from the final product.
Other
products, like human red blood cells and live attenuated viral vaccines are
delicate and cannot be harshly treated.
A theoretical risk of processing also exists, the risk that an agent in
the raw material might either bind selectively to some component incorporated
into the final product or, as recently demonstrated by our committee, the
Chairman and her colleagues, for cultured mouse fibroblasts exposed to strains
of scrapie agent. The agent might even
replicate in the cell substrate used to prepare some medical product. Fortunately, that has never been recognized
to happen with cell substrates used to make medical products.
The
third element of microbiological risk for products is the end use of the single
dose volume, the total volume per course of treatment and lifetime use, and the
route of infection.
Parenthetically,
the easiest and most effective way to reduce risk by control of end use is
probably to avoid inappropriate use of medical products.
Next
slide.
A
number of factors should be considered in assessing the risk of infection after
an exposure to the infectious agents of TSEs.
Years ago, Richard Kimberlin introduced the term "effective
exposure to a TSE agent," meaning an exposure sufficient to infect an
animal.
The
factors resulting in such an effective exposure, and they are not really
different from those affecting infections with other more conventional agents
are the dose of agent, the route of exposure, and the susceptibility of the
exposed host to the agent.
For
discussion today, it's important to note that invasive exposures, introduction
into the CNS or bloodstream or peripheral tissues, usually require less agent
to infect, and injectable and implantable medical products are intentionally
introduced into the body by invasive routes.
The
last factor is host susceptibility.
There is a so-called species barrier that doubtless conveys to some
hosts a relative or even absolute resistance to infection with certain TSE
agents adapted to other species.
However,
one especially painful lesson of the BSE epidemic in the United Kingdom has
been that the species barrier is variable, not always predictable, and not
necessarily absolute. The species
barrier may have protected people and their cats against infection with the
scrapie agent, but it has not been completely effective in protecting both
those species against infection with the BSE agent.
Next
slide, please.
Now
I want to introduce quantitative or probabilistic risk assessment, the kind of
assessment coming up next. Such risk
assessment's attempt to express risk as an overall probability by proposing
scenarios, a series of steps or, perhaps better, missteps, a chain of accidents
or system failures that must occur before an adverse event results, like, for
instance, a human infection with a TSE agent.
The
probability for failure at each step in a scenario is estimated, and then the
final probability is toted up. For an
assessment to be most reliable, quantitative data should be available to
estimate the probability of failure at each step, and it can be very hard to
estimate the probability of even simple failures.
For
example, the rupture of some mechanical item like a rubber O ring, although
search of quality control records or articles from engineering journals might
help with that. It's even more
difficult to estimate the probability of some infrequent biological event, for
instance, the probability that single
cow has been exposed to the BSE agent.
An
assessment should take into account biological variability. For example, the possible variations in BSE
infectivity content in tissues from one infected cow to another, and
uncertainty, the many things, some of which we've heard about today, about BSE
and variant CJD that are imperfectly understood.
One
way to do that is by avoiding the temptation to estimate the probability of
failure at each step as a single number, and instead to use reasonable ranges
or distributions of probabilities.
Doing that is often found annoying because we prefer to see simple
estimates of what a risk is, rather than distributions of possible risks that
might be, but the latter is clearly more realistic.
A
well-constructed quantitative risk assessment has a number of advantages, one
of which is that it allows a sensitivity analysis.
Next
slide, please.
Not
all quantitative risk assessments are structured in this way, but here's a
brief, general description that may help to understand the general idea. Each failure step or assumption is described
and assigned an estimated probability or, better, a distribution of
probabilities. The probabilities for
each assumption are varied, and then a series of final outcomes, final
probabilities for the adverse outcome are computed.
When
the failure pathways are multiple and complex, the number of combinations of
probabilities for failure at each step is huge. That's why sophisticated risk assessments require special
computer models, the concentrated efforts of institutions like the Harvard
Center for Risk Analysis, and a long time to develop.
One
major benefit of a well-constructed, probabilistic risk assessment is that it
permits a sensitivity analysis that is systematically varying the probability
of each step individually to see which steps have the greatest impact on the
final likelihood of diverse outcome.
Such an analysis answers the question, what might happen if the
probability of some failure step has been seriously underestimated or over
estimated and suggests the most effective actions to consider for risk
management.
For
example, the Harvard risk analysis identified ruminant feed controls as having
a great benefit in reducing risk, although that was also the intuitive
conclusion based on U.K. experience.
Next
slide, please.
The
greatest single advantage of quantitative risk assessments probably lies in
their transparency. Other risk
assessors can examine the underlying assumptions and scenarios used, and if
they disagree they can change them, put them back into the model, which is
usually made available and then compute the new results.
They
also have a couple of weaknesses. If
the data used to estimate the probabilities are not reliable, then the
estimates may not be, and they must assume no surprises. Well, while we know that life is full of
surprises, but ordinary nonquantitative risk assessments and expert opinions
suffer from exactly the same weaknesses.
In
my view, the single greatest weakness of probabilistic risk assessments is that
they may appear to be more accurate than they really are. Presenting subjective probabilities as
numbers with estimated uncertainties make them look very much like mean values
with standard deviations, and they certainly are not.
Next
slide, please.
A
popular risk assessment used for medical products containing bovine components
is one developed several years ago for PhRMA by Fred Bader and his colleagues. The FDA used it to estimate BSE risk for
vaccines almost four years ago.
And
I summarize here on the left side some of the steps by which the probability of
BSE contamination of some material can be estimated, as well as the probability
that a single dose or a total dose of the treatment with some hypothetical
product might contain a human infectious dose.
The
original model used single point estimates and did not account for biological
variability or uncertainty, and I listed some of the uncertainties in the
right-hand column to consider the next time that the model is used, but the
model is transparent, and it is or at least it originally was made available to
anyone who wanted to modify it. I know
at least that was Fred's original intention when he developed the model.
The
next slide, please.
One
problem associated with all risk assessments is that they are susceptible to
bias because the probabilities of failure at each step are assigned at least
partially subjectively, and I list on this slide some of the common sources of
bias.
But,
again, nonquantitative risk assessments and expert opinions are subject to the
same biases without the same transparency.
One
way in which bias of a risk assessment may be balanced is to submit it for
independent review by other risk analysts and to run it again using their
assumptions. The Harvard BSE risk
assessment was, I believe subjected to such an outside review.
Next
slide, please.
Now
I'll address the possible steps to reduce the risk of transmitting TSE agents
in general and the BSE agent in particular through medical products. Assuring that animal-derived or
human-derived source materials are free of contaminating agent serves to reduce
risk, and that can be done in two ways:
First,
by obtaining the material for animals or humans with a history suggesting a
very low TSE risk. For human blood and
plasma, that's controlled by donor questionnaire and deferral policies. For human tissues, by history, usually from
a surrogate respondent post mortem.
For
bovine materials, safety of sources probably has to be controlled by
certification that all safety policies had been maintained. For some infectious agents, safety of source
material can also be assured using a screening test, either a direct test for
the presence of the agent in the material or by some surrogate test, most often
an antibody test, as evidence that the host has been infected.
Unfortunately
there is still no accessible and validated antemortem screening test for BSE in
cattle or for any TSE in humans. Why
not simply eliminate the problem at the source by removing potentially infected
bovine-derived or human-derived material, replacing them completely with
vegetable or synthetic reagents?
That
certainly should be encouraged when feasible, but it's most appropriate during
the initial development of a new product.
For some established biologic products, including important vaccines,
it's probably not feasible to replace traditional bovine components like fetal
bovine serum. Even a one log drop in
the yield of virus, something that might easily happen if calf serum were to be
replaced with some synthetic substance in cell culture medium, a drop of that
magnitude would probably be enough to render the modified product unusable.
Next
slide, please.
Manufacturing
methods that eliminate agents' contaminating source material can provide
additional protection. Inactivation of
agent is preferred to physical removal because of a theoretical risk for
downstream recontamination of the product after the infectious agent has been
removed.
In
that regard, as this committee discussed during its last meeting, effective
cleaning and decontamination of equipment and facilities used to manufacture
medical products are also important.
Tomorrow
Dot Scott will review these issues for the manufacture of blood products, but
the same general risk reducing steps in the manufacturing products are also
relevant to other medical products.
I'll leave to Dot further comments on what constitutes acceptable
validation of the ability of various single manufacturing steps to reduce
infectivity, evidence required to accept the additivity of multiple steps based
on different physical chemical principles, and the relevance of results from
pilot studies to the full-scale manufacturing process.
We've
also reviewed those issues here in the past.
Next
slide, please.
One
troubling question that frequently arises is this. Why spend so much effort in attempting to reduce risks that
appear to be extremely small for products that have enormous benefits? I cannot pretend to understand the
psychology of risk perception or management decisions, but over ten years ago,
M. Granger Morgan, a well-known risk analyst, explained it this way in a Scientific
American article.
In
making risk-based decisions, people may operate using different sets of
rules. The decision rules we ordinarily
use or we think we use might be called utility-based. Estimate the benefit and the risk and accept a small risk to
achieve a substantial benefit, but there is another set of decision rules that
we may also be using, and those might be called technology-based rules.
Technology-based
rules impel us to use the best available technology to reduce some small risks
even further even when the cost of doing them is great. We are especially likely to require best
available technology when trying to protect certain especially- vulnerable
populations like healthy children too young to give informed consent and
required to be vaccinated in order to attend school.
We
want to afford children every possible protection and to maintain a high level
of confidence by their parents. So we
take extraordinary steps to reduce risk in products administered to them.
Next
slide, please.
The
BSE firewalls, a series of safeguards put in place by the USDA and the FDA and
enhancement to those protections have already been summarized for you. I tried to list them together on this slide
as well as reference to the series of guidances that we believe have further
reduced risk issued from the FDA during the past ten, 11 years.
I
also show here the agency responsible for them and the year the safeguard went
into effect. At the bottom of the slide
are the two planned enhancement to FDA regulations. The concept is that although no single safeguard against BSE is
likely to be foolproof, taken together they should provide a very high degree
of protection, reducing both the likelihood that cattle are infected, and if
they are, that humans will be exposed to the infectious agent.
Several
of those safeguards, those intended to reduce the risk of BSE agent infected
cattle and contamination of low risk tissues with infected tissues should also
reduce the risk that bovine-derived materials infected with BSE agent would
enter the manufacturing process as used for medical products.
As
I mentioned earlier, we might consider whether the bovine- derived materials
used to manufacture injectable and implantable medical products, products
administered by routes known to facilitate infection might require additional
safeguards. In the past the FDA has
recommended a special safeguard for bovine gelatin used in injectable,
implantable, and ophthalmic products in addition to those safeguards for
gelatin in oral and topical products.
So
there is at least one precedent for such a special policy for medical
products.
For
purposes of discussion only, on the next slide are listed several possible
additional safeguards -- next slide, please -- that might be considered if
they're judged to be both necessary and potentially effective in maintaining
safe medical products and are found to be feasible in practice.
We
are interested in hearing opinions of the committee members about those and any
other related issues.
At
the last meeting it became clear to us that the concept of a closed herd of
cattle remains without any consensus definition. So perhaps it would be more useful to consider instead whether
medical products might be prepared using bovine-derived materials from cattle
originating from some kind of select herds and perhaps select individual cattle
and select tissues as well.
It
appears that the United States is already moving towards some system of
improved traceability for cattle.
Perhaps it is not premature to encourage full traceability for select
cattle use for medical products even before that is required for all cattle.
It
is clearly desirable that select cattle have never been fed or otherwise
exposed to prohibited materials. How
might that be reliably certified? It
certainly could not be certified unless the animals were fully traceable.
It
would be even more reassuring if certified select herds had adequate
surveyance, as well as active surveyance as well as passive surveyance for BSE,
but how should the adequacy of a BSE surveyance program be evaluated?
Should
there be additional firewalls for selecting cattle suitable for producing
materials used in medical products, safeguards besides those already in place
to maintain the safety of edible beef products? Is that really necessary when the risk seemed so small? If it is justified, what might those
additional safeguards be?
Should
we recommend using the products from cattle only younger than 30 months? If so, how much younger? Fetal calf serum, which is arguably a very
low risk material is obtained at slaughter from the fetuses of older breeder
cows. So age restrictions of that kind
for such cows would be unfeasible and probably unnecessary.
Should
removal of specified risk materials from younger select cows be required? If so, at what age? And you've just heard that the USDA outside
subcommittee recommended that most specified risk materials be removed from
bovines older than a year in intestines at all ages.
Should
a test for abnormal prion protein be required for some cattle? If so, starting at what age? What tests should be used?
The
USDA has not approved any rapid PrP test for use with bovines yet. It would certainly not be useful to test
brains of very young cattle because specimens from cattle of that age have
rarely, if ever, contained detectable abnormal PrP even when they came from
animals infected with the BSE agent.
At
any rate, we welcome a general discussion of those and other issues relating to
BSE risk and the safety of FDA regulated medical products.
Last
slide, please.
With
that, I thank you very much, and I surrender the microphone to our next
speaker.
CHAIRPERSON
PRIOLA: Thank you, Dr. Asher.
Are
there any questions or comments for Dr. Asher?
Dr.
DeArmond.
DR.
DeARMOND: Several times you asked, are
the safeguards necessary when the risks are so low, and for the small
pharmaceutical company they're absolutely necessary, and again, I talk to a lot
of them because one mistake, one traceable event that was related to a product
they put out wipes out the company.
It's gone, and so it's only because of our litigious society that the
risks of having any medical procedure can destroy companies, as we saw with the
silicon breast implants.
So
I think it's a real risk to a lot of people who were involved in their
livelihoods and so forth, even though the risk is very small to the individual
population. In the quantitation of risk
assessment, very little is placed upon importation of beef, although there was
some alluding to it, and yet that was the main problem here in December. It was a cow that came in and some cows that
came in from Canada.
Should
those be treated differently? Should
those be tagged somehow with a subcutaneous implant that can be followed anywhere
so that we could understand which cows actually did come from other
countries. So mostly it's kind of that
second issue. What about importation?
In
this, the United States tends to be a free trade type of country with a lot of
trading partners. If we just were very
strict about following a cow from a friendly country like Canada, should we do
that so that we can continue to trade with them?
DR.
ASHER: Someone, Lisa, might answer
this. The likelihood of importing
actual identified contaminated bovine products, identified bovine products, I
think, has been relatively small since the import prohibitions on ruminant
products from BSE countries were put into effect by the USDA.
Now,
the importation of products containing bovine materials that are unknown to the
importer and to the USDA is another issue, but of course, in controlling the
source importation, as well as internal controls are very important.
At
the moment, of course, we're left with only two countries in the world that are
considered impeccable BSE-free countries and also have sufficient capacity and
general level of animal health to provide the United States.
To
me, one of the problems is going to be as we deal with a changing view of the
situation in our own country is keeping consistency with other countries. Obviously I can't comment on specific trade
policies with regard to Canada. I
believe -- Lisa may correct this -- that boneless beef is now, at least from
younger animals, is now permitted into the United States. Other bulk products are not.
The
level of concern with regard to Canada was, I think, revealed at the last TSE
advisory committee when it was made clear that we weren't proposing any new
blood donor deferral policies for Canada, and there have not been substantial
changes in importation of medical products from Canada that I'm aware of,
although there has been some concern about that.
DR.
DeARMOND: And yet a lot of the new
regulations and restrictions on use of bovine products is a result of the
events of December 23rd. It has nothing
to do with what was going on in the U.S.
