FOOD AND DRUG ADMINISTRATION
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE
October 31, 2005
Holiday Inn Bethesda
Bethesda, Maryland
Proceedings by:
CASET Associates, Ltd.
10201 Lee Highway, Suite 180
Fairfax, Virginia 22030
caset@caset.net
PARTICIPANTS
Freas, William, PhD
Priola, Suzette A, PhD
Bias, Val D
Creekmore, Lynn H. DVM
Hogan, R. Nick, MD, PhD
Telling, Glenn C, PhD
Kranitz, Florence J.
Johnson, Richard T, MD
Salman, Mo D. DVM, PhD
Sejvar, James J., MD
James R. Allen, MD, MPH
Paul Brown, MD
David C. Bolton, PhD
David Gaylor, PhD
Michael Geschwind, MD, PhD
Bernardino Ghetti, MD
Susan F. Leitman, MD
James W. Lillard, Jr, PhD,
MBA
Arthur W. Bracey, MD
CONTENTS
PAGE
Administrative Remarks -
William Freas, PhD, CBER,
Executive Secretary,
TSEAC 1
Recognition of Committee
Service - Jesse L. Goodman,
MD, MPH, Director, CBER 9
Opening Remarks - Suzette
Priola, PhD, NIAID, NIH,
Chairperson, TSEAC 9
Informational Presentations
Update on US and worldwide
BSE status - Lisa Ferguson,
DVM, APHIS, USDA 9
Scientific issues in
evaluating products intended to
decontaminate surgical
instruments exposed to TSE agents:
discussion of a recent FDA
Device Panel 16
Topic 1: Progress Report on
FDA's Risk Assessment for
Potential Exposure to
Variant Creutzfeldt-Jakob Disease
in Human Plasma-Derived
Antihemophilic Factor (FVIII)
Products
Introduction and Questions
to the Committee - Dorothy
Scott, MD, OBRR, CBER 26
Variant CJD risk associated
with human plasma
derivatives: Introduction
and overview of risk model
Steven Anderson, PhD, OBE.
CBER 32
Update on vCJD in UK and
other countries: estimates of
prevalence
Richard Knight, MD UK
Director, CJD Surveillance Unit
Edinburgh
62
Azra C. Ghani, PhD, London
School of Hygiene and
Tropical Medicine 83
Modeling risk of vCJD in US
donors - residual risk
and efficiency of donor
deferral - Alan Williams, PhD,
OBRR, CBER
104
VCJD infectivity of plasma -
estimates from
experimental models - David Asher, MD, OBRR, CBER 119
Review of TSE clearance in
FVIII product manufacturing
Dorothy Scott, MD,
OBRR,CBER 128
FVIII product usage in
clinical settings - Mark
Weinstein, PhD, OBRR,
CBER 135
Open Public Hearing 146
Committee discussion and
recommendations 164
Topic 2: Labeling Claims for Filters Intended to
Remove TSE Infectivity from
Blood Components
Prospects for reduction or
removal of TSE agent
infectivity from blood
components by filtration and
criteria for allowing
claims: Introduction
Jaroslav Vostal, MD, PhD,
OBRR, CBER 219
Evaluation of prion
reduction filters
Mark Turner, MB, ChB, PhD, FCRP(Lond) University of
Edinburgh
230
Performance of Pall
Corporation Leukoreduction filters
on TSE infectivity of blood
components: experimental
studies and European
experience - Dr. Sam Coker,
Pall Corporation 242
Selection and performance of
resin-bound ligands for
removal of TSE infectivity
from plasma - Robert
Rohwer, PhD, PRDT (with
ProMetic and ARC) Rockville, MD 251
Other industry/academic
filter chromatography developer
Dr. Ralph Zahn, CEO, Alicon
AG, Schlieren, Switzerland 266
Open Public Hearing 275
Committee discursion and
recommendations 275
P R O C E E
D I N G S 8:06 AM
Administrative Remarks – William Freas, Ph.D., CBER, Executive Secretary,
TSEAC
DR. FREAS: Ms.
Chairperson, members of the Committee, invited guests, consultants and members
of the public, I would like to welcome all of you to this our 18th meeting of
the Transmissible Spongiform Encephalopathies Advisory Committee.
I am Bill Freas. I will the Executive Secretary for today's
session. The entire meeting today is open to the public.
At this time I would like to go around the head table and
introduce to the public the members who are seated at the table.
Will the members please raise their hands as their name is
called.
In the first chair on the right side of the room, that is
the audience's right is Dr. David Bolton, head, Laboratory of Molecular
Structure and Function, New York State Institute for Basic Research.
Next is Dr. Richard Johnson, professor of neurology, Johns
Hopkins University.
Next is Dr. Glenn Telling, associate professor, Department
of Microbiology, University of Kentucky.
Next is Dr. Lynn Creekmore, staff veterinarian, APHIS
Veterinary Services, US Department of Agriculture.
Next is Dr. James Lillard, associate professor of
microbiology, Morehouse School of Medicine.
Next is Dr. James Sejvar, medical epidemiologist, Division
of Viral and Rickettsial Diseases, Center for Disease Control and Prevention.
Next is Dr. Nick Hogan, assistant professor of
ophthalmology, University of Texas, Southwestern Medical School.
In front of the podium is Mr. Val Bias, Co-Chairman, Blood
Safety Working Group, National Hemophilia Foundation, Oakland, California.
Next is Dr. James Allen. Dr. Allen is Chair of FDA's Blood
Products Advisory Committee. He is, also, president and CEO of the American
Social Health Association.
Next is the Chair of this Committee, Dr. Suzette Priola,
investigator, Laboratory of Persistent and Viral Diseases, Rocky Mountain
Laboratories.
Next is Dr. Arthur Bracey.
Dr. Bracey will be serving as a non-voting consultant today. He is
Associate Chief of Pathology, St. luke's Hospital, Houston, Texas.
Next is our consumer representative, Mrs. Florence Kranitz.
She is President of the CJD Foundation, Akron, Ohio.
Next is Dr. Michael Geschwind, assistant professor of
neurology, University of California, San Francisco Medical Center.
Next is Dr. Susan Leitman, Deputy Chief, Department of Transfusion
Medicine, National Institutes of Health.
Next is Dr. David Gaylor, President, Gaylor and Associates, Eureka S[ring, Arkansas.
Next is Dr. Bernardino Ghetti, distinguished professor,
Director, Indiana Alzheimer's Disease Center, Indiana University, School of
Medicine.
Next is Dr. Mo Salman, professor and Director, Animal
Population Health Institute, College of Veterinary Medicine and Biomedical
Sciences, Colorado State University.
The chair at the end of the end of the table will soon be
filled by Dr. Paul Brown. He is a consultant from Bethesda, Maryland.
Our non-voting industry representative could not attend
today's meeting due to a medical emergency. Our efforts to recruit a
replacement in time for this meeting were not successful.
I would like to thank the members for attending this
morning. I, also, have one announcement to make. Dr. Alan Jenny passed away
last Thursday night. Dr. Jenny served as a member of this Committee since
September 2004 and was a consultant and speaker at many of our meetings prior
to his service on the Committee. Dr. Jenny was a pathologist at the National
Veterinary Services Laboratory for the US Department of Agriculture in Ames,
Iowa. He was well known and respected for his research on investigative studies
on numerous livestock diseases in the United States.
He was a kind and gentle man. He was a wonderful person.
Alan Jenny will certainly be missed by his family, this Committee and many
people the world over.
I would like to ask for a moment of silence in his honor.
Thank you.
I would now like to read into the record the conflict of
interest statement for this meeting. Some of you might think you are in the
wrong room. This has just recently been revised by our attorneys.
The Food and Drug Administration is convening today's
meeting of the Transmissible Spongiform Encephalopathies Advisory Committee
under the authority of the Federal
Advisory Committee Act of 1972.
All members of the Committee are special government
employees or regular federal employees from other agencies and are subject to
federal conflict of interest laws and regulations.
The following information on the status of this Committee's
compliance with the federal conflict of interest laws including but not limited
to 18 US Code, Section 208 and 21 US Code, Section 355(n)(4) is being provided
to the participants in today's meeting and to the public.