It was what was brought into the U.S.
DR.
ASHER: Yeah. Well, the concern with Canada, of course, arose on May 17th with
their recognition of BSE in a breeding cow.
To me one of the greatest concerns is that there have been two different
herds, albeit both in Alberta, that have been implicated in BSE, and in
Canada. Fortunately both of those are
born before the feed ban so that there's still some hope that the feed bans in
Canada and the United States, which are arguably inside the country the single
most effective disease control mechanism might have -- they should have --
reduced the risk markedly, although it is one of multiple firewalls, and
they're, of course, not foolproof. That
was the impetus behind the enhancements that are planned for the feed ban.
DR.
DeARMOND: I only make these comments
because we saw lots of slides, lots of risk assessment and very little about
importation.
DR.
ASHER: Yes. Well, you're absolutely right.
In insuring the quality of the source, the importation is very
important, and that's why we stopped importing from BSE countries as soon as
the magnitude of the problem became clear.
CHAIRPERSON
PRIOLA: Okay. Thank you very much, Dr. Asher.
I'd
like to just reinforce, I think, to the committee that what Dr. Asher just
discussed is sort of at the heart of what we're supposed to be considering and
discussing today, and that is looking at the adequacy of the current safeguards
and then based on the scientific merit trying to determine the risk benefit and
feasibility of any additional safeguards that might protect products regulated
by the FDA.
Now,
we're running a bit behind time. Dr.
Asher's talk was actually scheduled for 30 minutes, but we're running behind
time. So my question is this: should we go on through or should we take a
ten-minute break? This will be the only
thing the committee will vote on this committee meeting.
(Laughter.)
CHAIRPERSON
PRIOLA: What would you prefer do? A ten-minute break?
Okay. We'll take a ten-minute break and reconvene
at ten till four.
(Whereupon, the foregoing matter
went off the record at 3:44 p.m. and went back on the record at 3:59 p.m.)
CHAIRPERSON
PRIOLA: Okay. If we could get all of the committee members back at the table,
we'll start with the next presentation, which is Dr. Joshua Cohen, and since
these next two presentations are both associated with risk models, maybe we'll
do the two talks and then ask questions after both talks have been completed.
So
if Dr. Cohen is ready.
DR.
COHEN: Well, I'm glad Dr. Asher gave a
lot of the background on some of the general issues dealing with quantitative
risk assessments, which we usually don't have the luxury of going into all of
those issues. If you can keep them in
the back of your mind, of course, it's pretty relevant to what we did.
If
you could proceed to the next slide, please.
Just
first, I want to recognize a bunch of the folks who worked on this project with
me and George Gray, who are still at the Center for Risk Analysis. We had a group of us up at the Center for
Risk Analysis, also a team of investigators down at the College of Veterinary
Medicine at Tuskeegee University.
Next
slide.
So
first some background, now, this model.
How did this come to be? Why
were we asked to do this?
Well,
USDA was interested in the following questions. First, they were interested in identifying the possible sources
of introduction of BSE into the United States cattle population. Of course, there was a good idea of what
that was, but they wanted us to go through and review that.
And
then to get more to the heart of what we were looking at, they wanted us to
identify and quantify the relative importance of pathways by which BSE
infectivity might spread among U.S. cattle.
So the real question was: what
happens once it gets here?
And
to evaluate the implications over time of possible introductions of BSE into
the U.S. agricultural system, in particular, this is how we expressed the question
was really about was this co-called reproductive constant of the disease. If you're familiar with epidemiology, this
is sometimes designated the R0 constant, and all it is is if you have one
diseased animal, on average how many more diseased animals are going to result
from that index case or any case in general actually?
If
that number is less than one, then of course, the disease tends to die out over
time. It may blow up temporarily if
something unlucky happens, but the law of averages comes into play over time
and the disease tends to die out if that constant is less than one.
If
that constant exceeds one, then of course the disease tends to grow over time,
and you can get a situation like that in the U.K. in the 1980s. So that is the real key question that we
were after.
And
then second to that at least causally is once you figure out how the disease
circulates in the cattle population, what is the extent of human exposure going
to be.
Next
slide please.
So
in terms of what the report history was, we first got involved in this in
1998. About three and a half years
later, we released the report with USDA at the end of 2001.
During
2002, the report was reviewed under an independent contract with Research
Triangle Institute through USDA, and they had some four primary investigators
on that review, including John Wildsmith from the U.K., who was intimately
involved with the U.K. outbreak during the 1980s, and the revised report was
accepted by USDA and released several months ago.
Next
slide.
So
all right. What do we mean -- well,
I'll get a little later to what we mean by a simulation model, but why did we
use a simulation model rather than using statistical analysis, such as what was
done in the U.K. by some of their investigators over there, or a qualitative
analysis, something like that?
Well,
you can't really do a statistical analysis for the United States because, well,
until this past December, there are absolutely no data, and even now there has
been only one case. So there's no
information, no quantitative information on which one can model, statistically
model the behavior of the United States agricultural system in response to a
challenge, a BSE challenge being introduced into it.
Now,
there are certain mathematical techniques that one can use rather than building
a simulation model, but first, a simulation allows you to characterize the
evolution of the disease over time, both within animals so that the disease
moves from one part of the animal to another and the disease load increases and
so on, and then, of course, through the cattle population over the years.
As
I began to say just a moment ago, BSE is not amenable to conventional epidemic
disease modeling. There are a series of
complications, and, in short, the spread depends on how and when the animal was
slaughtered, for example, and because of these particular issues that you need
to keep track of, the math just becomes intractable or at least it became too
hard for us.
Next
slide, please.
A
model allows you to quantitatively compare the importance of different pathways
by which the disease spreads, and it allows you to evaluate different risk
management strategies. You can turn
things on and off. You can say, no
specified risk material fed back to cattle or into any feed at all, and hence,
could not get back to cattle through leaks in the feed ban.
And
finally, through the use of sensitivity analysis, it allows us to identify
where we need more information to better understand how the agricultural system
would behave if BSE is introduced, which apparently it has been.
Next
slide, please.
So
what did we do? We started with the
basic model, which is that somehow -- we don't know how -- in the U.K. scrapie
may have crossed over into cattle or spontaneous development of BSE within
cattle. Somehow BSE got started in the
U.K., and then through feed and the recycling of feed the disease was
amplified, and that was the basic model we started with, and we figured that if
BSE came to the United States somehow, that would behave in a similar manner.
Next
slide, please.
So
we took that basic model, and we developed a computer model which has the
following structure.
First,
we consider the whole series of exogenous sources of infectivity that come into
the cattle population. Cattle are
slaughtered. They may die by other
means as well. Some parts of the cattle
go to human food. Some goes to feed.
That division depends on how long it has been since the animal was been
infected, again, because the disease moves from some tissues to different
tissues as the incubation period progresses.
It
depends on slaughter plant practices, and finally it depends on the animal's
age because the animal's age is going to influence what the slaughterhouse does
with the animal.
The
material that goes into feed, some of that is going to go to uses that pose no
risk to cattle in the United States, such as export, at least from the U.S.
cattle population that becomes a non-risk or to pet food, and then there's
going to be some feed that manages to get back to the cattle population through
leaks in the feed ban.
Next
slide please.
So
what were some of the key assumptions we made?
And this is very brief. The
report is available on the Web where there is a lot more detail, but in brief,
the exogenous sources we considered were imported cattle, imported feed,
sporadic disease, that is, a spontaneous development of disease in cattle with
no apparent outside source or cross-species transmission, for example, from
scrapie.
In
terms of the spread of the disease among cattle, we did assume imperfect
compliance with the feed ban. We
considered contamination of non-prohibited materials in mixed use facilities,
both rendering facilities and feed plants.
We
considered mislabeling of prohibited materials, and we considered misfeeding.
Next
slide, please.
In
terms of the infection probability, so now the material has gotten into cattle;
what's the probability that an animal is going to become sick, given a certain
dose?
We
considered changes in exposure and susceptibility with age. So, for example, young animals are often the
ones that have the greatest consumption of meat and bone meal. They also happen to be the animals that it's
believed are the most susceptible to disease just, again, because of the
biology of the animal early in its life.
In
terms of the disease course, as I've been suggesting, the agent moves from some
tissues to other tissues at the beginning of the disease process. It's in the gut and it moves to the central
nervous system over time, and while that's happening the total infectivity load
grows especially rapidly in the months prior to the development of clinical
signs.
In
terms of human exposure, we considered contamination of advanced meat recovery
products and consumption of variety meats.
Next
slide.
The
model is probabilistic, as Dr. Asher was explaining, that is, a way of taking
into account variability and uncertainty.
What's illustrated in this slide is how we took into account variation,
and here I mean variation in how history might unfold. So if you imagine infected cattle being
introduced into the United States, different things might happen over
time.
Those
animals might be slaughtered before much disease or much infective agent
develops in their body. That would be a
good thing, or you might get unlucky.
They might happen to be slaughtered at an advanced age when there's a
lot of infectivity. They might go to a
plant where there is both prohibited and nonprohibited material being processed. That material might be contaminated, or the
material might end up on a farm where there is misfeeding.
And
because of all of these different possibilities, when you run the computer
model over and over, and for each scenario we looked at we ran it 5,000 times,
different things can happen, and so you get a range of different results. So one of our key outputs, for example, was
the number of infected cattle or the number of cattle that become infected in
the United States during a 20-year history, and there were a range of values.
Next
slide.
So
this is what the output looks like, for example. So the horizontal axis is time going from zero years out to 20
years. This is the number of infected
cattle, and it's a log scale, and so when you start out in that first year,
you're almost certain to have ten infected cattle, and as time goes on
different things can happen.
These
are box and whisker plots of the output of the output of the 5,000 runs. The middle mark right here is the median
outcome. The box represents the range,
the interquartile range. So 25th
percentile to 75th percentile for this particular output.
The
whiskers are the fifth to 95th percentile, and then the Xes are values that lie
outside that range.
So
as time goes on, you get a spread.
Different things can happen, and in the worst cases -- this happens to
be an introduction of ten infected animals -- you get as many as 100 infected
animals at some point, but over time that tends to die out. On average, if you average all of these
results and add up all of the infected animals over 20 years, you get something
like four new cases in the 20-year period.
Next
slide.
Even
if you increase the number of animals introduced, the number of infected
animals introduced to 500 animals, you get a similar result. It takes longer for it to die out, of
course, but the disease tends to die out.
Now,
the important point here is that that key parameter, the reproductive constant,
R0 almost certainly seems to be less than one.
That means that we almost certainly would not get a U.K.-type situation,
an epidemic blowing up in the United States.
Could
you get additional animals infected?
Yes. Will we get a million
additional animals infected like in the U.K.?
No. It doesn't seem that way.
The
next slide.
In
fact, here's the behavior of the system in terms of what's the probability that
BSE is still present in the United
States after 20 years as a function of the number of infected cattle that you
introduce at the beginning of that period?
Well,
if you introduce one infected animal, there is only one chance in 1,000 in
these computer runs that after 20 years the disease is still present.
If
you introduce 500, the chance is as much as ten percent, but that means that
even if you introduce 500 animals, you end up with a 90 percent probability
that BSE would be eliminated if that's the only introduction within 20 years.
And
I should say that all of these introductions are hypothesized to occur after
the 1997 feed ban was implemented. Talk
about what happens if that isn't the case a little later in this talk.
Next
slide.
In
terms of human exposure, what's the total number of cattle oral ID-50s, which
is our accounting unit for looking at infectivity. A cattle oral ID-50 is the quantity of infectivity which, if
orally administered to a bovine, has a 50 percent chance of producing
disease. The risk in humans is thought
to be much, much less. Nobody knows
exactly how much less, but substantially less.
The
total number of ID-50s to humans in our base case where we introduce ten
animals was 40 ID-50s to humans over that 20-year period, and this is how it
splits out so that we also know which types of food are the most important
sources. Advanced meat recovery is the
largest source, and that's because, well, lots of people eat AMR meat.
But
this number, you've got to remember, we don't know exactly how many ID-50s went
to humans in the U.K., but it has got to be many orders of magnitude larger
than that since there were 200,000 animals there that displayed clinical signs
and perhaps a million that were infected overall, and it wasn't for many years
that the U.K. and the scientific community in general understood that this was
something that we needed to worry about in terms of human exposure.
Next
slide.
We
also looked at risk management scenarios to see how they would decrease the
number of additional infected cattle and how they would decrease human
exposure; so a ban on specified risk material.
So, in other words, we're just going to incinerate that material or
something, totally get rid of it. That
reduced the number of additional infected cattle by 90 percent. It reduced human exposure by 95 percent.
A
ban on the rendering of animals that die prior to slaughter. That was a surprising one for us. That reduced the number of additional
infected cattle by 80 percent, human exposure by only 20 percent, and that's
because these animals weren't going to human consumption anyway, but they do
potentially have a lot of infectivity because they're animals that die on the
far. One reason they might have died is
that of BSE, if they died of BSE, that means they had a full infectivity load.
Next
slide.
We
conducted a sensitivity analysis, a pretty extensive one, as Dr. Asher
described. So here are a whole bunch of
parameters that we looked at, and what we did is we looked at what happens to
the results if we take the worst plausible value for each of these parameters
one at a time in this particular slide, and the good news is that this happens
to be the result, the total number of cattle infected, excluding those ten
initial imports, and the result. Here's
the average.
And
remember in the base case, the average was around four, which is right here,
and so for most of these assumptions you put the worst case value in, and it
barely budges the result.
However,
there are a couple. This one, I think
this was -- I can't remember which one.
This is the render factor. I'm
sorry. Yeah, perhaps it's the render
factor. That's how efficient rendering
is at reducing the amount of infectivity in material that increased the
projected number of animals a little bit, like four up to six or seven.
But
the ones that made a big difference were leaks in the feed ban. When you have leaks in the feed ban, things
are not nearly as good.
Next
slide.
You
get a similar picture when you look at potential human exposure. Again, and remember, this is a log scale
over here. So a little move up in this
direction, you know, like from here to here, is a factor of ten, and so, again,
leaks in the feed ban lead to substantial changes.
Next
slide.
So
here are the key findings. First of
all, following an introduction, the incident tends to decrease over time. R0 is less than one. After 20 years, BSE is most likely
eliminated from the United States, and the results hold regardless of the
source, whether we're talking about live animals being imported, contaminated
feed, whatever.
After
you get that initial insult, the number of animals with disease tends to
decrease.
Now,
I will say the sensitivity analysis, if you put some worst case assumptions
together, especially with regard to the feed ban, you can get R0 greater than
one, but you have to make a number of pessimistic assumptions for that to
happen.
Human
exposure is limited. As I said, it
seems to be orders of magnitude less than the U.K., and here are the sources
most responsible for human exposure.
Next
slide.
The
risk mitigation measures that we looked at that seemed to be most effective
were eliminating CNS material from animal feed and human food, and stopping the
rendering of animals that die before slaughter.
The
key sources of uncertainty, as I mentioned, have to do with compliance levels
with the feed ban.
I
will say that we were coming up with these parameters in like the year 2000 or
so, and it seems just based on some of the information I've seen at this
meeting that the FDA and USDA, they've gathered some much more extensive
information about compliance, and it looked pretty encouraging to me, at least
what I saw in thee slides. So perhaps
the feed ban is in pretty good shape.
Next
slide.
I
just want to spend a few slides here. I
think it's four slides in all, talking about some work we did this past year
looking at the Canadian BSE case.
We
considered here various introductions of BSE into the U.S. from Canada, both
live cattle imports, contaminated feed imports, and we also considered
introductions from time before the feed ban.
We ran the model out through the year 2020.
Next
slide.
And
this slide describes how the results, how the number of infected cattle from
introducing five infected cattle, how the number of additional infected cattle
depends on when the introduction occurred.
If the introduction occurred here in 1998, most likely you get very few
additional animals. However, if it
occurred as early as 1990, well before the feed ban, and things had a chance to
get going when R0 was greater than one, then the number of infected animals can
be much greater, in the very worse cases even up in the area of 1,000.
Next
slide.
Human
exposure, a similar type of picture.
Again, if we are fortunate and the introduction occurred later in time,
the number of animals or the total amount of human exposure is quite limited.
Next
slide.
So
our findings were timing of introduction matters a lot. Contaminated feed produces more cases than
imports of infected animals, and that's because if you imagine five cattle
being imported and then slaughtered, well, not all of their remains is going to
go to cattle feed. Even in the era
before the feed ban was put into place, there were other uses for meat and bone
meal.
Virtually
all of the introductions -- and this is, you know, the not so happy part --
virtually all of the introductions yield too few clinical cases to be confident
that they would have been found by surveillance. So, you know, what does that mean?
Don't
forget those animals that I was showing you in those plots on the preceding
slides, those weren't necessarily all clinical cases. A bunch of them were likely slaughtered before they developed
signs. So they had disease, but there's
no way they could have been detected by surveillance.
The
introduction of the feed ban in 1997 reverses the growth and starts the
prevalence of disease towards zero. So
again, even with those early introductions, if you trace out what happens over
time, the disease goes up and then it turns around a little after 1997 and
starts heading back towards zero.
And
I think -- is there another slide? I
think that's it. That's is.
CHAIRPERSON
PRIOLA: Thank you, Dr. Cohen.
Dr.
Epstein?
DR.
EPSTEIN: Dr. Cohen, could I just ask,
if I could, have you attempted to validate the model by putting in input
parameters compatible with the U.K. to see if it predicted the bovine epidemic
curve in the U.K.?
DR.
COHEN: What we did do, we did not do
that with the U.K., but we did do it with Switzerland because there was
information that we could use there to trace what happened with the outbreak,
and with our very first shot, in other words, we did not play around with the
parameters at all. Our first guess, we
were within a factor of two of the total outbreak, which is really close in
this business, and we had the timing down really well. And with changing some parameters which are
certainly within the range of uncertainty, we are easily able to reproduce what
happened.
Now,
does that mean that the model is valid?
It certainly doesn't guarantee it at all. You know, in this business, you can easily be right for the wrong
reasons, and you can't necessarily generalize the results.
But
we felt that it at least gave us comfort that the model wasn't completely out
to lunch, and we're not either, I guess.
CHAIRPERSON
PRIOLA: Dr. Linden.
DR.
GAMBETTI: I wonder whether you can
clarify for me this statement that you have in the findings. Virtually all intervention into too few
clinical cases to be counted, that they will be found by surveillance.
Now
we know that by testing what is ten percent of the highest risk animal, one was
found. So in view of this, you would
say that your model is not valid anymore or has to be corrected for this
finding?
DR.
COHEN: No.
DR.
GAMBETTI: Can you explain it for
me? Probably I missed something
somewhere.
DR.
COHEN: All I meant by that is that ex
ante, so before December when all we knew was there were cases up in Canada or
a case up in Canada and there were a lot of cattle moving across, there could
be an introduction in to the United States.
If that happened, would we know that it happened?
In
other words, if it happened and our model correctly predicted what happened,
would we be guaranteed of finding it?
And
the answer as far as we could tell was, no, we couldn't be absolutely sure that
we would find it. Does that mean that
we absolutely wouldn't find it? No.
Now,
actually if I can just take this moment, I want to say one thing about that
animal that was discovered because I've gotten a lot of calls, especially from
the media, people trying to figure out, well, what does this mean in terms of
the total number of animals in the U.S. that might have BSE.
And
I'm sure that's something that's on a lot of people's minds, and it's very hard
to say. As Lisa Ferguson said, the purpose of the
surveillance is not to nail down exactly how many animals are infected in the
United States. It's to detect a certain
number.
But
you know, that said, I think someone in the meeting said, "Well, if we
tested ten percent of the animals and one was sick, does that mean that there
must be around ten?"
Well,
that depends on extrapolating from this animal to the rest of the 200,000
nonambulatory animals that are slaughtered each year, and there are problems
with that. This animal may be at
particularly high risk because it was born before the feed ban.
Now,
I don't know what the distribution of ages is among other downer cattle, but if
they tend to be younger, then they would, I think, tend to be at lower risk,
but that's just sort of a, you know, don't hang your hat on that. I just want to say that extrapolating from
that one animal to a total number in the United States is tricky business.
DR.
GAMBETTI: Well, wouldn?t it make sense then to test all of them so
eventually you know?
DR.
COHEN: Well, I think, first, you know,
I completely agree with what Lisa said.
What you have to do first is figure out why are you doing this, and if
your purpose of doing this is to figure out what the prevalence is, then you
have to have a plan for figuring it, for nailing that number down.
But
then you have to ask yourself, well, why do you want to know the exact
prevalence. I mean, isn't it good
enough to know that the disease is here at some modest rate and based on that,
we are taking these steps?
If
we knew that there were ten animals or 100 animals, would that change the risk
management actions that FDA is taking already?
I don't know. We're not in the
risk management business. I just throw
that out as the type of question that, you know, folks like you and FDA need to
be thinking about in terms of trying to figure out, well, what's the right way
of going about surveillance.
CHAIRPERSON
PRIOLA: Dr. Linden.
DR.
LINDEN: Thank you.
Did
you look at your key assumptions and attributes of the U.S. system to question,
try to determine which of those were most significant in contributing towards
the R0 being less than one in terms of like the feed ban, for example? I.e., if we had not had that, if you took
that out of the equation, would we have been at risk? Does your model then turn out to have us be in the same situation
as the U.K.?
I
mean, did you try that modeling using a different set of assumptions and see
what happens?
DR.
COHEN: During our original project,
well, actually there were some scenarios that we ran without the feed ban, not
necessarily to see what would happen without the feed ban, but because the
scenarios we were running just historically involved times before the feed ban,
and what we found was that, you know,
things blew up.
So
although we didn't set out to answer that question directly, you know, the
answer was really clear, just as a byproduct of the other scenarios we were
running. Yes, without the feed ban,
things blow up and, you know, you could have the U.K. here.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: A couple of comments. First, the extrapolation from a ten percent
sample to the hole depends critically on how that sample is selected.
DR.
COHEN: Absolutely.
DR.
BAILAR: If the inspectors are picking
the animals that look like they might have BSE and ignoring the ones that are
downers because they have a broken leg or whatever, then that may be a better
sample than if it's just higgledy-piggledy.
The
second comment is that if you're interested in trends, and I think we are, then
there is a need for much more precise data.
The difference between one, ten and 100 may not be critical for a single
shot, but if you want to know is it going up or down, then you need much better
estimates.
DR.
COHEN: Well, first, I totally agree
with your first comment, and that was the whole point of what I said. There are attributes of this animal that was
selected that make it different from the other 200,000 downers.
As
to your second comment, I think first the decision makers, the policy makers,
the interested parties need to lay out, all right, what options are we going to
be considering in terms of risk management.
How is our selection among these options going to depend on what we know
about the trend?
And
if our selection among options depends critically on whether the trend is ten
to 100 or, you know, whatever the result it, it's only then that you need that
degree of resolution. In other words,
the degree of -- you can always get more resolution by having more sampling,
and the question is: how much
resolution do you need for the decision you have to make?
There
are other ways, in fact, of getting at whether things are getting better. If we understand whether compliance with the
feed ban, for example, is improving or not improving, that would, I think, give
us a pretty good handle on whether things are getting better or not getting
better, and it might be easier to do that than looking for the needle in the
haystack.
Now,
again, I have not studied the sampling problem and, you know, the pluses and minuses of
surveillance. That is outside of what
we looked at, but I'm just trying to say that the solution needs to be tailored
to the question, and the question is, what risk management strategy should be
selected and what information do we need to know in order to select among them.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: It seems to me there are two
important questions though. There is
the one question from the agencies that overall incidents and the up and down
of incidents, and then three is the perspective from the public, from the
consumers, whatever. It's like the
CDC. It would be very nice to know the
incidence of SARS in the United States, but the public, they only care if the
person next to them has got it, who is coughing on them.
So
there is a reason to test widely in a sense to find those individuals that are
right next to you or the beef products that you are going to have or the
pharmaceutical agent that you are going to use.
As
I say, there are two different questions, and they should have two different
approaches.
DR.
COHEN: You know, I agree with you
completely. You know, there is a
perception issue, and certainly with respect to our foreign trading partners,
you know, that has been made real clear.
I mean, if tomorrow we could demonstrate with 100 percent certainty that
there's no BSE in the United States, that would be worth a lot to the beef
exporters. So there is value to the
information there.
So,
I mean, that's exactly right. Now, I
was not thinking about that, and again, this isn't my area, but you're
right. If someone can sit down and say,
"Hey, if we could show with this level of certainty that the prevalence is
below X, then you know, these countries would open up to our imports again and
that would be worth a lot to us," well, then you can say if we need to
demonstrate that the prevalence is below X, our surveillance needs to be
tailored in the following way.
So,
again, you go from your objective to the surveillance program you need in order
to address that objective, and there might be other reasons why we need to know
beyond the two that you just identified.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
GAMBETTI: Just for the record, the
issue of one BSE animal versus ten was a question. I raise it as a question, not as a statement.
DR.
COHEN: What -- what --
DR.
GAMBETTI: You asked this question. I didn't make the statement.
DR.
COHEN: The question?
DR.
GAMBETTI: I didn't make the statement
that if you find one animal and you test ten percent of the high-risk animal
you'll find ten if you test all of them.
I asked the question whether this was possible or not.
DR.
COHEN: Oh, okay.
DR.
GAMBETTI: Just for the record, just for
the record.
DR.
COHEN: All right, fine, and the answer
is you don't know because it's not a random sample. So you can't extrapolate, and you have to make assumptions, and
that's what makes it hard.
CHAIRPERSON
PRIOLA: Dr. Schoenberger, do you have a
comment?
DR.
SCHOENBERGER: Yeah, I would say that
there's a very important, but expensive risk management decision that has yet
to be made in the United States, and that's whether to ban the specified risk
materials from animal feed altogether, as has been done in Europe and the
U.K. Their experience has been that
without such a ban altogether, you do get occasional cross-contaminations.
So
in making that decision, it may well be important to know the difference
between one, ten or 100 infected cattle.
DR.
COHEN: Maybe. I mean, I guess, you know, you'd have to structure out, you know,
again what the decision problem is. We
will take Option A if we know X is true, and we will take Option B if we know Y
is true, and if we make a mistake, then our penalty is going to be this. So it's worth the following for us to be
this certain, and as a result, we should do this kind of sampling.
So
it's that sort of thinking that, I think, needs to be done, you know, because
it's very easy to say, "Well, you know, if we just test more animals, then
we'll know."
Well,
why do you want to know exactly?
Because you might find out that in order to know what you really want to
know, you should have even tested more or fewer. You need to map out the problem.
That's all I'm saying.
CHAIRPERSON
PRIOLA: Dr. Will, do you have a
comment?
DR.
WILL: Yes, I would just like to ask a
question, a short preamble. In 1996,
when variant CJD was identified in the U.K., it caused major public concern,
although we believed that the exposure to BSE probably happened years before in
the 1980s, prior to the introduction of any measures to protect public health,
though we couldn't be sure about that, and we still believe that.
The
risk assessment you showed very clearly relates mainly to the events after the
introduction of the feed ban in 1997.
However, if a case of variant CJD was identified in the United States
this year, it's highly likely that the exposure took place in the 1990s prior
to the introduction of the feed ban in 1997.
So
one of the questions I have to ask you is: what was the input into the risk of
exposure of the United States to BSE?
The reason I ask the question is that in Europe the GBR risk assessment
originally suggested there was some countries, mainly in Central or Eastern
Europe that were at very low risk of getting BSE because they had imported very
little directly from the U.K.
But
it then became apparent that they were at risk, and the reason was that there
had been imports form other countries in Europe that were then BSE-free that
exposed these countries.
When
you look at the U.S. exposure to BSE, do you look just at the exports from the
U.K. in the 1980s and 1990s or do you look also at exports to the U.S. from
other countries, such as Germany, France, Italy, et cetera?
DR.
COHEN: The response to that question,
in general, is that we did not estimate the probability that BSE came into the
U.S. We assumed that it came in. We assumed that as many as 500 animals came
in because we really couldn't quantify what the probability of an introduction
was from all the myriad of sources.
I
mean, it appears that Canada is the one that we know about now. We just said if it gets here, what will
happen.
Now,
I said in general. There was one
particular country that we considered in terms of probability of an
introduction, and that was the U.K., and what we found -- I think these numbers
are correct -- we estimated that there was around a one in five chance to some
infectivity from the U.K. was introduced into the U.S. cattle supply and that
there was some considerably lower chance, few percent -- again, I'm doing this
from memory. I might be wrong ‑-
that that actually resulted in a case here.
But,
you know, the details of that are in the report, but again, the main point to
keep remembering was our focus wasn't figuring out what's the probability that
it got here. We assume that it would
get here and what will happen if it does.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Cohen.
I
think we'll move on to the next speaker, who is Dr. Steven Anderson.
DR.
ANDERSON: Okay. I'm going to talk about the work that I've
been doing on looking at Canadian and U.S. BSE risk.
The
next slide.
Actually
this analysis I'm going to talk about is actually two sort of mini risk
assessments in one study. So I was
approached with two different questions.
The initial question in May was:
what is the BSE risk for the U.S. and Canada? So in Part 1 of the talk I'm going to talk about estimating the
BSE risk by evaluating these potential exposure pathways in the U.S. and
Canada, and I'm just going to sort of summarize things right now and say that
this is mostly a qualitative analysis similar to the reasons that Josh pointed
out.
It's
really difficult to say when you're importing in animals and feed materials, et
cetera, what the probability of actually introducing the BSE agent into the
country is. So I'll talk more about
that in a minute.
And
then the second question of importance to us is what is the risk for the
general U.S. population and what are some of the implications for the blood
supply.
And
we're doing this by estimating BSE exposure, human exposures, and the risk in
the U.S. Now, this is a focus a little
bit different from what Dr. Cohen was speaking about. We're focusing more on the human health side of things.
So
next slide.
I
thought I would give just an overview, and you've seen this before, and we've
talked about cattle statistics and beef statistics, I think, earlier in the
day. Total cattle in the U.S., about 96
million, 13 million in Canada, slaughtered population annually about 35
million, and about a tenth of that in Canada.
I
think the one important fact on this that I'll point out is that we export
approximately ten percent of our beef.
Canada exports about 60 percent or more of their beef, and it's
important to remember that about half of that beef comes into the United
States.
The
next slide, please.
Now,
starting on our first part of the exercise, estimating the BSE risk, the
exposure pathways that we're interested in are imports from BSE countries of
these two things: live animals that we looked at and then mammalian-derived
feed ingredients, mostly meat and bone meal and animal meals, et cetera,
animal-derived meals, et cetera.