FDA has determined that members of this Committee are in
compliance with federal ethics and conflict of interest laws including but not
limited to 18 US Code, Section 208 and 21 US Code Section 355(n)(4). Under 18
US Code, Section 208 applicable to all government agencies and 21 US Code,
Section 355(n)(4) applicable to certain FDA committees, Congress has authorized
FDA to grant waivers to special government employees who have financial
conflicts when it is determined that the agency's need for the particular
individual's service outweighs his or her potential financial conflict of
interest, Section 208, and when participation
is necessary to afford essential expertise, Section 355.
Members of the Committee are special government employees
including consultants appointed as temporary voting members. Committee members
have been screened for potential conflicts of interest of their own as well as
those imputed to them including those of their employer, spouse or minor child.
Related to the discussions of progress in the development
of a risk assessment model for vCJD in human plasma-derived Factor 8 products
and discussions of the reductions of TSE removal, TSE agent infectivity from
blood components by filtration, these interests may include investments,
consulting, expert witness testimony, contracts, grants, CRADAs, teaching,
speaking, writing, patents and royalties and primary employment.
Today's agenda topics are considered general matters
discussions. In accordance with 18 US Code, Section 208(b)(3) general waivers
have been granted to all Advisory Committee members including Val Bias, Lynn
Creekmore, Nick Hogan and Richard
Johnson, Florence Kranitz, Susan Priola, Mo Salman, James Sejvar and
Glenn Telling.
In addition, a general matters waiver has been granted to
Paul Brown. A copy of the written waiver statements may be obtained by
submitting a written request to the agency's Freedom of Information Foundation
Office, Room 12A30 of the Parklawn Building.
With regard to FDA's guest speakers the agency has
determined that information provided by these speakers is essential. The
following information is made public to allow the audience to objectively
evaluate any presentation and/or comment made by these speakers.
Dr. Lisa Ferguson is employed by the USDA in Hyattsville,
Maryland. Dr. Azra Ghani is Director, UK, CJD Foundation, London School of
Hygiene and Tropical Medicine, England.
Dr. Richard Knight is Director, UK CJD Surveillance Unit, Western
General Hospital, Edinburgh, Scotland. Dr. Marc Turner is Clinical Director,
Scottish National Blood Transfusion Service, Edinburgh, Scotland.
As guest speakers they will not participate in Committee
deliberations nor will they have a vote. They are more than welcome to answer
questions though of the Committee and we hope they stick around to answer
questions of the Committee.
In addition there may be regulated industry and other
outside organizations making presentations. These speakers have financial
interests associated with their employer and with other regulated firms.
The FDA asks in the interest of fairness that they address
any current or previous financial involvement with any firm whose products they
which to comment upon.
These individuals from industry were not screened by the FDA for conflicts of interest. The
conflict of interest statement will be available for review at the registration
table. We would like to remind members that if the discussions involve any
products or firms not already on the agenda for which an FDA participant has a
personal or imputed financial interest the participants need to exclude
themselves from such an involvement and their exclusion will be noted on the
record.
FDA encourages all participants to advise the Committee of
any financial relationship you may have with firms that could be affected by
the Committee's discussions.
That ends the conflict of interest statement.
Before I turn the microphone over to our Chair, I would
like to request that everybody check their cell phones and please place either
in the silent mode or turn them off so that it won't be so disruptive to the
meeting.
Thank you.
Dr. Priola, I turn the meeting over to you.
DR. PRIOLA: Okay,
everybody. There are lots and lots of
questions and the first topic is basically to assess the risk assessment model
for variant CJD exposure. They want us to refine the input parameters and help
them to define input parameters. They just want advice. I am going to hold
questions after each speaker to just technical questions and only one or two of
those. We can ask after each group of speakers all the questions that we
couldn't get to in that first part and also ask some questions in the
discussion period.
Dr. Goodman?
Agenda Item:
Recognition of Committee Service – Jesse L. Goodman, MD, MPH, Director,
CBER
DR. GOODMAN: Okay, I have the opportunity to recognize the
services of three very distinguished individuals here and I would appreciate if
they would each come up, Richard Johnson who is of course a distinguished
neurologist. Should I do it one by one?
Okay, so, okay, it is the picture again. Dr. Johnson,
thanks so much.
Then we have Dr. Arthur Bracey and I will try to do better
with Arthur. Thank you, Dr. Bracey.
Okay, and Dr. Bracey, by the way is going on an HHS
committee or has already done that. So, thank you for that, too, and then Sue
Priola who obviously in addition to being a member has been the Chair of the
Committee for the last 2 years.
Thanks, Dr. Priola.
Agenda Itedm:
Opening Remarks – Suzette Priola, PhD, NIAID, NIH, Chairperson TSEAC
DR. PRIOLA: Okay,
we are ready for the presentations. The first is Dr. Ferguson from USDA.
Agenda Item:
Informational Presentations – Update on US and Worldwide BSE Status –
Lisa Ferguson, DVM, APHIS, USDA
DR. FERGUSON: Good
morning. I just have a few brief slides. You probably get tired of hearing me
every time you get together. Anyway I thought I would go over a little bit an
update both on what we are doing for BSE here in the US, also, a brief summary
of data from Europe as that is where the vast majority of BSE cases have
occurred worldwide.
Total BSE cases worldwide at this point greater than
189,000 cases worldwide with a couple of important points to remember about
that. First of all more than 96 percent of those cases have been in the UK but
more importantly more than 89 percent of those have really occurred in 1996 and
before.
If you are really interested in specific information on
individual countries and cases reported by year I have listed the OIE web site
and OIE is the world organization for animal health and as countries report
cases OIE has a specific table for BSE status and a calculated apparent
incidence rate.
Let us talk a bit about what the Europeans have done. They
have had very intensive surveillance since 2001. So, we have very good numbers
for comparison within the EU. One point though, as of mid to late 2004 there used
to be 15 member states in the European Union and now it is 25. So, that has
changed the numbers somewhat with the addition of 10 new member states to the
EU, but in 2004 they did a total of more than 11 million tests.
Of those about 9.5 million were apparently healthy animals
greater than 30 months of age at slaughter. One point five million are what
they call risk animals. These would be the same as our targeted population in
the US. These are animals with some type of clinical signs, falling stock, non-ambulatory
animals.
Out of all of those tests in 2004 they had a total of 865
positive cases and this is a decrease in the number of cases by about 37
percent and overall apparent prevalence also was decreased by about 38 percent.
If you look at the numbers for the year before similarly in
2003 they had about a 35 percent decrease form 2002. So, you see things
continuing to decline in Europe which is very encouraging. These reductions and
also the increasing age of positive cases really indicates the success that
they have had in Europe with their control measures. So, those measures that
they have imposed increasingly stringently do seem to be working.
If you look at an analysis by year of birth the positive
cases and we are assuming that most exposure occurs in that first year of an
animal's life, at this point with the 2004 data and granted this can change;
with long incubation periods you can still see increasing cases, but there do
appear to be exposure peaks pretty well defined in certain member states,
obviously the UK but outside of that. The data in 2004 show that France and
Ireland have an exposure peak about 1995, Germany, Belgium, Italy and
Netherlands about 1996. So, it would be interesting to see is that stays the
same as they get more data over the next couple of years.
There, also, is one note. They have increased their TSE monitoring in small ruminants and
are doing extensive analysis with that data from sheep and goats and they did
find one goat positive for BSE. It is an animal that was actually slaughtered
in 2002 with extensive analysis of how to define that case.
So, let us jump a bit to the US and I think as everybody
knows we have been doing an enhanced surveillance program since June 2004. I
would note we have done active surveillance for BSE in the US since 1990 but in
response to the cases in Canada we ramped up our surveillance a drastic amount
beginning in June 2004, and our goal of our enhanced program was to get as many
samples as possible from the targeted population in a 12-to-18-month period.
So, we were trying to go out there and get all the samples we could from that
population where you are most likely to find disease present.