And
then finally, a question about the U.S. and Canada. What are the things that are coming across the border and
switching back and forth? And that has
implications for the movement of potentially infected cattle and contaminated
products back and forth. So if you have
an infected animal or infected meat and you import or export that, you're
actually moving the risk around and shifting it from one country to the other.
Now,
in the actual imports, I'm going to focus mostly on the U.K. imports that came
in since 1980, since from about 1980 to the early 1990s was the major portion
of the BSE epidemic, and then BSE countries, mostly in Europe, since 1986.
The
next slide.
I'm
going to gloss through a lot of this information. I think we've seen it in some forms and just because of the
lateness of the hour, but this is looking at cattle imports from the United
Kingdom, and this is mostly before 1990 that these cattle were imported.
Total
animals imported into the United States, 334; into Canada, 288. Disposition of about 50 percent of the
animals was known. Disposition of the
others are unknown mostly.
And
I think one important thing to remember is that there was a BSE positive
identified in one of these cows from the U.K. in 1993, and Canada, I think, has
accepted imports from U.K. farms with known BSE cases, and those animals
numbered ten animals, ten cows from U.K. farms with known BSE cases.
So
I think just looking at this, you can see that there is a potential for importing
risk into this country of the BSE agent, but looking at this, you can't really
tell what the probability is. You know,
are all of these animals infected? It's
likely not the case. It's only about .1
percent was the incidence in animal herds in the U.K.
So
it's very difficult to predict from looking at these was an animal actually
imported or not. It's hard to say.
Next
slide.
I
think one thing we can draw, the conclusion that we can draw is the risk at
least seems to be fairly low.
All
right. Expanding our analysis and
looking at total animals imported from BSE countries, and these include the
animals from the United Kingdom we just talked about.
The
United States received an estimated 1,671 animals. Canada received just over 600, and here is the number
breakdown. One important thing is some
of these imports from Europe and Ireland are thought to be low risk. That accounts for about 500, 300, and then
from other BSE countries, mostly European countries, Japan, of this total we
got 800. Canada got 47.
So,
again, you can see that there is potential here, and we don't know how much.
Next
slide.
Okay. Now, shifting over to the next potential
pathway, feed meal imports since the 1980s from the U.K., a total of
approximately 81 tons. Here at the
numbers per year. USA imported, again,
about 10,500 metric tons of animal meat byproducts from BSE countries during
1980 to 2000.
So,
again, potential pathways by which infectivity could have been introduced. Canada reported no meat and bone meal import
since 1980, but there were imports of, of course, 8,500 metric tons of flours,
et cetera, from these BSE countries, and I think other countries in Europe as
well.
So,
again, just looking over this, again, there is a potential. It's highly uncertain, especially for feed,
figuring out what the probability of that feed will actually cause the disease,
although we know that it is an efficient vector for transmitting the disease.
The
next slide.
So
now we get to the question about the U.S. and Canada and what's coming across
the border. So we looked at cattle and
beef, and what was coming across the border for each country. So considerable movement of animals and feed
ingredients and beef products across the border, and I'm going to show you
those data in a moment.
Trade
and production practices, actually this should just be production practices,
are very similar for each country. In
fact, many of the companies collocate both in Canada and the U.S. So there are operations in both countries.
And
there is an exchange, definitely, of animals between those companies, and then
it's just important to remember from this that import or export, again, as I
mentioned before, can be a mechanism by which to introduce or spread infected
animals or contaminated products.
The
next slide.
So
these are data showing cattle trade in North America. We're going by U.S. cattle imports and exports, and what this
shows is that here's the one million mark.
We're basically importing in from Canada a significant number of
animals. In 2002 it was about 1.6, 1.7
million animals coming in. Again, far
fewer animals going out and being exported to Canada.
So
we're actually importing a fair number of animals into this country from
Canada.
The
next slide.
And
just to show you beef imports and exports, again, the red is Canada. Imports have been increasing into this
country, about 350,000 metric tons, actually 370,000 metric tons came in in
2002, while about 60 or 70,000 tons was exported to Canada from the United
States.
So,
again, a big disparity between products, and especially food products coming
in. Canada is by large shipping much
more of its product to us than we are to them.
So a tremendous change, and actually if you look at that, this is one
mechanism by which we're actually accepting -- I mean, these aren't high risk
products, most of them, but if they were, we'd be accepting that risk from
Canada as well. They would be accepting
some risk from us as well.
The
next slide.
So
conclusions in Part 1. Now, this is a
qualitative assessment that I use to answer the question. It's really difficult to estimate absolute
risk for U.S. and Canada. Again, it's
very difficult to predict how many of those animals that came in could have
been infected, and the feed as well.
You know, when did it come in and was it infected? Did it contain infected material or not?
It's
very difficult to note that with any sort of confidence. And again, and now as we sit here almost 15
years or more after those events happened because many of these animals and
products were introduced into the U.S. prior to 1990, you've had all of this
time for these numerous chance events to occur in the production system, and
that means animals might have been rendered.
They might have been rendered properly, not rendered properly. Feed might have been fed; infected feed
might not have been fed feed. An
infected cow might have died on the farm; it may not have died on the
farm. It may have been in the system,
et cetera.
Let's
see. So I think just in conclusion,
basically, considering the size of the production systems just from looking at
what was brought into the country, both countries, imports with live animals
and feed materials occurred since 1980 but was relatively small. A qualitative estimate that we would use
would say that the risk that we would predict from this is that the risk would
be low, but again, it's difficult to estimate with any uncertainty. So we're giving it this qualitative: we think the risk is low.
Let's
go on to the second part. Okay. The second part, we're looking more at the
human side of the equation, and I think Josh and the Harvard Center for Risk
Analysis have done a really nice job of looking at animal production and then
what goes into beef, but I think into the beef production cycle, but the issue
with that is it just sort of stops there, and so this is somewhat of an
extension of that work. It's like,
who's eating what? We're trying to
begin to estimate who's eating what and how much people are eating of these
risk materials to get a better estimate of the risk.
Again,
many potential routes for human exposure to beef and bovine products. Now, the primary source of potential BSE
exposure in this country or in any country is probably through the food supply,
mainly through consuming these high risk tissues. Again, these two account for about 90 percent of the total
infectivity in a cow, and then eyes and dorsal root ganglia and small intestines have somewhat less infectivity.
Other
sources include dietary supplements though, and those should be considered, and
then medical products as well, devices, biologics, and drugs, and you're going
to hear more about those tomorrow.
And
I should emphasize that what we've got is sort of a narrow focus here on some
of the higher-risk products. So what
we're trying to do is estimate risk for some of the higher risk products, but
what we then need to do is take those estimates and sort of slowly work out and
look at the risk, for instance, for the other products. For instance, we need to include dietary
supplements in our risk estimates because those are responsible for exposure,
and then eventually the risk for medical products, which are probably lower in
many cases.
So
we need to have a more sort of holistic picture, and what we're trying to do is
get a start on that by looking at the larger items responsible for risk.
The
next slide.
All
right. I always think it's interesting
to talk about some of these products that people eat because organ meats and
the types of things that are consumed are very unusual.
So
we looked at BSE exposure pathways for the U.S. population by beef products,
and we're looking in the first instance.
We divided it into two things.
We divided it into bovine brain or potentially spinal cord, but mostly
focused on bovine brain, and what this is is consumption of potentially large
amounts of high risk tissue, but people don't consume brain very
frequently. So there are certain
populations in the United States that do consume it, but for the general
population, it's a pretty rare event.
You
can go into a French restaurant and get calf brains, and I've seen cow brain
sandwiches in some restaurants in the Midwest.
So there are opportunities, but pretty low risk.
And
then the second type of food product that could offer a potential risk is
consumption of small amounts of these high risk tissues in processed
foods. So mainly what we're concerned
about is the advanced meat recovery product in this case, and those would
include advanced meat recovery, is in many products.
For
instance, ground beef products can contain some beef sausages, hot dogs,
processed meat sauces, et cetera. So
it's in many types of foods, types of beef products, beef foods.
Let's
go to the next slide.
So
looking just at our overall risk, I took this as a start to start looking at
this year and what the risk is for this year, and we need to also expand these
calculations out to prior years and then move them forward as well, but we started
with 2003 because we have a fair amount of information to offer predictions.
So
one positive animal identified out of 35 million slaughtered. So we know at least that we have a one in 35
million probability at the low end, and I have to -- Josh corrected me on this. It's 3.5 times ten to the negative
seven. It's probably about an order of
magnitude lower than I represented here.
That's not going to affect the calculations though, but I'll show you in
a minute, but you're going to see this number repeated, and just remember that
it's about three times ten to the negative eight.
We
accepted that as a lower boundary for our risk estimate. As a higher boundary, I actually just looked
at what USDA was doing, and their estimate was they were looking at about a
risk of one in one million in detecting their animals. I took that, actually, as a higher end. So if we have 35 million animals slaughtered
per year, as our worst case scenario we assumed that potentially 35 animals
could enter the food supply.
Again,
it's an estimate. It's the same that
Josh is doing. Basically, he stocked
his with ten, 20, 100 animals. I'm
stocking mine with one or 35 animals to do my analysis.
The
next slide.
All
right. So, to focus just on brain
consumption for a moment, we've looked at the consumption databases that we
have access to that are produced by USDA, and from that -- and we looked at a
few other sources, too.
We're
estimating right now the brain is rarely consumed by Americans, about 100,000
to 180,000 servings. So this is about
half of a percent of all the brains at most that are produced of the cows that are slaughtered. So I think it represents about half a
percent, no more than one percent.
And
I think one thing to remember, the databases don't distinguish between calf
brains from low risk animals versus high risk animals. We know there are cow brains that are being
sold in the marketplace, too. So those
aren't distinguished. So we're just
making a worst case assumption that those are high risk for this purpose.
The
probability of an infected brain then, we assume that people would eat about --
that those servings was a whole brain, a worst case shot. But the risk of that would be one in 35
million to one in one million of the eating an infected brain potentially.
And,
again, your sample, only a very small percentage of people are eating this
food. So, again, the risk would be very
small that somebody would happen to get a brain that was infected, given the
low prevalence of this disease, the low incidence in this country.
But
I think it's important to indicate that the quantity of exposure would be
pretty high, about 5,000 to 6,500, a conservative estimate for the cattle oral
ID-50s that they might consume. That's
a pretty big hit, and it's still unclear whether that would cause an infection
in a person or not.
Again,
a person would have to be susceptible to the agent as well. Remember the methionine homozygous at codon
129. So presumably 40 percent of the
population would be susceptible to infection if they ate that much material
possibly. Again, but that's highly
uncertain.
So
what we did, our conclusions from this are there is a risk of exposure via this
route, but the risk to the U.S. general population, the larger population, is
very low.
So
let's move on to the next slide to get into advanced meat recovery. Now, this is sort of the flip side of the
coin where we had a low probability of consuming high infectivity. We're at the flip side of that. We have a very -- sorry. My mouth is kind of dry.
So
for the brain we have a low probability of consuming -- yeah, I think I'll
actually take a glass of water.
So
with brain we have a low probability of consuming perhaps a high infectious
dose of material, and with AMR, we have a higher probability, although not
extremely high, of consuming very low amounts of infectious material if the
disease is present in an AMR process.
So
just to remind people what AMR processing is, it's advanced meat recovery. It removes remaining meat from carcasses,
the vertebral column and bone using machinery, and I think it's important to
remember the spinal cord is usually removed before this process, but the dorsal
root ganglia can serve as a source of infectivity because you can't remove that
very easily from the vertebral column.
And
I think about 70 percent to 80 percent of carcasses annually are processed
annually with AMR as an estimate. That
comes from a study commissioned by the USDA by the Sparks Company, and I think
the one important thing about AMR is that when I look at this process, this is
a process that really would mix and dilute the residual BSE agent that's
present.
So
you might imagine that there's residue in the spinal canal where the cord was
where it is removed. There might be a
little residual material there, and then there would be the dorsal root ganglia potentially that
could serve as the sort of depot for any residual BSE agent if that animal was,
indeed, infected.
The
next slide.
Again,
just continuing on, machines based on the Sparks study, again, machines can
process 4,500 to 7,000 pounds of bones an hour. We estimated that this represents material from 20 to more than
35 animals. I think the high end of
that estimate we still need to work on a little bit.
And
from each animal you get approximately five to ten pounds of meat recovered per
carcass. Again, we're being
conservative on our estimate here.
These are somewhat high, but actually within the realm of reason.
We
estimated, and then based on a GAO study estimate as well, that approximately
as much as 250 million pounds of AMR meat are produced annually. We also estimated on the low side of this,
too. I think we went down to about 100
million to 250 million pounds because the estimates are very variable in the
literature.
So
the next slide.
So
probability of exposure to advanced meat recovery product which is consumed
frequently. Dilution of BSE, now there
is this, again, as I mentioned before, there is this dilution of BSE
infectivity through the batch of AMR product.
So what you've got is you can imagine this machine that's moving these
cow bones around and material is coming off.
There might be water, brushes, artificial fingers, et cetera, artificial
rubber projections, pulling meat off of these bones.
So
you have all of these cows and all of this material moving around in this batch
of AMR product. Now, the probability
again -- again, this is incorrect, but it was one in 35 million to one in one
million probability that you would have an animal in one of those batches, an
infected animal going into one of those batches of AMR.
And
from that what we estimate based on this range is that the amount of BSE
infectivity present is estimated to be low because of dilution, and what we
estimated was less than two times ten to the negative second cattle oral ID-50s
per average serving of AMR, and that could be as low as four times ten to the
negative third. So we do have an
interval here on the potential amount of exposure, the amount of agent that one
could be exposed to.
And
I think it's important to remember that you can have a significant number of
servings coming from batches of AMR product.
You're going to have greater than 100 servings or more, perhaps upwards
of 1,000 coming from each batch of AMR product.
So,
again, this would be distributed throughout that product by serving.
So
the next slide.
Again,
so what I just calculated for you was the probability -- the amount of agent
that could be present per serving. Now,
the question is: what's your
probability as a consumer of getting one of those doses of material?
So
we not only have to have the quantity of agent you might be exposed to, but
what's the probability you might be exposed to that agent in the food supply?
So
the probability of exposure by AMR is assumed to be low in our
calculations. So, again, one times ten
to the seventh to two times ten to the negative fifth per serving of beef AMR
product per year.
I'm
not going to go through the entire modeling process just because of the
lateness of the hour.
Now,
this is exposure. So that's important
to remember, and these are exposures.
So the next thing we have to do is what's the probability of infection
because if you look at that at its face value, you might think that these
numbers -- actually, given that we have 280 million people in the United
States, you might be concerned looking at this, but exposure doesn't cause
infection.
So
the probability of infection, we separated that out, and we assume the species
barrier -- assuming the species barrier of 1,000 and oral route reduction of
greater than 90 percent, and then assuming 40 percent of the population is
sensitive, we assumed 60 percent was not.
The
probability of infection then adjusted would be about you might expect
something like on the order of less than three times ten to the negative nine
infections annually in the United States, and again, we put an interval on that
of two times ten to the negative ten, and then our higher boundary was three times
ten to the negative nine.
So
the next slide.
The
conclusions. So just to conclude, our
preliminary estimate suggest there's this low risk of human exposure to the BSE
agent via beef AMR product. So to low
probability of exposure and then an even lower probability of infection.
Again,
I caution people that there is uncertainty in these estimates. We've made assumptions just like the Harvard
Center for Risk Analysis made assumptions with their model, and that does add
to the uncertainty in our risk estimates.
Again,
just concluding from this, we assume that the risk to the general population is
low. Again, we don't think these
exposures -- that there's a potential for much of infectivity, and that's by
AMR and brain, but again, we need to consider other potential pathways.
And
then if you move on to expand that, our interest is in the blood supply. So not only do we assume from these
findings, initial findings, that the risk to the general population is low, but
also then accordingly the risk to the blood supply would be low.
The
next slide.
And
then I just put down these measures.
I'm not going to go through them since we just had a little tutorial on
them from Mary Porretta and Dr. Steve Sundlof.
The
USDA measures and also the FDA feed ban improvements should definitely lower
that risk even more. So if we come back
and review our calculations in 2004, that risk should be even lower.
And
I think the final slide is just an acknowledgment of this was not only work by
me, but mostly by Dr. Sonja Sandberg, who was in our office, and Rene
Suarez-Soto, who is an intern in our office, and then, of course, help from
David Asher, Rolf Taffs, and Pedro Piccardo, and then advice from many others
at CBER.
And
that's it. Thank you.
CHAIRPERSON
PRIOLA: Thank you, Dr. Anderson.
Dr.
Ferguson, do you have a question?
DR.
FERGUSON: Yes. Sorry.
I was saying goodbye.
Actually
I'd like to clarify some of the import data that you have on your slides. I think especially the live cattle numbers
are a bit misleading. The U.K. and the
Irish in numbers are correct, but I think -- I was trying to find my handout
but can't find it -- you reported that we imported animals from BSE countries
after '86. I mean outside of the U.K.
and the Irish ones, and that's inaccurate.
Actually we imported some animals, about 360 or so from continental
Europe, but all of that was done prior to 1985.
DR.
ANDERSON: Oh, okay.
DR.
FERGUSON: So, yeah, there are some
significant differences there.
I
think also for purposes of this discussion a lot of not specifically those
animals. There were some animals
imported from Japan, some animals from continental Europe, a limited number, in
'96-'97, but we've traced those animals, and the vast majority of those have
been completely excluded from the system.
So,
yeah, you can say animals were imported, but did they present a risk? No.
DR.
ANDERSON: Right.
DR.
FERGUSON: Similar type things on the
data for feed imports, especially if you're pulling that from Customs
data. There's a lot of flexibility and
a lot of leeway and a lot of misreporting in Customs data. We've made every effort to go back and trace
down some of these things that are reported.
Some of them are reported completely inaccurately. Some of them are noted in those HS codes,
but specifically, you know, there's a lot of that that was coming in in the
late '90s and into 2000. It's a porcine
collagen binder that comes from, you know, a sole source facility in Denmark
and Sweden and is going into pet food.
So we know exactly what that is, and we know that it's minimal
risk.
So
don't take those figures and assume that that is ruminant derived meat and bone
meal from a high risk country going directly into ruminant feed. In the vast majority of instances, that is
not the case.
CHAIRPERSON
PRIOLA: Dr. Khabbaz.
DR.
KHABBAZ: Yeah, thanks, Suzette.
Actually
my question did pertain to the numbers given for the feed meal import
specifically from the U.K. I'm a little
confused by them because you said, you know, the imports were small. Yet I see for 1997 -- and this is just the
U.K. -- 37 tons, and so, you know, is that small?
And
then the numbers given, I mean, we have 81, 84 in '97, and then there was
nothing before that '89. So what
happened? We didn't import any since
'89 and all of a sudden in '97 we have three times what we imported before?
Quite
confusing, and you know, inconsistent with the conclusion, I think, that the
risk is small.
DR.
ANDERSON: Lisa, do you want to comment
about the total amount of feed materials that are produced in the U.S. and
consumed? Because it's on the order of,
I guess, what, four to six million?
DR.
FERGUSON: Yeah. I mean, definitely, this type of stuff is a
drop in the bucket, but I think looking at like that specific U.K. one, there
were a couple of instances, and I'd have to go back and get my actual data, but
you know, a specific manufacturer or pet food manufacturer requested import of
a specialty poultry product for product testing.
So
in certain instances, we would allow non-mammalian or single source species,
non-ruminant type stuff, to be imported.
Unfortunately in the data, you know, especially if you're deriving this
information from Customs data, that level of detail rapidly gets lost.
DR.
ANDERSON: Right. Actually I wanted to clarify. We actually pulled the feed import data from
the GBR report. So whoever derived
that, I thought that was you, actually.
DR.
FERGUSON: Well, we had some issues with
some of that also. So we won't get into
that.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: Somebody would have to go
through this pretty carefully to identify all of the assumptions in the
analysis. That's true of the other risk
assessments here, too, but there seemed to be two assumptions that are
particularly critical or strike me as being particularly critical.
If
I haven't misunderstood, you assumed first that the population is divided into
two groups, each with uniform level of susceptibility, zero and a higher level.
And I think that's most unlikely to be
the case. We simply don't know about
susceptibility factors, except for that one item, and I think that's going to
attach a lot of uncertainty to anybody's risk assessment.
The
second is, you seem to assume that if there is some infected material in the
AMR recovery meat products, that it's uniformly distributed, and I think that
also is not --
DR.
ANDERSON: That is an assumption. So it could be clumping that could be --
DR.
BAILAR: It's virtually certain to be
clumping. You know, you've got an
animal. It goes through all at once,
and it goes out in a small number of packages.
It's not uniformly distributed.
DR.
ANDERSON: But I think having come from
USDA, that's how we actually modeled risk because ‑-
DR.
BAILAR: Well, then you're modeling
wrong.
DR.
ANDERSON: Well, you know, modeling
clumping is a little bit more complex, and again, we don't have information on
that to accurately do that. So we have
that uncertainty versus just an assumption, a simplifying assumption of
homogeneous distribution.
So
that's what we're stuck with right now.
I think the problem is this isn't a data rich environment that we can --
DR.
BAILAR: Well, you know, if I can expand
on that a little more, there are a lot of different ways people could do risk
assessments, and we've heard some range of them here that's a widely accepted
paradigm with the four steps of hazard identification and so forth; was
actually worked out by a committee at the National Academy of Sciences for
estimating, assessing the hazards of carcinogens, and it doesn't generally
apply across the board. There are a lot
of ways it doesn't.
We
have fault tree analyses which are a different approach. I've recently been involved in a third
approach that uses multiplication of probabilities. We were trying to estimate human risks of feeding antibiotics to
livestock for growth purposes, and there are still others.
One
thing I would like to see is a full range of methods of risk assessment, each
with the assumptions laid out. Some of
them take more assumptions than others, and then I might have greater
confidence that somewhere in that set of results there's something fairly close
to the real situation.
DR.
ANDERSON: Well, the answer that I have
to that is we're very early in our process.
So this is really a rough risk assessment, a rough estimate, and so this
is just the start, and we hope to continue the process and add those layers of
complexity and add more data and information, and even augment the modeling
techniques and perhaps generate, you know, additional models.
But
at this time, I mean, this is our first one.
So it is the first start. So
we're not necessarily married to the technique at this point. So I think we'll consider it in the future.
CHAIRPERSON
PRIOLA: Okay. Let's move on to the open public hearing portion of the
afternoon.
DR.
FREAS: So far I've received six
requests regarding the open public hearing session this afternoon, and before
we begin, I would like to remind those presenting of the statement that our
Chair read into the record this morning that we ask you to comment on any
financial affiliation with any firm or product that you may be talking about
during your open public hearing talking.
The
first request is from Sue Sutton Jones.
She's a Vice President of Quality Technical and Compliance
Serologicals. These are all
presentations that will be timed for six minutes.
MS.
JONES: Well, thank you.
I
want to make the point that we believe that bovine derived- products are safe,
as well as other animal protein products.
You
can go to the next one.
And
what we'd just like to do in just the essence of time here is I'll summarize
it, is trying to make the point we totally agree with FDA's point of view of
working with risk management as a way to prove this, and as we go through the
slides very quickly, I'll show you that because we do believe that we should
stay in the market, that turning away form animal protein products is not
necessarily the answer, for many of the reasons that Dr. Asher gave earlier in
his presentation.
The
next one.
Now,
I do work for Serologicals. We supply
animal blood protein products, and we are divided into two segments. Limited is overseas and then Serological
Proteins operates here and in Canada as well.
The
next one.
We're
a medium size company; within our industry, we're roughly medium sized. We make 90 distinct animal protein products
like BSE. We also make tissue culture
media products. So you'll find
companies within our industry either much smaller than we are or much
larger. So we are a medium-size
company. These are some of the products
that we make.
Next
one.
But
basically the products that we make are intended for further manufacturing
use. So I always like to use the
analogy that BASF does. They don't make
the paint green. They make it greener
or make it look prettier. Well, that's
what our industry does. We don't make
the product, but we make it better, and in many cases what you'll find is that there
is no product, for instance, for the biologic drug without these animal
proteins. They're critical to cell
culture. They may be critical to an
analyte that you use in an IVD. They're
critical to vaccines. So they are very
important and are not easily replaceable.
The
next one.
So
what happens? Well, we're one of those
companies that, as you were told earlier, we're dual. We have a manufacturing facility in Canada. We also have one in the United States.
So
when May hit us, we very cleverly turned that into a U.S. source plasma plant,
and then we spent Christmas going, "Oh, no," with the rest of the
nation, as well.
So
our only alternative then, we were told, was, well, get it from New
Zealand/Australia. Well, that presents
its own problems. There have been
problems in the past with supply.
There's also a problem if we have validated processes. So now to bring in plasma that has been
frozen rather than fresh creates a whole new problem for us and our customers.
There
is alternative material. It's
recombinant. However, there is one
thing I'd like to point out, is that you'll see with many recombinants as you
go back through their genesis as a product you will find one, two, three levels
down that actually animal protein product was in the cell culture media that
many of these proteins are made of.
So
few of them are truly animal free in the sense that no animal product has ever
touched them, and then we also go through the hoops, and we've been very lucky
with CFIA and USDA in that we've managed to work with them very well, and
they've assisted us with getting back into business, as well, once we've
demonstrated the safety of the processes.
The
next one.
So
recombinants' bottom line. There's a
whole list of reasons, but they're unrealistic to think that we can just turn
the faucet on tomorrow and all of our products will be replaced with
recombinant that will work just as well.
We'll have the same results.
We'll be economic because some of these you'll get much lower yields when
you use them, as well as not every animal protein works just the same in each
of the products as well. So we do
negatively impact worldwide economies by turning away from proven products that
work.
The
next one.
Now,
this is just a strategy here that I put together, and we can replace anything
in the middle there. I put the USDA
because they have been instrumental with us, and the problems we face with BSE
and Canada as well as here in the States, but we can put any agency there. We can put any public group there, and we
can also put the industry there because the point I'm trying to make here is
that as a group we can't do this by ourselves as an industry and come forward
with a path forward and a way to stay in business or the answers to all of the
problems, such as risk management, nor can the agencies or the public do it on
their own as well.
So
the goal of this whole presentation was, one, to ask that we step back and take
a rational, logical, and reasonable approach to dealing with this problem and
minimize the risk of BSE and animal protein products because we don't know that
BSE is the only thing we need to worry about necessarily from here on out, and
also maximize, though, the benefit of these important products in the
marketplace.
The
next one.
Now,
our response to this with shared responsibility is that we've pretty much been
on our own and with some of our colleagues with our own industry where we tried
to respond and been very reactive every time there's a problem that has come up,
and so our response to minimizing risk is that now, for instance, with this
last BSE case, we restrict our acceptance of plasma to animals less than 30
months old. We're out of business in
Canada. We just a week ago started
again, and we're able to ship plasma back to our plant there that uses only
U.S. source material to make products.
We
have now rigorous internal policies that every time something happens that we
ratchet them up a little bit, and we have sent them to the USDA and CFIA is
part of the review process, although they don't get approved there, and there
are manufacturing processes we have demonstrated that, in point of fact, they
can reduce prion and viral loads.
Next
one.
So
why do we want to advocate that? In
point of fact, we have studies, which is a little unusual. Usually it's the regulators that say we need
to be regulated or we need some guidance rather than industry, but the optimum
assurance of a medical device product safety or medical product has several
essential elements that we try to address.
One
is absolute safety can't be guaranteed each and every time. It's a risk management issue. It's closely aligned with the product in its
effectiveness and performance.
It
also has to be considered throughout the life cycle and span of a product. It's not a one-time thing, and then it
requires responsibility from all the stakeholders, which goes back to the
circle that was there before. Where is
the agency? It's the public. It's the industry.
And
then the next one?
And
also it's just deal with that public perception for a moment, and that is the
public is the ultimate beneficiary of any medical product, but they have to be
fully aware that all products have some certain amount of risk, some greater
than others. The public can health
promote safety though through self-education, and in putting we, the
manufacturer, into a situation where we have customer pressure, which we do
right now, on manufacturers to comply with some standard, but what we don't
have is that standard. What is it that
we should be doing and what should we comply with?
I
feel strongly that the government has the responsibility to also oversee the
efforts that we make and make sure we're consistent, make sure no one has a
competitive advantage over another one because we have an in with somebody or
with a government agency and have some inside circle.
Also,
provide the leadership that's going to create that system of cooperation
between us, the public, and the agencies, and then make sure the policies,
whatever we come up with, standards are reviewed on a periodic basis so they
keep up with changes in technology, such as there may be a test that is
approved in the near future for prion detection in products.
So
the next one.
Now,
we can just go all the way to the end.
I included these slides here just to give you an idea of all of the
kinds of studies we've done, you know, but you can go back and you can question
whether or not they're adequate simply because do we do spike in more than you
would ever seek in a tissue, as many of the examples we've seen here.
And
we can show you if you just flip through them all there are different levels of
-- the next one -- there are different levels of infectivity.
Next
one. And then just go to the very last
slide.
As
you'll see, we have done these studies.
We think they're good. We think
they're very rigorous.
You
can go to the next one. Stay on that
one.
But
what we don't know though is how much do we spike in. Should it mimic reality?
What is reality? How much could
we expect to see, for instance, from a tanker load BSA plasma that comes in
that we're going to make product out of?
So
that's what we're asking for, is what type of testing or why is it that we use
Western blot, that type of thing. So
there is some need for guidance within the industry simply so we can provide
guidance back to our customer and say, "This is the information that
you're going to need to have a successfully approved drug."
So
in conclusion, the ideal conditions that will insure the safety and performance
of medical products required all our shared responsibility. We have enough information now, and we
showed you some of it very quickly, but I believe we can make very credible
risk management plans, put them in place, and be able to show not only to a
regulatory agency; also to the public, to our customers, and these are based on
our own experience. They're based on
computations and science and technical evaluations.
And
we're at the point that we can even consider cultural and political
implications of these plans as well so that we reflect that climate. We have also shown that these processes can
be validated. The processing now and
manufacturer is at the point that it's very robust. We do validate. They are
consistent, reproducible, but we're not the only ones that can make the product
safe as well.
And
one of the things that we want to really endorse and support is the fact that
we do have to take steps a little further and that we don't allow any SRMs into
the food chain, whether it's human or for animals, and we have to take more
rigor in there because the one way that we can minimize the risk the best is to
keep the infectivity of BSE completely out of the animal food chain and
completely out of the chain that goes into the pharmaceuticals and biologics as
well.