Our targeted population is those animals that have some
type of a clinical sign that could be considered consistent with BSE. So, this
is a pretty broad definition. It includes animals that have classic clinical
signs of BSE, animals that have central nervous system signs, other types of
clinical signs that could be considered consistent, animals that are
non-ambulatory, animals that have died for unexplained reasons and then we are
also sampling animals that are condemned on antemortem inspection at slaughter.
This talks a bit about our assumptions. We are looking in
this targeted population as we have been since 1990 with the assumption that if
we can't find disease there in that population where we are most likely to find
it if it is present then we are even less likely to find it in a broader cattle
population or in a non-targeted population, but we can use the data that we get
from this targeted approach and extrapolate that as we try to estimate
prevalence in the broader cattle population.
Then just a summary of the targeted populations where we
are getting samples and we are working with diagnostic labs and public health
labs around the country also as they get neuro cases or rabies cases. We ask
them either to forward those samples on to us or to work with us to obtain
those.
This actually is previous surveillance. I didn't put in all
since 1990. So, you can see where we have been. Beginning in about 2002 we were
looking at between 19,000 and 20,000 samples a year and then in our enhanced
program since June 3, 2004, we have looked at more than 510,000 samples. So, we
have had very good success in obtaining access to the populations that we need
and getting these samples.
Out of all of this we had one positive case in June 2005, a
case found in Texas. This was a 12-year-old animal, a Brahma-cross, so a Bos
indicus type breed. We did an extensive investigation. Our FDA colleagues did
an extensive feed investigation. Clearly with a 12-year-old animal it is
sometimes a challenge both on the feed history
and trace backs and trace forwards. We were a bit constrained by records
on the premise of origin but we attempted to trace birth cohorts which we
defined very broadly from this animal due to the lack of records, traced those
animals, and we actually euthanized 68 animals total and tested those as birth
cohorts.
Our FDA colleagues in their food investigation really
didn't find something specific that they could pinpoint and say, "Here is
a likely source of exposure," but then that is not entirely unexpected
again especially if you are working with 12-year-old records.
As we go through my program we are continuing to evaluate
where we are and to ensure that we are accessing appropriate representation
around the country and we are getting pretty good geographic distribution.
The vast majority of our samples tend to be from dead stock
and non-ambulatory animals. This is entirely what we expected and really what
we wanted.
We are getting good representation from all the different
collection sites but clearly the majority of these samples that we are getting
are from animal disposal facilities, rendering facilities, what we call 3D, 4D
plants or salvage slaughter plants, dead stock. This is where our targeted
population shows up. So, that is where we are getting those samples.
We will be doing a very detailed analysis when we complete
our program. We are now in the 18th month of this and we hope to do an analysis
and have that out for public release very shortly thereafter after we are done
completely with the program and I just realized I didn't actually put anything
in about our Canadian colleagues and their situation. I know there is lots of
interest in what the Canadians are doing and have done. They have a total of four cases and the last
cases were those two in December 2004, January 2005.
They have ramped up their surveillance similar to what we
have done, also, doing targeted surveillance and at this point in 2005, they
are up to close to 40,000 samples.
So,they are, also, having very good success with obtaining
the samples that they need and with no further positives since those four in an
apparent cluster out there in Alberta, and in line with Sue's push to keep us on time if you are
looking for more detail, more info we do try to post everything that we can on our web site including updated numbers
and you can always look there to see the latest release from us.
Thank you.
DR. PRIOLA: You
will be around for the next few hours?
DR. FERGUSON; Actually I need to leave at the end of the
morning.
DR. PRIOLA: Our
second international presentation is by Dr. Sheila Murphy and she is going to
update on a new FDA Device Panel that discusses scientific issues in evaluating
decontamination products.
Agenda Item:
Scientific Issues in Evaluating Products Intended to Decontaminate
Surgical Instruments Exposed to TSE Agents:
Discussion of a Recent FDA Device Panel – Sheila Murphey, mD, CDRH
DR. MURPHY: Good
morning. Thank you for your interest in our committee. The Center for Devices
and Radiologic Health has asked one of our advisory committees to address the
scientific issues related to TSE screening of products intended to
decontaminate surgical instruments. This was our general hospital and personal
uses devices panel. The advisory
committee is asked to address the issues surrounding the evaluation of products
or processes intended to reduce the viability of CJD transmissible agents on
contaminated surgical instruments.
We believed that we needed more guidance on these issues.
There are a number of scientific issues addressing the removal of TSE from
instrument proxies is increasing in the literature.
Public interest about CJD and variant CJD and its potential
for causing disease in the United States is in fact increasing and DAGID
believes that it should prepare for the possibility that products or processes
intended to reduce TSE infectivity on surgical instruments will be submitted to
FDA for premarket evaluation.
There were a number of presentations at the scientific
panel. I am going to give you just some quick background on the four from FDA.
First, Dr. Elaine Mayhall presented a general overview of transmissible
spongiform encephalopathy concentrating primarily on iatrogenic transmission.
There are only six reported cases in the literature and
four of those are considered possible, not probable. None have been reported
since 1980. Small epidemiologic studies of the potential association between
surgery and risk of CJD have not resulted in consistent associations, some of
them positive, some negative. There are reports of patients exposed to
instruments used in the care of patients with Jakob-Creutzfeldt disease where
the recognition of that exposure did not occur until after the instruments had
routinely processed and used on other patients.
There have been at the present time no reports of
transmission of disease related to these exposures. TSEs of course in man are
rare diseases. Iatrogenic transmission has been quite rare. We have a number of
clinical procedures now in place to reduce this risk but the question is could
we do better and how should we evaluate the possibility that products could in
fact do this. I was asked to present the experimental design issues on this
point. We looked at such things as the types of prions and animal models which
could be used to possibly validate such studies, the problems with such
validation which particularly relate to the small, simple instrument proxies on
the one hand and the reality of complex used surgical instruments on the other
hand with their hard-to-clean shapes and the realities that that poses.
This, of course, is a huge surface which is obviously dirty
after initial cleaning. There are other
issues such as the proper design of large animal studies which would be
appropriate not so much to the making of a scientific point but rather to the
validation of a commercial product with a degree of statistical significance
that would be appropriate for that which is a little bit different from
scientific investigation.
So, we asked the committee to consider the risk/benefit
ratio in possibly approving such products. the benefit of course of having a
product that could in fact reduce TSE transmission by contaminated surgical
instruments would be to further reduce risk to patients.
Are there risks involved?
These would be primarily behavior risks, the creation of a false sense
of security about the possibility of transmitting TSE by contaminated
instruments perhaps leading to the failure to adequately follow the practices
currently recommended to reduce that risk for surgical instruments.
Is the potential benefit of approving processes or products
which could reduce risk significant? Does this benefit outweigh the potential
risks?
Dr. Estelle Russell-Cohen from the Division of
Biostatistics in the Office of Biometrics and Surveillance gave a presentation
on the statistical considerations of study design for product evaluation. The
studies of course must support the intended use claim.
Again, this is a little different from scientific
investigation. The labeling instructions for product use do need to be
supported by the study design and there needs to be a reasonable degree of
statistical confidence in those results.
Good study design of course would include removing
systematic error and reducing bias, looking at the endpoint, the time to death
or range of symptoms. Are there extraneous variables particularly in veterinary
study design which could have an impact on study performance? What about
calculation of uncertainty and/or statistical significance?
We paid particular attention to the most common endpoint in
the prion literature which is the log reduction endpoint. In the device literature we pay particular
attention to a 6 log reduction in infectivity in our evaluation of sterility
processes. That is sterility not prion decontamination.
In conclusion Dr. Russek-Cohen pointed out that the actual
study design will vary with the scientific model and exactly what is being
examined. This will drive how the systematic sources of variation will be
designed but it is very important that the study be sufficiently sized to
produce an appropriate level of certainty in the results. Again, we are looking at the product
evaluation not just the scientific studies.
To put our risk in a little perspective Dr. Ron Brown from
the Office of Science and Engineering Laboratories presented a risk analysis on
the likelihood of transmitting sporadic CJD in the United States by
contaminated surgical instruments at the present time. Dr. Brown did not
address the risk assessments that were developed in the United Kingdom but he
has done it with numbers that are appropriate to the United States. He did not
consider in this analysis the risk of transmitting variant CJD.