So
thank you.
MR.
FREAS: Thank you for your comments,
too.
The
next open public hearing presentation is Mr. Daniel Kinburn. He is senior counsel for the Physicians
Committee on Responsible Medicine.
Mr.
Kinburn.
MR.
KINBURN: Thank you.
I'm
here to speak on behalf of the more than 100,000 physician and lay members of
PCRM. I want to start by thanking the
committee for the critically important work it is doing. Strong, decisive action is needed now in
order to prevent an outbreak of variant Creutzfeldt-Jakob disease, rather than
delaying such action as the beef industry seems to be suggesting until
Americans start dying.
Last
week, the Foreign Animal and Poultry Disease Advisory Subcommittee appointed by
the Secretary of Agriculture made several policy recommendations after
concluding that it is highly probable that more American cattle are infected
with mad cow disease than the one found in Washington State in December.
To
the extent that these recommendations fall within the domain of the Department
of Health and Human Services, we urge you to support several of the
recommendations made by the subcommittee.
As some of these recommendations have already been implemented by the
FDA in its interim final rules this January, we ask that you support making
those interim rules final.
We
also identified some other measures that should be taken to adequately
safeguard public health.
First,
cattle feed. We all understand that mad
cow disease is caused by a deformed prion protein that spreads when cattle
consume feed supplemented with brain and central nervous system tissue from
infected animals.
Therefore,
we urge you to adopt the subcommittee's recommendation to prohibit any mammalian
or poultry meat, bone, or other byproduct from all cattle feed. Because factor farm fish are also fed cattle
byproducts, we urge you to recommend that factory farm fish and their
byproducts be prohibited from cattle feed.
In
order to effectively prevent the spread of mad cow disease as well as any
cross-contamination of ruminant and non-ruminant animal feed, PCRM also asks
you to prohibit the use of any animal, whether mammal, avian or aquatic, or its
byproducts, from the feed of any other herbivorous animal used for human
consumption, such as pigs, sheep, goals, chicken and turkeys.
Next.
Specified
risk materials and downers. We urge you
to adopt the subcommittee's suggestion to exclude all SRM from both human and
animal food, and to ban any material from downed cows from entering the food
supply.
To
the extent these recommendations have been implemented by FDA's interim rule,
then to ban SRMs from downer or dead cow material and from FDA regulated food,
dietary supplements and cosmetics, we also ask that you recommend making these
interim rules final.
Additionally,
this committee should go beyond the subcommittee's recommendation to insure the
safety and well-being of all Americans.
Under the subcommittee's recommendation, downed pigs, sheep, lamb, and
other animals, except cattle, cannot be fed to cattle, but they can go straight
into the human food supply. People
should not be eating food deemed too risky to serve to cattle. Thus, we urge the committee to recommend
that all downed animals, regardless of species, be banned from FDA regulated
food, medical products and cosmetics.
Finally,
source of origin labeling. To provide
full information to consumers who wish to take extra precautions to protect
themselves from vCJD, we urge you to support the source of origin labeling for
food, medication, and dietary supplements.
As proposed by Representative Nita Lowey in the 2003 Food Ingredient
Right to Know Act, H.R. 467, food manufacturers should be required to identify
the source of all food ingredients such as ?natural flavors and additives,? which
commonly contain spices, flavoring or coloring derived from meat, poultry or
other animal products.
This
committee should go one step further and recommend such source of origin
labeling for all dietary supplements and medications which also commonly
contain bovine or other animal byproducts.
I
want to thank you again for the important work you are doing.
DR.
FREAS: Thank you for your comments.
The
next request we had was from Mr. Keith Gittermann. He submitted written comments.
These comments are in his letter from Invitrogen. They're in your red folder, and they're also
out on the table.
The
next request to speak today is from Mr. Paul McQuarrie. He's Director of Operations, TerraCell
International.
MR.
McQUARRIE: Good afternoon or good
evening. To make it short, I could
probably just say what Sue said and just say "ditto," but I'm not
going to say that.
I
want to talk about fetal bovine serum, about fetal bovine serum being a minimal
risk material. Just to let you know
where I'm from, TerraCell International contracts the company I work for,
Cansera International, to sterile filter fill fetal bovine serum and donor
bovine serum.
Next
slide, please.
FBS
doesn't equal COW. Now, what in the
heck does that mean? All I'm really
trying to say there is that when you're considering trade and use issues you
shouldn't include all of the animals bits with how you're handling the animal
itself.
Restrictions
on trade and use of fetal bovine serum really are based incorrectly on how
cattle are being treated.
When
the borders closed down after the last two instances of BSE in Canada and the
U.S., the quality and regulatory affairs people in certain companies were
scrambling trying to try and figure out, okay, now where am I going to get
fetal bovine serum next.
The
quick answer, of course, was Australia and New Zealand, but not only is there
not enough to go around. It's not
really the right solution, regardless of supply.
Global
supply of fetal bovine serum, both 500,000 liters a year of which Canada and
the U.S. have a 65 percent share. Since
Canada and the U.S. really should be considered in the same boat when you're
talking about BSE issues, I think the international subcommittee has suggested
this. I think it makes sense.
If
that is the case and companies themselves or regulatory bodies decide that
medical products cannot be made from serum other than from GBR Category I
countries, there is going to be a shortage.
Hopefully the following slides will underscore the fact that fetal
bovine serum really is of minimal risk and that sourcing and use should be
considered accordingly.
The
next slide, please.
Favorable
FBS facts. As we have said, as
everybody has said, I think, off and on today, since BSE doesn't manifest
itself till the animal is a few years old, a 30-month age criterion has been
set for the animal. I think the fetus
can be said to be slightly less than 30 months old. I think that's an important consideration.
When
you're dealing with animal byproducts that are harvested at the slaughterhouse,
you need to address the slaughterhouse activities. I've got some pictures following these slides that I hope will
prove or show to you that there's absolutely no chance that fetal bovine blood
can be exposed to specific risk materials.
Next
slide, please. The next picture.
The
blood is collected in single use sterile collection bags.
Next
slide, please.
In
segregated areas in the slaughterhouse, totally separate from the kill floor.
Next
slide, please.
The
fetus comes down to the segregated area totally enclosed in the uterus. As you can see, there's no chance that it
can be contaminated at all with the SRMs.
Next.
This
isn't the kitchen downstairs. The
blood is collected by a direct cardiac puncture, so the whole system is a
closed system.
Next
slide.
More
facts. The fetal bovine serum is
considered as a Category IV risk material by the EMEA, i.e., no detectable
infectivity. Most serum manufacturers
have received certificates of suitability from the EDQM confirming that their
product meets the criteria for TSE reduction.
Next
slide, please.
Risk
benefit. I believe FBS warrants an
independent assessment, as I believe CBER and the joint committees have said
that the benefits of vaccines far outweigh the remote risk of CJD. By sourcing FBS from countries that have had
few or sporadic cases or zero cases of BSE and who have good surveillance
programs can further minimize the risk.
Last
slide.
We'd
just like to encourage the FDA to do something similar to that which the EDQM
did in developing a new European monograph for animal sera, and that is getting
together the scientific community, pharmaceutical companies, regulatory bodies,
and sera manufacturers in order to review and assess all of the issues towards
developing a policy regarding the safe use of animal serum products.
Cansera
and TerraCell look forward to helping in any way they can.
Thank
you.
DR.
FREAS: Thank you very much, Mr.
McQuarrie.
Our
next speaker is Dr. James Polarek. He's
Vice President of Fibrogen.
DR.
POLAREK: I want to thank the committee
for having a chance to talk to you for a little bit this afternoon. What I'm going to tell you about is a time
when we can, indeed, look at replacements for bovine-derived materials, in
particular, for collagen and gelatin.
And
I have up here the fact that I do, indeed, work for Fibrogen, which is a
country in South San Francisco focused on making some of these materials, and I
put up Kari Kivirikko's name because I want to make sure I had mentioned that
this technology came originally from work done at the University of Oulu in
Finland.
Next
slide, please.
Collagen,
as I think everyone is aware, is a triple helical molecule. It's the major protein of the human body,
and it is used in a large number of different medical devices and
pharmaceutical products, both extant and products of the future, particularly
in the tissue engineering area.
The
way the human body and any other cell that makes collagen gets to a triple
helical molecule is through the co-expression of both collagen genes and genes
encoding modifying enzymes, in particular, one called prolyl hydroxylase.
We've
been able to take that same system and put it into a yeast. We make, therefore, a human collagen, and
we've made a number of different human collagens. In yeast, we use no animal derived proteins during any part of
the production process. Yeast don't
need anything in the media besides carbon sources and salt. So you can, indeed, at this point have a
recombinant process that does not require anything that came from animals.
Proof
that this material replaces the bovine-derived material is probably best laid
out in the fact that we now have 65 different feasibility agreements underway
with medical device and pharmaceutical manufacturers for this materials, and in
each case, they've been able to show that they can replace on a one-for-one
basis the material they use today with the recombinant material.
So
I think in this case there is an alternative.
Next
slide, please.
We've
gone further to look at, in particular, the gelatin that's used in
pharmaceuticals and what they call gelatin hydrolysate. As I think you're probably aware, gelatin
hydrolysate is a mixture of proteins derived from gelatin through the further
breakdown of the chains into a soluble product.
What
we did that's shown on this slide schematically is break the collagen gene down
into individual fragments. So rather
than hydrolyzing the protein, we have chosen to express individual fragments of
gelatin or of collagen.
Next
slide.
We
have taken one of those, in particular, a ten or actually an 8.5 kilodalton
fragment and shown in collaboration with a vaccine manufacturer that this
single fragment of the collagen molecule, which would be represented within
that mixture of proteins in the gelatin hydrolysate can replace the biological
activity, the stabilizing activity that that manufacturer uses in their
influenza vaccine in this case.
And
you can see in this slide that there is no measurable difference between a
single gelatin fragment and the hydrolyzed gelatin that is used in the
commercial product today, but what this allows the manufacturer to do now is
replace this mixture of proteins that's very hard to characterize, somewhat
hard to control, with a single molecule that is fully characterizable, has one
end terminus, one C terminus, a sequence that's easily determined.
Next
slide, please.
The
final part of the development of this material was carried out in Europe late
last year by our subsidiary, FibroGen Europe.
What we did was actually take the material into a human safety study
designed to mimic a vaccine safety study, but did not have an active
component.
So
the gelatin was formulated into three different dose levels. The middle dose in a dose escalation sort of
study, the middle dose is typically not a gelatin any one vaccine would expect
to have. The 60 milligram dose was a
fourfold safety increase to prove that the material would not have problems at
higher doses.
We
looked for both injection site reactions, as well as looked at the sera for any
reaction to the material or any reaction that may be related to the fact that
it was yeast-derived.
Next
slide, please.
The
results the we found in this study was that there was no evidence of any
dose-related effects on the safety or tolerability of the material. We didn't cause local or systemic injection
site reactions. We saw no biologically
significant changes in antibody production to either the material itself, the
yeast host cell proteins, or a common yeast contaminant called mannan.
We
also, just for safety sake, looked at antinuclear factors and rheumatoid
factors and saw no stimulation of those either.
So
in conclusion, I think we can, indeed, say that there is the potential for
replacement of some of these materials with more efficacious or safer
alternatives.
And
I thank you for your time.
DR.
FREAS: Thank you very much for your
presentation, Dr. Polarek.
Our
next presentation is Dr. Michael Hansen.
DR.
HANSEN: Thank you.
My
name is Dr. Michael Hansen. I work for
Consumers Union. They're the publisher
of Consumer Reports magazine.
Members of Consumers Union are people that subscribe to Consumer
Reports. We have 4.5 million
subscribers to the print magazine and over one million subscribers to the Web
version of that.
We've
been actually, since 1997, have been trying to get FDA to take action on the
feed rule. We first would like to
commend the FDA for the actions that they took earlier this month, but we
believe more needs to be done.
First,
specified risk materials in the present feed rule, specified risk materials
from TSE positive animals are permitted to go into the animal and pet food
chain as long as they're labeled "do not feed to cattle and other
ruminants." We don't think this
should be allowed.
Furthermore,
we've been promoting or proposing that we should follow the European model,
which is no mammal to food animal should be allowed or the International Review
Subcommittee said that mammal and poultry protein should not be allowed to be
fed to ruminants.
Either
one of those, I think, would be fine, but I think it is important as the
International Review Committee pointed out that with any program, quote, this
recommendation must be enforced through an inspection program, including
sampling and testing of feed.
We
heard this morning that there's only five institutions out of compliance with
feed rules, but that ignores the fact that, as Dr. Sundlof said, they're not
really testing or looking at what the million farmers who have cattle are
actually feeding because you can still go into feed stores and other places and
buy these feeds.
So
we need to know what's happening on the farm to see what the real compliance
rate is.
Another
part of the feed rule had to do with record keeping. In the rule that was finalized, all of these facilities were told
that they needed to keep records for one year.
We had argued that, given that the incubation period averages five
years, that they should actually be keeping records for ten years, and we would
argue that if the United States and Canada had done that when they passed their
feed rules in '97, that for the first year of life of both of the cows we could
have actually traced where they got their feed from and then where those
batches of feed were fed to other animals, which would have helped a lot in the
epidemiological investigation.
The
other area that we're concerned with is the whole area of supplements. The FDA has now said that SRMs from 30
months and older cannot be allowed to go into supplements. We don't think that's good enough because if
you look at the DEFRA Web site in the U.K., they actually list the youngest age
and the second youngest age of animals
positive for BSE every year, and throughout the '90s there were animals always
below 30 months.
I
point out in 1992 there was an animal as young as 20 months, and to give you an
indication of the glandular area where brains and other things are being used,
it has been estimated to be 50 to $100 million a year. I would like to give you, just as an
example, there was a report in The New York Times. I told the reporter about a company, and he
actually did a little investigation I'd just like to read a few from this. This is from the January 27th New York
Times. I think it will show you the
problems with the supplements.
For
example, Health Genesis, a Florida company, sells 100 capsule bottles of bovine
brain concentrate -- it's actually 360 milligrams -- promising, quote, tissues
processed at low temperatures to ensure rawness. David, a salesman who would not give his last name or the name of
the owner of Health Genesis, said, "This whole thing about mad cow disease
is so new," and explained, "We assume it's safe because it's made
available by the people who make it."
After
telling a reporter that "there are people selling fried brains in
Alabama," David insisted that the reporter call the manufacturer of the
supplements, Rocky Fork Formulas of Newark, Ohio. Ken Michaelis, who said he was "just a phone answerer"
for Rocky Forks' president, but who according to the company's website is one
of the founders, said Rocky Fork did not make its own brain concentrate and who
did was "privileged corporate information."
Mr.
Michaelis said that he had not heard of Monday's FDA ruling, but said that he
believed that concentrate was safe because "you can't get glandulars from
countries with mad cow," end quote.
He could not name the country the brains came from, but said there were
"tons of manufacturers," some domestic, nor did Mr. Michaelis know
how old the animals were or whether they were ever tested for prions. Mr. Michaelis said there were no tests for
prions -- there are several -- and insisted that "they've never been able
to prove that mad cow is transmitted to humans." Health authorities emphatically disagree.
So
I think the supplement industry can be problematic.
We
would also point out that besides the SRMs mentioned, we're particularly
concerned with velvet antler, which comes from deer and elk, particularly
elk. There have been cases of champion
elk producers in terms of velvet antler having come down later with chronic
wasting disease.
Now,
velvet antler has never been tested, but since it is primarily nerves and
blood, I would bet that it probably would be infectious. So we think that's another supplement that
should be looked at.
Finally,
at a meeting a couple of years ago Paul Brown brought up the fact that in the
sports supplements, that the calcium often comes from bones, and the concern
there, of course, would be the bone marrow that would be inside. That would be at the lower end, but I think
this whole area of supplements does need to be looked at, particularly these
glandulars.
And
I would urge that the committee look at this issue again and also look at the
feed rule.
Finally,
I'd just like to make the comment that it was brought up about these atypical
animals in Japan. Earlier today, since
I was interested in the Italy and France and Japanese cases, I asked Paul Brown
about them, and he showed me a slide, and you should look at it because it
looks like the 21 month old from Japan was an atypical, but the 23 month old
actually looks like classic BSE by immunohistochemistry, electrophoretic
mobility, and other characteristics.
So
you should talk to him about that, but again, in sum, we think that the feed
ban needs to be strengthened, and we would urge this committee to also look
more carefully at the supplement area.
Thank
you.
DR.
FREAS: Thank you very much for your
comments, Dr. Hansen.
Is
there anyone else in the audience who would like to take advantage of this open
public hearing and address a comment to the committee?
Yes,
yes. You can use whatever microphone
you want. Is that microphone on?
DR.
GOLDSMITH: Yes, it is. Thank you.
DR.
FREAS: Would you please state your name
and any affiliations you may have with anything in common?
DR.
GOLDSMITH: Yes. My name is Jonathan Goldsmith, and I'm the
interim president of the Immune Deficiency Foundation, and I represent the
Immune Deficiency Foundation today and our sister foundation, which is known as
Single Use Device. I'm a full-time
employee of the Immune Deficiency Foundation.
Discussion
this morning raised important questions about human-to-human transmission of
variant CJD. We are concerned about
risks to vulnerable populations, such as those with primary immune deficiency
disease and, of course, the larger population.
Currently
various types of single use medical instruments, including endoscopy equipment,
vascular catheters, and biopsy instruments, can be reused after cleaning
without notification of the patient.
However,
these devices may have hard-to-reach areas that could inadvertently transfer
blood from person to person. We
respectfully ask the TSE Advisory Committee to review this situation, including
the adequacy of the cleaning protocols, to address the potential role of reuse
of medical instruments in the transmission of variant CJD and other blood-borne
infectious agents.
Thank
you.
DR.
FREAS: Thank you for your comments.
Would
anyone else like to make a comment?
Yes. In the back of the
room. Please come to a microphone, give
your name and state any affiliations you may have with a regulated industry.
MR.
ROACH: Yeah, my name is Steve
Roach. I'm with Food Animals Concerns
Trust. We're a nonprofit that deals
with how livestock are raised, trying to improve animal raising to protect
public health.
I
basically have a comment about Dr. Gambetti's question about, well, if we had
one out of a million, does it mean we have ten, and one thing that I am
concerned about is that kind of the way it was answered was, well, maybe the
inspectors are actually selecting things because I guess Josh Cohen said that
because of the attributes it might not be the same population.
But
I think that's not really correct. If
you look at it, it was selected because it was believed to be a downer because
of a calving injury, not because it was showing signs of BSE. So there wasn't any selection in terms of
that attribute.
And
also initially, we believe it was four years old, not born before the ban. So it wasn't selected for that reason.
Also,
we originally had -- The USDA says their sampling was to look at one out of a
million, but then they assumed that all of those one out of a million would be
in that 200,000 that were going into slaughter, and then they would have
detected it.
But
now this year they say, well, actually that calculation was 600,000. So what that suggests to me is that if it
really had been one out of a million, we weren't really sampling enough to find
one out of a million so that we found it.
We probably have more than one out of a million. You know, if they assumed -- if you looked
at what the USDA said, they assumed that all of the 45 cattle that they would
have found were in that 200,000, and that did not include any cattle that
didn't come to slaughter, and now they have moved it up to 600,000.
And
in terms of that, my final question or my final statement is, the USDA has
said, "Well, we've doubled that number to 40,000 for next year," and
I think that's been used as a way to say, "Well, we're doing enough testing," and USDA has said and it's been
reported in the media that we have done enough testing, but I think the problem
is that we've already set our target for this year, but we haven't decided the
rational.
And
what this committee has heard by several of the speakers is what your target
for surveillance is depends on your rationale.
But we already have a target, but we don't have a rationale, and so what
I really strongly suggest is that, one, from the evidence that we have, we
probably do have more than that. Just
this probably wasn't a fluke case.
Otherwise we wouldn't have picked it up.
And
also that we really do need to have a public meeting to discuss what is the
rationale for the surveillance program.
And again, that's more of a USDA question, but I think it really needs
to be addressed, and I think it hasn't been addressed, but we do have a target,
and I think that's very misleading to the public to choose how many cattle
we're going to sample without deciding why or what we're sampling for.
If
testing doesn't protect public health, then we shouldn't do testing because it
costs a lot of money.
DR.
FREAS: Thank you for your comments.
Is
there anyone else who would like to address the committee at this time?
(No
response.)
DR.
FREAS: Seeing none, I close the open
public hearing and turn the microphone over to you, Dr. Priola.
CHAIRPERSON
PRIOLA: Okay. So as everyone can see from our schedule now is when we're
supposed to engage in committee discussion on factors to consider in risk-based
sourcing models for bovine materials.
A
lot of comments were made during the questioning after the various talks today,
and I know the FDA has been listening to that and taking notes. So those comments are out there.
Are
there other things that anybody on the committee would like to comment on about
the question today? Yes, Dr. Linden.
DR.
LINDEN: Well, this is actually a
question that was prompted by some of the public comments.
Not
being an expert remotely in this area, I have a question for somebody with
expertise in BSE. Have there been cases
of vertical transmission of BSE? And
it's a question of whether a fetus is really considered young without
considering the age of the mother cow because we know that viruses are transmitted
transplacentally all the time. If the
mother had prionemia, do we know that the fetus could not get prionemia if she
were shedding prions? Has that ever
been observed? Do we know in BSE
countries, you know, relevant to this, you know, 30-month question?
Because
that's assuming exposure after they're born, and this is a whole separate
question.
CHAIRPERSON
PRIOLA: Dr. Jenny or Dr. Creekmore, any
USDA people want to comment on that?
Dr. Jenny?
DR.
FERGUSON: Thanks, Al.
CHAIRPERSON
PRIOLA: Okay. Dr. Ferguson.
DR.
FERGUSON: I don't think there's a
specific answer to that question. I
don't think anybody knows, you know, truly is there a barrier there between the
dam and the fetus.
There
has been one study done on maternal transmission. It still leaves a lot of unanswered questions. It could not completely rule out the
possibility of maternal transmission, especially with a higher likelihood of a calf being infected the closer it
is or the longer it is into the incubation period.
Sorry. I get sort of brain dead at this hour.
Anyway. So if the dam had clinical signs or if she
was close to expressing clinical signs, you had a higher probability of
transmission to that calf, but even if that truly does occur, it's not at a
significant level. So that type of
transmission is really not contributing to the ongoing epidemic in the U.K.,
for instance. It wouldn't be sufficient
to maintain that level of an epidemic.
Can
we say it doesn't happen? No, I don't
think we can say that.
There
has been some interesting work done with the scrapie stuff. I don't know that I'm familiar enough with
it. I'd have to go back and review some
of that with the scrapie research that has gone on. I don't think it's safe to extrapolate that directly to BSE,
however, in any way, shape or form.
DR.
LINDEN: Well, my question is, can we
say that the fetus is absolutely safe regardless of the age of the mother,
which is what the manufacturers are saying.
DR.
FERGUSON: I don't think we have enough
scientific information to say that at this point.
CHAIRPERSON
PRIOLA: Okay. Dr. Bailar.
DR.
BAILAR: I have just a question because
I'm confused about something. I think I
heard two contradictory statements here.
How many apparently healthy cattle are tested at the time of slaughter,
not the downers, not the dead ones? You
know, the run-of-the-mill cow or whatever that doesn't have any signs of
illness, are any tested?
DR.
FERGUSON: No, not at this point.
DR.
BAILAR: I saw some numbers on a slide that
left a gap of about 600, but if there aren't any, that's fine.
DR.
FERGUSON: Yeah, I think if you're
referring to my slide where it showed, you know, the total number and then we
listed on ambulatory animals and we listed deads, the other population out
there are CNS signs, sick or suspect animals.
So they are not health animals.
They have some type of clinical signs that could remotely be considered
consistent with BSE.
DR.
BAILAR: Thank you.
CHAIRPERSON
PRIOLA: Dr. Nelson.
DR.
NELSON: Yeah, I just wanted to ask one
question. We're relying a lot on the
pathology and the immunohistochemistry for signs of infectivity, but I just
wondered how well immunohistochemistry and infectivity correlate.
In
other infectious diseases we often see infectivity before there's pathologic
evidence of, you know, in tissue that infection is present, and we're certainly
-- that may be difficult to answer in this question or in this circumstance,
but I think it may be an important question.
CHAIRPERSON
PRIOLA: Okay. This time, Dr. Jenny, you have to answer that.
DR.
JENNY: The correlation is very well in
the scrapie, and I'm really not sure with BSE.
There hasn't, to my knowledge, been a report on where they've compared
the testing to infectivity.
Immunohistochemistry
is considered the gold standard for BSE testing by OIE, but I know of no study
that -- you know, we say that the demonstrating -- demonstrating the protein,
that is used as marker for the disease, but is that the same as infectivity? That's to be answered.
DR.
NELSON: I'm sure it's specific, but is
it sensitive? I guess that's the issue.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Yes. All of the evidence argues that the protein
is the infectious agent. The question
is how much protein per infectious unit and for each strain of agent and for
each animal species.
In
the hamster models, like I think I mentioned before, about ten to the fifth
prion protein molecules per infectious unit.
So the other question though is sensitivity of the test. The immunohistochemistry -- let's say the
most sensitive tests available today, which are these real fancy ELISA-type
tests using europium and phosphotungstic acid, precipitation of the abnormal
forms of the prion protein are two to three logs more sensitive than
immunohistochemistry and one to two logs more sensitive than Western analysis.
And
certainly with this approach it has been possible to find infectious or
abnormal prion protein in regions of the brain without pathology or without
immunohistochemical evidence of disease.
So
it's a difficult -- the testing doesn't necessarily, with Western analysis or
with immunohistochemistry, doesn't necessarily identify where the infectious
protein is located. You need a little
more sensitive tests, and right now these high throughput assays are even
better than bioassays. You can see
protein even when no animals come down with infectious infectivity.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
GAMBETTI: Just to add to what Steve has
just said, there are human prion diseases that simply cannot be diagnosed by
immunohistochemistry, but they are diagnosed by Western blot and, of course,
even by more sophisticated methods as Steve was indicating or mentioning.
DR.
DeARMOND: Yes, Pierluigi made that very
clear to us when we misdiagnosed a case, and he showed us that it had to
be. So we went back and looked again,
and we did find it.
DR.
JENNY: The one thing that you have to
remember is, you have to have the right part of the brain. The amount is so variable that you have to
look at the right part of the brain.
CHAIRPERSON
PRIOLA: Dr. Hogan.
DR.
HOGAN: I'm going to go back a long way
to the FSIS presentation, and since she's not here -- I don't see her -- I'll have to ask you, Lisa. Sorry.
How
do you confirm that AMR material has no brain, spinal cord, or dorsal root
ganglia? I mean, do you take a product
and test it? So how, or do you just
take the manufacturing process?
DR.
FERGUSON: Okay. Actually FSIS has been testing that product,
and I can find some of these and perhaps bring them in tomorrow, but they did a
survey, and they have results posted on their Web site of the type of testing
that they have done, both for beef AMR product and pork-derived AMR product,
and essentially it's a test looking for the presence of central nervous system
tissue.
I
am going to misspeak if I try to say an ELISA if they are just doing
microscopy, but anyway, it is a test.
Now,
they are doing this on lots of product.
I don't know if you've ever, you know, been in a slaughterhouse to see
the size of the bins and the type of lots that are used, but it's not just a
reliance on certification.
Now,
in addition, though, with the new regs that they do have out, not only is that
testing a significant part of it, and that also deals with some of the labeling
issues, but they're prohibiting that process to be used for skulls and
vertebral columns of animals greater than 30 months of age.
DR.
HOGAN: It seems to me it's critical in
terms of labeling or not labeling something as MS.
The
second question, the whole issue of feed ban has to do with compliance. Has USDA looked in any study to assess
compliance?
I
can tell you, you said you talked about cowboys in Arizona. I was there three weeks ago, and there's a
large cattle rancher there who says that he can go into his feed store and buy
ruminant material that's designated for poultry and feed it to his cattle. He sometimes has to look for that because it
has to be labeled on bag, and he has to find which one is necessary.
So
it's possible that that could be done inadvertently, but has there been any
kind of study done to see what actual compliance is? It becomes an education issue for the rancher.
DR.
FERGUSON: You mean compliance at the
farm level?
DR.
HOGAN: At the farm level.
DR.
FERGUSON: No, not exactly, although is
anybody from CVM still here?
(No
response.)
DR.
FERGUSON: No, unfortunately not.
They
have done some on-farm inspections. I'd
have to go back and look for those numbers.
So some of that has been done.
You know, do we feel like that's, you know, representative of a real
picture across the U.S.? I don't
know. I doubt it.
But
the on-farm level, that's the real issue.
I mean, as you say, you could go out and buy whatever, and if you choose
to knowingly go against that, you know.
DR.
HOGAN: There's an economic advantage
to, in one case, to be compliant, and it's also not be compliant if it's
cheaper to get the stuff from poultry.
Like
I came here in a cab last night. The
speed limit on 16th Street is 30. We
were going 55. He wanted to get here
faster so that he could get another fare.
So I think it's a critical issue of how ranchers are being educated to
not break the rules.
DR.
FERGUSON: Yes, I think that's crucial,
but I think also, you know, there has been some monitoring done on price
differentials between meat and bone meal, poultry meal, soybean meal, that type
of stuff, and there's not been a significant -- you know, I mean, there's normal
fluctuations in the market obviously, but there has not been a major
differential at least until now.
DR.
JOHNSON: There was an earlier quote, a
study that someone quoted that 15 percent of the farmers didn't know the food
ban existed, but I suppose after December that's probably improved a lot.
DR.
FERGUSON: Oh, I don't know. There's a lot of folks out there that don't
know a lot of things exist.
CHAIRPERSON
PRIOLA: Mr. Bias.
MR.
BIAS: Based on the information I've
heard today, you know, I get a little punchy here at night, so USDA, FDA, FSIS
needs to put together a group that looks at inspection and compliance outside
of the current process. There needs to
be some separate group put together that looks at this process from the
different point of view because it just sounds too much like business as usual.
Now,
we have put all of the safeguards prior to finding a cow in place. Now we found the cow, and we need to take it
to the next level because everything I've seen or read says that if there's one
cow, there's potentially more cows.
So
before this thing works its way into the United States human population, as the
United Kingdom is now dealing with, we have to take this to the next level,
whether it's inspection, compliance.
There are just too many factors I have heard today that are just sort of
unchecked out there that are just being allowed to go about and assuming
everybody is doing the best they can.