This is the formula that was used for a deterministic model
and the default values are listed. He also looked at a probabilistic as well as
a deterministic model and again used our default values appropriate to the
United States in terms of number of neurosurgical procedures, estimated
prevalence of sporadic CJD in the United States and when you solve these
equations this is the range for the probabilistic model.
On the average you get a figure of a risk of less than one
transmission of CJD by contaminated surgical instruments in the United States
per year. It may be as low as .1. With a worst case scenario for the range of
parameters it possibly could be as high as 3-1/2 to 4 cases over year, but we
consider that rather unlikely.
So, we really feel that in the United States at the present
time the risk of transmitting sporadic CJD by contaminated surgical instruments
when the appropriate precautions are used is quite low. It is certainly not
zero.
We were fortunate to have a guest speaker from the United
Kingdom from our sister agency and that is the Medicines and Health Care
Products Regulatory Agency. Mr. Hidderley is the representative at MRHA who is
particularly in charge of products involving TSE contamination and I have
shortened his speech to the high points which are his opinion that new
decontamination products are being presented to the market but the models
chosen may not be substantive enough to assure that the product or process is
adequately validated.
I should point out that the product has been approved in
the United Kingdom at the present time for reducing the risk of TSE
transmission related to surgical instruments.
In the United Kingdom the processing of contaminated
instruments has been centralized to a specialized center. They are not using
this product at the present time. Mr. Hedderley also pointed out that there is
a great deal yet to be understood about reducing prions on materials other than
simple surgical instruments and at the present time there is not uniform
agreement in the scientific community on the appropriate animal prion strain
model which is most representative for variant CJD and studies appropriate to that.
I am going to present to you the questions that we asked of
our panel and the answers which they gave us.
The first question was assuming that a product sponsor seeks a claim for
reducing TSE infectivity on stainless steel instruments is it in fact reasonable
for such an indication to be validated using animal studies of TSE transmission
and the committee pointed out that while there are other ways of studying the
general issue of TSE biology that at the present time looking at such a claim
animal studies would be the reasonable way to go. In fact, they are probably
the only way to go today.
The committee was then asked to discuss the relevance of
various design features for such validation studies. This was a rather
wide-ranging discussion but the advisory committee agreed that the following
points were particularly relevant to validation studies for a claim of TSE
reduction and those were maximum study validation. One should try to go beyond
1 year in particular in observing the animals. The study population should be
large enough for sufficient statistical validity.
Now, that was not further defined, but the committee made
very clear that we want large-scale very statistically significant
studies. The log reduction in
infectivity shown by such studies should be as large as possible. The committee
declined to put an exact numerical figure on that log reduction. The committee
decided that human prion sources would be the most appropriate to these studies
for both variant and sporadic CJD models and the committee did point out that
they really felt that variant CJD strains as well as sporadic strains should be
studied.
Transgenic mouse models were felt to be most appropriate
for these studies and should a sponsor need a new not previously studied human
CJD source the committee pointed out that it would be appropriate to
characterize such a strain against known animal TSE models and/or the WHO
reference strains.
There was a question as to whether or not the WHO reference
strains should be suggested for actually doing these studies. It was pointed
out by Dr. Aher that they are intended to be reference strains not primary
study strains.
Another question for the panel of the three study endpoints cited in the literature log
reduction in infectivity, mean incubation time and survival, either median
survival or percent survival, which if any might be adequate for the validation
of a reducing TSE infectivity indication.
Should demonstration of a particular level of reduction of TSE
infectivity in one or more endpoints be expected in order to support such a
claim and how may clinical benefit be estimated from these endpoints?
The advisory panel agreed that the log reduction in
infectivity is the appropriate study endpoint for the validation of a reducing
TSE infectivity claim. The committee declined to specify a particular level of
reduction and stated that linking the mean incubation time to a log reduction
in infectivity could demonstrate clinical relevance.
They asked what additional issues should be considered by
FDA when evaluating indications for use for devices other than simple stainless
steel surgical instruments. How can devices constructed from or including
materials other than stainless steel, devices with complex shapes or
difficult-to-clean surfaces be in fact validated, and the panel suggested that
we should look at modification of the test wire surface, consider testing different materials and test simulated or
surrogate device shapes.
The committee was asked how closely should we consider the
treatment conditions for a product or process that would be used for such a
claim. Should we look at things like instrument cleaning, the risk of
fixing proteins, interactions between
various steps in the cleaning procedure and the committee said,
"Yes," they wished to see the study conditions simulate the clinical
conditions of instrument processing as closely as possible and specifically
mentioned attention to a large bioburden dried on the instrument before
reprocessing.
Finally, we asked the committee considering the current
state of the science could an indication for use of complete elimination of TSE
infectivity in fact be validated, and the committee said, "No."
This was the substance of our discussion.
Thank you very much for your time.
DR. PRIOLA: I think
we will move on to Dr. Scott who will introduce the questions to the committee,
Agenda Item:
Topic 1: Progress Report on
FDA’s Risk Assessment for Potential Exposure to Variant Creutzfeldt-Jakob
Disease in Human Plasma-Derived Antihemophilic Factor (FVIII) Products
Introduction and Questions to the Committee – Dorothy
Scott, MD, OBRR, CBER
DR. SCOTT: I am
going to start with satisfactory products. Now, as of the last meeting we
presented to you a risk model looking at the potential risk of vCJD
transmission by plasma-derived Factor 11 and at that time we also presented to you a model for US plasma-derived products. As we started down
this way after that last meeting in
February we recognized the complexity
of the input for the risk assessment model for US products and so the purpose of
this topic today is to have a public discussion and to ask you for your advice
prior to selecting these input ranges.
Why a risk assessment? I am just going to go over this very
briefly. Blood plasma may have risk. There has been transfusion transmission of
vCJD reported in the UK, two cases and plasma has also been shown to be infectious
in animal models of spongiform encephalopathies.
However, I would point out that there have not been any
variant CJD infections diagnosed in derivatives of plasma recipients. Risk
estimates provide a basis for examining the adequacy of current measures to
protect blood in plasma-derived products and these assessments may trigger a
threshold for actions including risk management communications, surveillance
and these risk assessments contribute to public health decisions and I would
just point out that with regard to actions that the UK and France and some
other countries have taken actions based on their risk assessments.
Back in February we presented to you a risk assessment
model and you were asked to comment with regard to the model per se. You will be seeing this again today. Dr.
Anderson will be reviewing it for you and we also ask you what additional
information is needed to improve risk estimates with the various plasma
derivatives.
You approved in general of the risk assessment framework and
you felt that additional refinements should be made as more input information
is collected. Different products obviously may have different risk levels and
the committee recognized this. The donor travel history is important to
consider and you will find out today what some of the variables are in figuring
this out. The committee was also concerned about the 1-month exposure in the UK
by a Japanese traveler who later developed variant CJD because this suggested
that there may be a residual variant CJD risk in donors even with very brief
travel to the United Kingdom.
Very briefly these are the main elements of risk
assessment, the prevalence of variant CJD in US plasma and of course this is
linked to the exposure to BSE and basically to travel in the UK and other
countries, the amount of variant CJD infectivity in plasma, TSE clearance by
plasma derivative manufacturing processes and patient exposure, that is how
much of a product the patient has used.
The main outcome of a risk assessment for the main parameter
is exposure per patient per year to one infectious dose 50 or more and 1 ID50
is only defined in animal models but it represents a 50 percent risk of
infection in these animal models.
Another outcome of risk assessments is to identify sources
of uncertainty. That is what we will be talking about a lot today. I just want
to point out to you that the uncertainty in a risk assessment model increases
with its complexity and when data is lacking from multiple input parameters. We
also get a sensitivity analysis out of the risk assessment and the sensitivity
analysis identifies input parameters that have the most impact on the outcome
and among other things this can focus data collection efforts to the most
important parameters.