I
can tell you from my own personal experience in the bleeding disorder community
when people begin to die, we will all have to live with those decisions. It won't be what we thought was going to
happen. It won't be a risk analysis. We will be actually answering some mother,
some father, some family members plea as to why didn't you do something about
this when you had the chance.
And
we will all have to wake up in the morning and look at ourselves in the mirror
and assure ourselves that we did everything possible to prevent this from
growing any further, and from what I've heard today, I'm just not confident
that we're taking that extra step.
I
think the appearance of a cow that was infected and that we caught it is a
great thing, but now we need to take it to the next step, and I just don't hear
us doing enough of that here today.
DR.
GAMBETTI: I agree. I agree.
DR.
FERGUSON: Well, I guess I'd ask folks
to clarify what exactly do you mean by take it to the next step. You know, are you talking about additional
regulations on top of the ones that have already been described?
You
know, if you're talking about compliance issues, that's sort of another
issue. If you're talking about third
party audit of existing government programs, that's also another issue.
I'd
just emphasize that, you know, especially on the FSIS side and also probably on
the FDA side -- and those that are still here
can correct me if I'm wrong -- you know, we're not starting from a
nonexistent system. We are building on
an already existing inspection system and food safety system and are just adding
other regulations on top of those.
So
there already are processes in place to insure compliance with basic public
health regulations, basic food safety regulations. So I'm not quite sure exactly what your issue is and what you're
recommending there.
MR.
BIAS: When you're dealing with safety
of the public health, sometimes you have to do all of the things you've
normally been doing, and I think you've been doing all of the things you've
normally been doing.
My
statements are not related to a question of blame about anybody about what
they've been doing so far. I think
you've done some outstanding things to place regulations in place, to avert
this incident in any way that you could.
But
now you have another opportunity to take what you've been doing and turn it on
its head and look at it again, and that's what I'm encouraging you to do.
And
my only suggestion here is that perhaps you should take a few of your best and
brightest people from each of these agencies, put them in a room and allow them
to go at the problem outside of the influence of Congress or the industry
involved.
DR.
FERGUSON: Realistically, outside the
influence of Congress, I think, is a bit of a challenge.
(Laughter.)
DR.
FERGUSON: And I think my colleagues in
this room would say we've been meting quite a bit, actually, since May 20th,
2003, and at an increased level.
MR.
BIAS: It's a little different when you
formalize the relationship and you're forced to give a report based on a new
relationship that you formalized between the agencies. It's more than business as usual.
And
I'm not saying business as usual has not been a good thing so far, but I think
you have another opportunity here, and I think you need to seize that
opportunity and make some changes in the way that you look at the problem.
And
one way to do that is to take a couple of your best and brightest from each
agency, and separate them from the current process and allow them to make some
stabs in the dark about what else we could do about this.
And
if you don't do that and we continue with business as usual, somewhere down the
line, I'm afraid we may regret it. I'm
not saying do it forever. Put it in
place for, you know, five years or so and see if there are any results, and if
there aren't, then do away with it.
But
in the immediate term, since we have identified a cow, do something differently
than we're doing it right now, in addition to the regulations that you have
proposed and implemented so far.
CHAIRPERSON
PRIOLA: I want to make the one comment
that, in fact, this is, exactly what you're saying is one of the major reasons
I believe that FDA has put this meeting together, is to look at the current
state of affairs, what we might do in the future, and is there scientific merit
to do those things in the future, and does it protect the public health in
terms of risk versus benefit?
And
so I think that's what today was all about, was in many ways gathering
information to do just what you say, to try to see if we have to, should, need
to take it to a different level. And
that's just my opinion, but I think you're exactly on track.
It
is Dr. Bailar, then Dr. DeArmond, then Dr. Bracey.
DR.
BAILAR: Mr. Bias is right on target,
and I thank you, sir. I can get us
started with three steps I think are feasible that can be added to what we
have. One is a national system for
tracking individual animals.
Second
is to have more and more realistic risk assessments. Now, what we've heard, I think, is a big step in the right
direction, but these need to be taken several steps ahead.
And
third is to expand testing. I don't
know if we need to go to testing of every animal, but certainly a great deal
more than we have now, including some testing of apparently healthy animals at
the time of slaughter.
DR.
DeARMOND: I'd like to follow up on your
comments also and similarly in that he says what would be the next step up, and
what if that cow had been slaughtered before any signs had shown up and it
wasn't a fallen cow? They decided that
they didn't want that cow anymore and they wanted it to go in to be processed.
No
one would have known that it had BSE, and it could have gone into the food
chain. So I would agree that from what
I learned today is, I was surprised to learn that we're importing 1.6 million
head of cattle from Canada, and we only send about 50,000 back to them, and I
keep wondering. No wonder we have a
deficit in our country, a trade deficit.
But
the other aspect of it, what else could we do?
I think we do have to track these animals, particularly the ones that
are coming in from outside, and then the next step would be our own animals,
and as I say there are ways of doing it today with subcutaneous tracking
devices.
But
the other is testing, and I go back to the argument that there are two
questions. One is an epidemiology
question in which you can do a more statistical approach, and the other is from
us. We want to know that that
particular cow didn't have the disease that we're eating.
So
that means increased testing, and if it means beginning by looking at the
animals over 30 months of age, that would be fine. Get the ones that are at higher risk and look at them. It can't hurt.
Calculations
say it's only -- I said ten cents per pound extra for beef, but I understand if
you look at the amount of beef you get, it's about three cents a pound, and by
golly, to be assured that you're getting a good product, that would be fine,
and certainly for the pharmaceutical industry if you could make it easy for
them to say that you've done all of the possible tests and this animal has been
raised in an environment that is free of BSE, why should they be getting serum
from Australia and New Zealand? They
should be getting it from the United States.
CHAIRPERSON
PRIOLA: Dr. Bracey and then Dr.
Gambetti.
DR.
GAMBETTI: Yeah, I'd like to echo the
comments made earlier. Coming from a
very regulated industry, I think it's very nice to assume that controls will
lower the risk.
However,
we know from transfusion practices and blood bank practices that there is no
such thing as zero risk.
Fortunately
for us, what we do have as a backup is the testing that we do, and we've been
very aggressive at using the testing.
So I think despite all of the controls that we have and despite taking
it up to the next level, we still will be at risk for error, and I think that
perhaps we can't test every animal, but we should test as many animals as we
possibly can.
DR.
GAMBETTI: I also agree with the comment
by Mr. Bias, and I would like to emphasize another issue. That is, other countries, the continental
European countries have gone through the same kind of agonizing decision about
testing, how much testing, whether testing at all or not, and some of them had
made mistakes initially that had to be corrected at a cost.
So
I would recommend that we analyze that error or that decision that were made
early by this country, and we don't repeat the error that they made.
CHAIRPERSON
PRIOLA: Dr. Sejvar.
DR.
SEJVAR: Just one quick comment, I guess,
since we're talking about testing, but it has been stated, you know, before a
couple of times that, you know, I mean, the level of testing, I guess, in a lot
of ways needs to be considered in the context of what we're going to do with
the information. I mean, I would assume
it's a fairly expensive proposition, and if the ultimate goal is simply to
reassure ourselves or to get a better sense of what level of infectivity we may
have, that's fine.
But,
again, I mean, I think that any decision along these lines needs to be made in
the context of what you're going to do with the data.
CHAIRPERSON
PRIOLA: Dr. Creekmore.
DR.
CREEKMORE: I guess I would second the
comments that were just made, and also sort of, I think this is a very good and
interesting discussion, but have we strayed from the need that FDA put before
us about factors to consider and risk-based sourcing models for bovine
materials versus overall surveillance strategies.
CHAIRPERSON
PRIOLA: I think we might have strayed a
little, but the FDA is hopefully still getting the information they need just
from the discussion, I hope.
Dr.
DeArmond.
DR.
DeARMOND: Well, I see testing as adding
one of the other factors, risk factors.
If it's positive, that cow goes.
I mean, it's a yes/no. It's a
digital type of decision, and today the testing is sensitive enough it can pick
up disease that you can't see by standard techniques.
So
if it's negative are you 100 percent sure?
No, but you're 99.9 percent sure that it's all right, and at least the
public and the industry knows that the best has been done to insure the safety
of the product instead of just saying, "Well, we don't want to test
because it's going to be too costly," so that the people never know and
industry never knows.
You
can give them a yes or no answer at least and a good one, good, educated one.
CHAIRPERSON
PRIOLA: Dr. Khabbaz.
DR.
KHABBAZ: Yes, along with the
recommendations of things to consider, I would add, basically strengthening the
feed restrictions. I know the FDA told
us that they've put some interim or they?ve already
put some restrictions in place, but I think consideration to strengthen them
along the line of what the USDA advisory committee has recommended ought to
also be considered.
CHAIRPERSON
PRIOLA: Dr. Hogan.
DR.
HOGAN: Yes. And, Lisa, I'm really sorry that I keep picking on you here. You're the only person here, but the other
question is I'm sure, talking about what Europe has done in terms of
consideration, they now do not allow feeding any animal proteins to
cattle. I'm sure that your committee
looked at that and the ramifications.
Was
there a decision to make what these regulations are now as a first step and
then later to prohibit any kind of animal protein feed or what were the
implications of that decision?
DR.
FERGUSON: Well, okay. One thing to keep in mind is that feed
restrictions are done under FDA's authority, and that was the USDA Secretary's
Advisory Committee. Okay? So there are some between-agency issues
there.
I
think though when you're looking at feed restrictions, what you need to
consider is kind of a broader picture.
I guess in many ways I look at the European experience as in some ways,
going way on one side of what needs to be done for various reasons, compliance
issues, you know, their own issues.
They
had several things especially on the feed side that led them to that decision,
not all of them solely TSE, and they had some several consumer confidence
issues in 2000-2001 that they had to deal with, and they chose various
different ways to deal with them.
Do
we need to do the same thing? I don't
know. Those are the types of things
that really seriously need to be examined rather than just saying, "Well,
Europe did it. We need to do it, too,
because we're the same."
I
don't think we are the same, and you know, the whole point about feed is to
prevent contaminated feed from being fed back to ruminants. So preventing ruminant protein from being
fed back to ruminants, yes; prohibiting the use of all animal proteins in
ruminant feed is one way to do that.
Is
that the only way to do that? No, I
don't think so. There are other ways to
do it, including using dedicated facilities and insuring that product is only
going one way, and there is no way, you know, for it to be diverted from the
poultry feed chain, things like that.
There
are other options out there, and especially as a regulatory agency, those are
the types of things that you really need to look at because sometimes it seems
rather straightforward and rather simple to say, "Oh, well, just prohibit
this."
But
what you have to look at is, well, what are you going to do with that
product. What other follow-on effects
is that going to have? How much is that
going to affect the economy and the infrastructure in the U.S. and what are the
other issues that that might create that might be bigger than the risk that
you've tried to mitigate?
You
know, so that's all of the types of stuff that needs to go into that type of
decision.
CHAIRPERSON
PRIOLA: If there are no other comments
except for Dr. Rohwer, Bob, would you like to say something before we close?
DR.
ROHWER: Yeah, I think you're missing
one of the prime values of testing that hasn't been discussed, and that is we
don't have any independent measurement of whether or not the feed ban is
actually working, whether the compliance is actually working, and the value of
testing is to track trends, to know whether the instance and the prevalence
rate is going down or it's going up at any given time.
And
personally I would like to see the testing ramped up, just so that we had a
handle on that particular piece of information.
I'll
leave it at that.
CHAIRPERSON
PRIOLA: Dr. Nemo.
DR.
NEMO: I'll just add into the fray. I think the beauty of testing is that it's a
good quality control check for all of the errors, all of the mischief, and all
of the mistakes that can be made, you know, getting the wrong bag of feed,
maybe not the surveillance that you'd like to see, but when that animal comes
to slaughter, if a test is done, then it certainly adds some assurance.
So
I think that's the beauty of the test.
The system isn't perfect for sure.
The USDA is trying their best and the FDA to make it as effective as
possible, and there's the economic considerations. I think everybody is sort of glossing over the economics, and I
think that's an issue, and it could be very expensive, and nobody wants to talk
about risk assessment in the terms of, you know, what does it cost per patient
year and those kinds of issues.
So
I agree. I think it should be
discussed. I think bright people are
involved in the discussion right now, but it's certainly worth looking at, what
the next steps are.
CHAIRPERSON
PRIOLA: Dr. Bailor.
DR.
BAILAR: Cost of testing, I think it's
now about 20 dollars per test, something like that.
DR.
JENNY: That's for lab tests. Now we've got a lot of other costs that are
involved when you consider the whole picture.
DR.
BAILAR: What is the total cost of a
test now? I can tell you what I would
say. If there is a major expansion in
testing, there will be an awful lot of people out there trying to find cheaper
ways to do it, and the cost per test will go down. I'm absolutely sure of that.
DR.
FERGUSON: But the significant point
there is not just the cost of the test.
That's really not what is the driving issue. It is all of those affiliated costs with who is collecting the
sample. Are you paying for, you know,
storage out of something before you get a test result back? Are you paying for disposal of certain
things?
That's
all of the affiliated costs that are far and above the, you know, 20 bucks a
test kit, 15 bucks a test kit, whatever.
DR.
BAILAR: But I think those costs will go
down, too.
DR.
FERGUSON: There are certain fixed
costs, you know, to pay a government employee to do something that really don't
go down.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Well, that's one of the
reasons this shouldn't be done by government employees because this is going to
generate more money, ultimately. If you
can insure that your beef is safe, people buy it, and again, the import/export
is unbelievable. We should be supplying
to other countries. Why should we be
not as good at preventing BSE than New Zealand and Australia?
We
should be doing it better than they're doing it, and that means more beef
products could be sold to industries as well as to individuals. More taxes are made. Then the government can get more employees
to do a lot of these other things.
It
just make sense that if you insure that you've got a good product and it's
safe, it generates its own money.
CHAIRPERSON
PRIOLA: Dr. Bracey.
DR.
BRACEY: I was just thinking in terms of
the requirement for additional associated cost with testing, well, I think you,
in essence, are going to have to have additional costs in order to better track
the animals, and if you're tracking the animals in testing and not releasing, I
mean, then you really are forced to have control. Otherwise you don't.
CHAIRPERSON
PRIOLA: Dr. Gambetti.
DR.
GAMBETTI: Again, I have to remind you
that all industrialized countries are already facing this cost. The United States and Canada are the two
major countries that have not. All the
others, all European countries, Japan are already facing this cost. Their beef reflects this cost.
So
they have already gone through this and decided to do it.
CHAIRPERSON
PRIOLA: Dr. Ferguson.
DR.
FERGUSON: Just on the cost issue, I
think the French did a calculation at one point in time and it had cost them
about a million euros per case that they've found.
CHAIRPERSON
PRIOLA: So I think what I'm sort of
getting from all of this is that one factor to consider in risk-based sourcing
is good surveillance, and whether that requires testing all animals or not is
up for debate, but good surveillance and compliance with regulations is
essential, I think, to do some of the things that people have discussed here,
if I'm understanding correctly.
Are
there any other comments or questions?
(No
response.)
CHAIRPERSON
PRIOLA: All right. I'll just remind people we have not broken
the overtime record. We're an hour
over, and that's actually pretty good compared to some other meetings, but I'd
like to thank all of the speakers and thank the committee members for their
patience and attention, and we'll reconvene tomorrow morning at 8:00 a.m.
(Whereupon,
at 6:36 p.m., the meeting was adjourned.)