Some aspects of risk assessment are important to
acknowledge. The uncertainties and ranges that are provided, it is really a
probabilistic model. It doesn't give you an exact number. It gives you a range
of numbers at the end. Data gaps need to be communicated with a risk assessment
to provide context to the people who are affected by the risk assessment. Input
parameters should be adjusted over time to reflect scientific findings and the
outcome should be compared to the actual observed risk over time.
These are the folks you will be hearing from in this
session. First Dr. Steven Anderson will give a review of the FDA risk
assessment model and then we will hear from Dr. Ghani and Dr. Knight about an update on vCJD in the UK and other
countries, estimates of prevalence.
Dr. Alan Williams will talk about the modeling risk of
variant CJD or rather the modeling of variant CJD in US illness, the residual
risk and the efficiency of donor deferrals, and we will hear from Dr. Asher
about the variant CJD infectivity of plasma, the estimates that have been made
from experimental models. Then we will be discussing a review of TSE clearance
in factory product manufacturing and then Dr. Mark Weinstein will be talking
about Factor 8 product usage in the clinical Setting. So, overall we are going
to be covering all those main parameters of input variables that go into the
risk assessment and we are going to ask you a lot of questions and don't worry
about remembering these right now because you will be asked these before each
individual talk and we will put these back up at the end but this is just to
start you thinking.
What is the estimate that should be used to reflect the
prevalence of variant CJD in the UK?
How effective are current donor deferrals for geographic
risk of variant CJD. In other words what is the residual risk in US plasma
after donor deferral?
What intravenous infectivity range in ID50 should be
selected for plasma based on animal studies?
Is there sufficient evidence to estimate when during the incubation period human plasma is
infectious?
Do you agree with our proposed approach for estimating
clearance of variant CJD infectivity from Factor 8 by the manufacturing
processes and what experiments might
enable refinement of these clearance estimates and allow comparison of clearance
offered by various steps and methods used to manufacture plasma-derived Factor
8?
What data should we use to estimate how much Factor 8 is
used by typical patients?
What is the effect of plasma pool size, that is the number
of donors that contribute to a final lot of product for Factor 8 recipients and
can a cumulative effect from repeated exposures to low doses of the variant CJD
agent be incorporated into the risk model?
We are also providing you with proposals to help you discuss these
questions, and finally at the end of all this we are also going to ask you
given the present scientific uncertainties in the underlying assumptions of the
Factor 8 risk assessment do you believe that the risk assessment model as
applied to Factor 8 could provide a useful basis for communication to patients
or families and health care providers?
Thank you.
DR. PRIOLA: Next is
Dr. Steven Anderson.
Agenda Item:
Variant CJD Risk Associated with Human Plasma Derivatives: Introduction and Overview of Risk
Model – Steven Anderson, PhD, OBE, CBER
DR. ANDERSON: Good
morning. As Dr. Scott alluded to I am going to give an update and a progress
report on the variant CJD risk model for US manufactured Factor 8 products.
So, I think most of you have seen this slide before in many
of my presentations. It is sort of the grounding framework that we use for all
of these risk assessments that we do. This is the elements of risk assessment
that were developed by the National
Academy of Sciences in 1983, and I am
just going to point to some of the highlights of this particular slide as it sort of relates to what I am going to be
talking about today.
Most of what I am going to be talking about today will deal
with the exposure assessment component and what we are interested in this
exposure assessment component is what is the frequency and level of exposure to
a particular hazard.
In this case the hazard we are interested in is variant CJD
agent in these Factor 8 products potentially and also then what we do is we
relate this exposure which gives us the dose, and we add that along with the
dose response information and the relationship which is a linear relationship
based on the ID50s that are published in the literature for animal experiments
to finally get the risk and then we characterize the risk in the risk
characterization section of the risk assessment.
So, this just sort of provides some basic background of
what risk assessment is. Risk assessment is basically conducted when
information is limited and uncertainty is high. So, throughout my entire talk one underlying theme throughout the
entire talk is going to be this issue about uncertainty because it is a
considerable element in risk assessment.
I think one of the important things to do though is to
highlight the value of risk assessments. What role do they play in our decision
making? Well, they are a tool that provides an estimate of risk and that can be
the magnitude of risk or more specific information about the level of risk.
It details the uncertainties around that risk. So, it gives
us a confidence level or confidence
bounds around our estimate of risk and also it allows us to determine the
effectiveness of mitigations, compare mitigations, identify which of those mitigations
are potentially most effective in reducing risk and then finally it helps us
identify data gaps and then determine research priorities.
All right, so again just to talk a little bit more about
uncertainty and how uncertainty arises in these models as Dr. Scott alluded to
uncertainty arises in risk assessment when there is only limited information
available or when data are lacking and if data are lacking where this
information is very limited it forces us to use assumptions or expert opinion
in the model which increases the uncertainty in the model. There are also
errors in measurement or data collection that can be an issue.
So, if the experimental data that we are basing a
particular parameter on are flawed then that potentially can add to our
uncertainty in the model.
There is also incorrect specification of the model. So,
there can be problems. The model
actually is incorrect. It is not considering all the factors that it should and
that is an important part of uncertainty as well. So, I think you will see in
some of the models that are going to be presented on predictive modeling for
the size of the epidemic in the UK that those models are, the earlier models at
least sort of just focused on the homozygous individuals at position 129 so
they were methionine homozygous at position 129 of the PRP protein.
Now, what we are finding out more about as time goes on of
course is that there are other individuals that are becoming susceptible to
this disease. Those haven't been included in some of these more recent models
and some of the recent models under development actually are going to focus on
those.
So, let me just go on?
Factor 8 risk assessment that we are developing, again I
have to say it is under development. So, we don't have any results from the
model specifically. So, we don't have any output. We haven't done any runs of
the model. So, don't ask which I know people are usually are very interested in
the results right away.
I think it is important just to tell you that the model for
variant CJD risk that we are develop really specifically models the risk for
these Factor 8 products made in 2002.
Again, 2002 we have a fair amount of data for that year. It
is a recent year and also was the first year that the FDA deferral policies for
blood donors and plasma donors was fully in place.
We can do assessments for additional years and I think you
will see that we have proposed to do 1999 as a potential year and that would be
prior to the implementation of the deferral policies here at FDA and through
the blood centers and the plasma centers as well.
I think it is important just to emphasize that this is the
beginning of a very long process to assess risk for plasma derivatives and in
the future we may assess variant CJD risk not only for Factor 8 products but
for additional product classes. So, for instance we can go down the line for
Factor 9 to anti-thrombin or a variety of other products.
We can also change the type of risk assessments so that we
can possibly assess risk by specific products and manufacturers that produce
those products. We could do it per individual per specific patient population,
per individual, etc.
So, there is a wide range of possible routes for
populations and products that we can potentially go with and choose to conduct
risk assessments for.
Again, what type of risk assessment are we talking about?
We are talking about a process model that analyzes the probability and quantity
that the variant CJD agent will be in plasma pools and then if it is
potentially in these plasma pools manufactured in the United States what are
the potential reduction levels during processing and manufacturing, in the
amount and levels of variant CJD infectivity in these pools and then what is
quantity of factor by used by patients and that gets really at the question of
exposure to variant CJD ID50s.
So, moving on I am going to provide just a brief overview
of this model in a sort of diagrammatic format.
So, let me just orient you. Going down the middle are the
modules and the components of the model. We have a four-part model here and on
the left hand side we have the input and this is very important to focus on
because these are the actual input information and data that we are using in
the model and then on the right hand side we have the actual outputs.
So, these are what is being predicted from the model; what
is the model generating as output, and it is important to note that is what is
generated here goes on and becomes input into the next stage of the model and
so on.
So, what is generated here goes here, here, goes here and
then what we are finally trying to do is to estimate the annual exposure of
recipients of Factor 8 products for the variant CJD agent.
I can walk you through at least a few steps of this. Our
first module we are predicting the variant CJD prevalence in the United
Kingdom. I will talk more about that in
a minute and I will talk more about each of these components in just a minute
but also we go from this variant CJD prevalence in the United Kingdom and that
is used as a basis to predict variant CJD prevalence in US donors.
I will talk and sort of detail that more. What we are
interested in with donors is donor travel history, specifically those
individual that traveled to the UK, France or Europe since 1980 and then what
we do is we adjust that donor travel
information that we have for each donor population, we adjust for duration that
they traveled, the specific year they traveled and then donor age and then
finally I think one of the most sort of
effective mitigations that we put in place is we analyzed in this risk
assessment the effectiveness of the screening questionnaire that reflected
policies for donor deferrals.
So, that is a large impact on the model because that is the
step where risk is reduced considerably. So, what we do then is we get the
total number of variant CJD donors, the number of variant CJD donors
post-screening and then the total number of variant CJD donations. That goes in
and once we have calculated this those donations end up in plasma pools.
So, we go down to our next step which is the processing of
those plasma pools into Factor 8.
We are interested in plasma pools because these donations
are going to be going into those plasma pools. So, what size pools do they go
into? What is the quantity of agent in the pools and then what is the reduction
level through the manufacturing and process that the variant CJD agent if it is
present undergoes during this manufacturing process?
So, just to sort of emphasize what we get after that, we
get the percentage of plasma pools and vials that may contain variant CJD agent
and that is if they are made from a pool that contains the variant CJD donation
from an individual infected with variant CJD and then what is the quantity of
variant CJD agent in those vials?
Then finally what we are interested in is if patients use
these vials what level of exposure will they be exposed to of this variant CJD
agent? So, what is the patient's annual
dose of Factor 8 and then finally we use that not only to predict annual
exposure to Factor 8, I am sorry to the variant CJD agent but then to calculate
their risk to that potential agent and I will explain a little bit more about
that toward the end of the talk.
What are our proposed modeling approaches for modeling
prevalence of variant CJD in the United Kingdom? Our proposed modeling approach
is we propose to use two sources of data to estimate UK variant CJD prevalence.
First would be a predictive modeling approach based on variant CJD cases in the
United Kingdom.
Our second approach would be to use surveillance data and
that surveillance data specifically involves the examination of tonsil and
appendix samples from UK patients I believe in the mid-1990s.
I should mention that there is a disparity right now of
approximately 10 to 100 fold between these two approaches. This seems to give a
higher level in prediction of prevalence than the models.
I think what we are going to find in the future is that
these two sort of estimates and these data sources are coming closer together
as far as their estimates and I think they are going to probably sort of meet
perhaps somewhere in the middle of these two estimates but we propose to use
actually data from both in our modeling. So, let me just go through what are
the predictive mathematical models.
These are some of the data we may use again. There are
probably hundreds of these types of models out there and hundreds of
publications.
Dr. Azra Ghani is going to talk more about here work and I
think I have got this right. Her publication in 1990, she estimated a median of
100 cases in confidence intervals of variant CJD in the United Kingdom. That
worked out to a median of about 1 in 500,000.
There are some other recent estimates, too, by a French
group and the author is Belleli et al. They estimated approximately 180 to 300
cases and then there is also Lewin who estimated a variant CJD infectious
prevalence in the population perhaps of 1 in 15,000 to 1 in 30,000. That works
out to about 1000 to 2000 infections. I think this one is probably quite
different from these other two.
These other two basically just model the clinical cases
that could potentially develop in individuals that are methionine homozygous at
position 129 of the PRP gene while this considers the other backgrounds, not
only those methionine homozygous individuals but also the methionine-valine
heterozygous individuals and also the valine homozygous individuals and just to
remind people that the methionine homozygous individuals represent about 40
percent of the population. The methionine-valine I believe represent about
another 40 percent as well.
So, again, this sort of brings home the point about model
specification maybe slightly incorrect for these earlier estimates but this is
an evolving field as we get more information about the infection and the type
of infections that can occur. These models are getting updated probably as we
speak.
Let me go on to the surveillance data. I just wanted to
remind people that the surveillance data is based on tissue samples in UK
patients in the 1990s. It was a surveillance study, a very large study and what
they found was 3 prion positive samples in appendices in 12,674 samples tested.
That works out to this mean positive of about 1 in 4200
individuals. That works out if you correct it to about 13,000 variant CJD
infected individuals. This isn't an age corrected number at this point. It is
just a rough estimate.
This comes out as a very high estimate you will notice and
this is, if you will remember the estimate that w used in the Factor 11 model
that we presented to the committee in February of this year.
At that time we thought that perhaps this type estimate was
higher and we used it because we thought it might capture some of those other
methionine, valine heterozygous individuals that are asymptomatic and then also
the valine individuals that are homozygous at codon 129, that it might also
catch those individuals and what you asked us to do with that data that we used
in that model was to age adjust that.
So, if we used this data we would of course age adjust this
because this was collected in individuals that were 20 to 30 years old. So, we
would adjust it to reflect prevalence distribution across all age groups in the
UK population.
I think it is important to talk about uncertainties in this
data because basically all data and all the information that we used in these
risk assessments have some sort of limitations or uncertainties associated with
them and the uncertainties of the proposed modeling approach is that predictive
modeling really is based on the known variant CJD cases in the UK for the most
part.
Most of the estimates although some of the models now are
estimating in other populations but most of the models are valid for clinical
cases of again this methionine homozygous codon in position 125 for those
individuals. It doesn't capture the other genetic backgrounds.
Again, they use assumptions in these models for incubation
period, time of infection and other factors. So, again that adds another level
of uncertainty to these types of approaches.
All right, the surveillance data are no better. Using those
again these are examinations on appendices samples. One sort of critical
drawback here is that you can't go back and determine what the disposition of
that patient was from which that sample was harvested and so we don't have any
idea whether those patients actually became symptomatic or not or whether they
actually came down with variant CJD or another TSE disease per se and another
sort of drawback is variant CJD agent maybe in the appendices at the time but
they may not really represent a threat for the blood supply if the agent isn't
in the blood.
So, we may be overestimating the risk if we use this
particular type of approach. Some people may say that we may underestimate the
prevalence of the disease again. In one cases, one of the infected cases that
were identified the agent actually wasn't in the appendices at the time the
infection was identified.
So, again, both types of data have particular drawbacks and
uncertainties associated with them. Again, probably neither case sort of
adequately addresses the clinical or asymptomatic cases for the methionine valines
or the valine homozygous individuals. That potentially could exist in the
population and then they probably don't also sort of well represent the variant
CJD infections in all of these groups that don't progress to symptomatic
disease.
Okay, just going on through model 1, I think it is
important at this point as I sort of end on this module that this is a critical
parameter in the model and it is used to estimate not only variant CJD. We are
not only using this for the UK population but we are going to be using a
relative risk approach to estimate variant CJD prevalence for France and for
Europe, and then ultimately what we do is we add up all those prevalences for
the donors in the United States that have traveled to those regions. So, we are
going to be using that for this variant CJD estimate of prevalence to also
estimate plasma donor risk in the United States.
So, this is a critical parameter really to get correct. So,
we need the best information available and possible for this particular point
in the model. Just going back to the
next step which is modeling prevalence of variant CJD in plasma donors and
there are several modeling approaches that were, not several modeling approach
that we are using.
Our goal is to estimate the size of the US donor population
with a history of travel to the United Kingdom, France or Europe since 1980.
Again, if you will notice this model if we go to 2002 is going to span 23 years
of information. So, it is a rather large model at this point.
If we model this portion correctly we plan to determine
travel characteristics from a survey that we have and that data was from the
American Red Cross and then what we would do is adjust the travel data for each
individual that has traveled by their duration of stay, the year of travel and
their age and then our plan is to estimate the probability of infection in
those individual donors based on the amount of time that they stayed in these
particular countries and then ultimately what we would do is we would hope that
we will add up the potential number of variant CJD cases in US plasma donor
groups and then get the number of donations that they would donate and those
would feed into the next portion of the model.
So, our model output, what we hope to predict would be the
potential number of variant CJD infected US plasma donors, the variant CJD
infected donors that are actually deferred from donation. The real risk that
lies here I should say is in the donors that aren't deferred.
Those donors that are deferred from donation even if they
have variant CJD don't really pose a threat to the blood supply or the plasma
supply. What we are interested in is those individuals that actually evade the
screening process by some way either incidentally or accidentally.
Then finally what are the potential number of donations
that potentially contain variant CJD agent that enter these plasma pools that
are used in manufacture of Factor 8?
All right, so moving on about prevalence of variant CJD in
the US plasma donors our major assumption in the model is that variant CJD in
US donors basically derives mostly from dietary exposure to BSE agent during
travel. Again this is mostly travel in the United Kingdom but then secondarily
travel in France and Europe.
Now, our current deferral policy is listed below. It defers
donors with a travel history for instance, travel to the UK for individuals
that traveled 3 months or more from the years 1980 to 1996, 5 years or more
from 1980 to present, either in France or Europe and I think the important
thing for Europe is that it is travel for 5 years or more from 1980 to the
present for blood donations only and not for plasma donors. Again, I think Alan
Williams is going to talk a little bit more about this in the subsequent talks
but we are estimating somewhere around a factor of 90 percent to 99 percent
factor of effectiveness in eliminating these variant CJD donors and the risk
they may pose in transmitting infection if indeed they have agent in their
blood or plasma.
So, what is the actual residual risk then after this policy
has been put into place and where may risk lie in the system for plasma and for
blood products?
What we have identified are two specific groups of
interest. Again, it is these with deferrable risk and it is those 1 to 10
percent that have the deferrable travel history but for some reason evade the
screen and get through and are able to donate plasma or blood and then the second source potentially would also be
those with short duration travel to these countries and that again would be
just what is not covered by the policy. So, that would be UK less than 3
months, France less than 5 years and Europe less than 5 years again during
these specific time periods.
So, again, we are not only
planning to model the deferrable risk but we are also planning to model
this short duration travel as well because we believe that may pose risk as
well.
Again, a number of individuals, probably the bulk of
individuals fall into this category and that is why we are modeling it whereas
fewer individuals have traveled to France for 5 years or more or to Europe or
the UK for these long periods of time.
So, then we move on to the concept of relative risk and how
it is being used in the model. Again, we are doing this modeling for a period
of about 23 years for all donors that potentially donate plasma in the United
States and how we are doing that and what we are using for prevalence is we are
using this concept of relative risk that was used when the policy initially was
set up and it is used to estimate the variant CJD prevalence for France and
Europe relative to the UK prevalence.
So, I will provide an example down below in a minute and
this relative risk estimate is based on a number of factors such as the
potential for BSE exposure in France or Europe, the number of variant CJD
cases, imports of feed and those types of factors. So, for UK the relative risk
assigned to the United Kingdom has been a value of one and that is equivalent
to the UK variant CJD prevalence.
France is thought to have about 1/20th of the risk or .05
of the risk. In our calculations these factors just become multipliers against
the UK variant CJD prevalence. Europe has a risk estimated at about 1.5 percent
or 1/60. Again that becomes a model, a multiplier in our model against the
variant CJD prevalence and then there are individuals that spent significant
amount of time in the military. That is estimated at 3.5 percent. Again, that
becomes a multiplier in our model as well and then a final group of interest to
us that may have been exposed to the variant CJD agent is those that received
Euroblood and Euroblood was blood that was collected in three regions in Europe
and then was used in the New York City region in the United States and given to
recipients from donors that lived in Europe.
So, that multiplier is .015 times the variant CJD
prevalence and then we have again further adjusted for the age of the European
donor in that case.
So, relative risk for UK plasma donors, for US plasma
donors with travel history -- so just to remind people what we are actually
doing is we are applying this relative risk concept to US plasma donors with
this history of travel to UK France or Europe since 1980. Again, as I mentioned
this is a 23-year period. I just wanted to reinforce that we are adjusting for
the duration of travel during this time period. It is a very critical factor
because a lot of individuals spend only a few days in the United Kingdom. So,
this is actually the biggest adjustment to that relative risk factor.
The specific year of travel we are also interested in
spanning this time period and what we are doing is we are linking this to the
variation in the BSE epidemic essentially linking it to the BSE epidemic curve.
So, somebody that traveled for instance at the height of the epidemic in 1993, would have a higher
risk than somebody that traveled for instance at the start of the epidemic in
1980 or at the end which is probably around 2000 or even currently, so, those
individuals or 2002. So, we account for the specific year of travel. We are
also accounting for the donor again to apply the age specific rates for variant
CJD in the United Kingdom. Again, the median age is 28 years and this is very
important since most of our blood and plasma donors fall into this around this
age category in the age 20 to 40. It is important to do this age adjustment for
the specific rate of variant CJD.
All right, so we adjust by those three factors. I, also,
wanted to say that we plan to model two types of plasma donors specifically the
plasma donors and that represents greater than 80 percent of the
donations. That is the source plasma
donors. Again, those are collected by
processes such as plasmapheresis.
Again, the second population then would be recovered plasma
donors. Those represent less than 20 percent of the donations and those are
whole blood donations actually that are recovered. The plasma is recovered from
those.
Again, we have age-specific donation rates for each of
these groups and we are planning to include those in the model as well.
Then finally just to give you an idea of where this plasma
donor travel information is coming from we estimated this from survey data that
was conducted by the American Red Cross. The survey was conducted in December
1998 and January 1999, and was presented in front of this committee I believe
in 2000 or 2001, and what that survey covers is it queried travel history and
accumulated stay information for the UK and Europe and from that we can make a
few assumptions and infer travel specifically for France during this period
from 1980 to 1996.
So, that gives us the bulk of the risk that we are
interested in and then we are having to extrapolate further to cover the
additional years since 1996 for France as well.
So, we do have some survey data and just to remind people
that this is survey data in blood donors; it is not for plasma donors. So, that
adds a level of uncertainty to this information.
Again, modeling the effectiveness of geographic deferral is
an important aspect to this model. Again, we have this deferral policy for UK,
France and Europe. Dr. Alan Williams is going to discuss more about that in his
presentation.
I think I would just lay out some of the basic values that
we are interested in that could be used in the model. We haven't particularly
modeled either of these yet but we could use a factor that reduces 90 to 95
percent of the risk for first-time donations and then add a second layer to
that which is a level of reduction of 99 percent of the risk for those that are
repeat donors, and I should mention that probably greater than 90 percent of
the donors of plasma are repeat donors.
So, we are eliminating essentially two logs of risk or 99
percent of the risk if we use this factor. So, that is something the committee
may want to think about as well when they are discussing this particular issue.
So, let me move on? Another key factor is when is variant
CJD agent present in blood during the incubation period. There is going to be a
detailed discussion of the data by Dr. David Asher.
I think that I should just touch on the two potential
approaches that could be modeled. What we could do is model if the agent is
present in the bloodstream or plasma during the entire incubation period and I
wanted to remind people that this is an assumption that we used in the Factor
11 risk assessment that we presented earlier.
We could model it as being present in the last half of the
incubation period or later in the incubation period and this is based on
experiments or one experiment by Dr. Paul Brown in which blood was found to be
present later in the incubation period for a specific TSE model. I think one thing to point out is that the
modeling in this case would be complex. It would increase uncertainty perhaps
in the model and then also we would have to make a few assumptions about the
duration of incubation periods.
So, we would have to think carefully about whether this
approach is really something that we want to do, but we would like, I think,
some feedback on that from the committee.
Uncertainties in the model, I will sort of speed through
some of this since I am running short on time. The survey conducted on whole
blood, so we have survey information on whole blood donations and the travel
history for those individuals but what we don't have is survey information on
the travel characteristics of source plasma donations and anecdotally people
believe, I think that source plasma donors may travel less. So, if that is true
then our blood donor travel information that we are currently using may
slightly overestimate the risk for the source plasma donations. So, that is a
little bit of uncertainty in the model.
Estimation of the deferral effectiveness is a challenge
because there is the issue of self-deferral. So, many people don't even come in
to donate blood or plasma because they know about the policy that is in place
and then they just don't show up to donate blood or plasma, and that is a
significant problem.
So, we don't actually know the total number of individuals
really being affected or deferred by this policy. We don't know the denominator
information. So, that is a challenge and then estimation again of when variant
CJD agent is present in the blood from the animal data whether this is accurate
or not for humans we don't know. It may be present the entire time in humans
and it may be present only toward the end of the incubation period. We just don't know.
Just going through quickly
for getting onto module 3 for Factor 8 processing and manufacturing our
proposed modeling approaches to estimate the probability that a plasma pool
will contain a variant CJD donation estimating the quantity of variant CJD per
ml of plasma and then the amount of agent per pool we would estimate the
efficiency of exposure and incorporate this into the model for the IV route
versus the IC route and we would also include log 10 reductions and the log
reductions in the quantity of the infectivity during the processing and
manufacture of these products.
So, once we have that type of information input into the
model then we would use t he model to output to predict the percentage of pools
and vials that contain variant CJD agent and then the quantity of agent per
vial.
So, we are getting further and further down the chain to
the point where we are at the point of estimating the percentage of vials and
the quantity of agent that may be contained in those vials.
A proposed modeling approach at least for the quantity of
infectivity, Dr. David Asher is going to discuss this more in a minute in his
presentation and this is intracerebral ID50s of the variant CJD agent per ml of
blood. We propose to use a triangular distribution with the minimum of .1, a
most likely of 10 and a maximum of 310.
Again, these are just sort of ranges that we found in the
literature and we are interested in what the committee's perspective is on
these particular data.
Again, this is just proposed approaches for the estimation
of the efficiency of the exposure route to variant CJD ID50s or
infectivity. In the Factor 11 risk
assessment we used a value with a range from 5-to-10-fold based on experiments
by Kimberline and also by Paul Brown's lab.
Recent unpublished data suggest that this might be lower.
It might be only 1-to-5-fold. So, that is a question for the committee. We
would propose again to use the estimate of 1-to-5-fold now for the adjustment
in efficiency from intracerebral to the intravenous route.
As far as the plasma pool size we would propose again, we
have information that suggests the plasma pool size used in the manufacture of
these products ranges from 20,000 up to 60,000 donations. I think it is clear
that we need more accurate information on the size of these pools used in
manufacturing. So, at this point what we would propose to do is we would
propose to use a bimodal distribution that favors sort of this 20,000 and also
favors the 60,000 as an estimate of pool size.
So, 20,000 to 60,000 is the estimate for pool size for
these products at this point. Just
getting towards the modeling of the reduction in the amount of infectivity
during the processing Dr. Scott is going to talk about this, Dorothy Scott,
some of the reduction levels again, we are expecting that at least some level
of reduction will occur during processing and manufacture of Factor 8.
I think it is important just to emphasize the designations
for the degree of Factor 8 purity whether it is intermediate or high purity
products may have little relationship to the level of variant CJD ID50
clearance.
So, I think that is an important thing to keep in mind.
Just because these are high purity we are not sure exactly if they are going to
be a high level of clearance or not.
We propose to use three values for the log reductions
around these ranges of two logs of reduction, five logs of reduction or eight
logs of reduction.
Again, uncertainties in the data, there is only a limited
amount of data available on TSE reductions for a small number of processing
steps and few products. The levels of reduction have been achieved in these
experiments with spiked infectivity. The question is will that reflect actual
levels of reduction using the endogenous material that is used during the manufacturing
process.
Experimental data obtained for TSE agents that are other
than the variant CJD agent that we are interested in; so the question is is
there going to be an exact correlation between variant CJD reduction and for
instance scrapie reduction or other types of agents that were used in these
experiments, and another bigger question is does addition of these orthogonal
reduction steps reflect the actual reduction of ID50s during manufacturing, so
a lot of uncertainties in this type of data.
Utilization of Factor 8 in module 4, again we are very near
the end of the models. So, our proposed modeling approach is to estimate. Again
we are getting this from the previous
section, the percentage of vials with variant CJD agent, the quantity of
agent per vial and then we want information on annual utilization and dose of
factor 8 that each patient might use or patient groups may use and our goal
would be to model the annual dose of
variant CJD that a patient is exposed to either per patient, per year is a
possibility and then a prediction of the risk ultimately of variant CJD
infection based on animal dose response relationship.
Just for time I think I am going to skip over an important
set of slides but moving on just to talk about utilization of Factor 8 some of
the utilization factors we are considering in the model is the severity of
hemophilia. So, we are going to be modeling risk for severe, moderate and mild
individuals and under different treatment regimens, prophylaxis and sporadic
types of treatment or episodic treatment.
The type of data we are interested in using for the model
would be the data for instance that comes from the Centers for Disease
Control's hemophilia treatment centers. They followed 3000 patients from 1993
to 1998, and have utilization information based on review of medical charts.
So, this is very good data and we may end up using it in the model if nothing
sort of more recent comes along, but if available we may use additional data
sources for instance from medical databases such as Center for
Medicare-Medicaid Services, HMOs or Medicaid organizations for particular
states.
Okay, so again just to highlight some of the uncertainties
I will sort of rush through these. The utilization data isn't the most current
and may not accurately reflect some of the current prescribing practices.
Patients may be on multiple products and the data don't
really sort that out. So, that is one challenge that we will have. Patients may move among categories and
that may not be captured in the data
specifically from for instance prophylaxis to episodic treatment.
So, we are seeking additional data sources in order to get
the best information possible on how patients utilize these particular products
for treatment of their disorders.
Should FDA model the apparent cumulative, non-linear
effects of repeated dosing? So, one question that we have is if you get a dose
one time of variant CJD agent how does that compare to somebody that is using
this product multiple times; you know, how does that risk compare to one hit
versus they take 10 injections of that product over a period of time? Is their
risk higher?
So, we would like to at least try to incorporate that into
the model in some way and we are sort of having a challenge as to figure out
how to exactly do that. So, we are interested in the single dose episode but
also repeated and cumulative doses.
Dr. Mark Weinstein is going to talk a little bit more about
the details of this but again it is a big challenge for us to model this.
The limited data available suggest in some cases there may
be an added non-linear increase in infection rates with repeated dosing. So, to
account for this what we propose is to model the cumulative variant CJD
exposure per annum or per year and we would assume a linear ID50 dose response
with that.
So, that is our answer right now is to assume exposure for
a year and then try to estimate risk based on the dose-response information
that we have.
That is certainly something that we are seeking input on.
Again, just to remind people this exposure assessment is going to give us
information on the dose of variant CJD ID50. So, we get this estimated dose
from the model coupled with dose response information that we have to finally
estimate risk.
Another issue that has come up is this sort of reflects our
relationship for the linear dose-response. We assume that an individual exposed
to one ID50 has a 50 percent probability of infection. Somebody exposed to .1
ID50 has a 5 percent probability and we don't really know if this is true or
not. What is the meaning of a fractional dose?
And that is an important question I think that we need to answer in the
future and definitely need more experimental data to resolve that issue, but
again right now we are assuming a linear dose response to estimate the risk.
So, we are taking dose times the dose-response relationship to estimate the
risk or the probability that a person will be infected with the agent.
Finally, again, a lot of uncertainties here; we are using
an animal dose response to estimate human risk, a lot of uncertainty there. It
is limited data to get that dose response. Human data are not available just to
remind people of that and the development of the human dose-response model
therefore is not possible at this time.
Some of the conclusions are the estimate risk of infection
based on the level of exposure can be predicted using the model. So, we can get
a relative estimate of the risk and the level of exposure that a person using
Factor 8 products may be exposed to this variant CJD agent.
The risk prediction is based on animal data and animal dose
response. So, again, it is going to be highly uncertain but I think one of the
important things is that it will highlight the data gaps and uncertainty and
hopefully t hose will improve in subsequent iterations of the risk assessment.
It is important to just sort of emphasize that risk
assessments provide information on relative magnitudes of risk and this is
somewhat useful for risk management purposes depending on the types of
predictions that are generated and that is the end.
DR. PRIOLA: Thank
you.
Next is Dr. Richard Knight, Director of the CJD
Surveillance Unit, Edinburgh.
Agenda Item:
Update on vCJD in UK and Other Countries: Estimates of Prevalence – Richard Knight, MD UK Director, CJD
Surveillance Unit Edinburgh
DR. KNIGHT: Thank
you very much. This is a two-part presentation and I am going to begin talking
from a clinician's point of view which is what I am and then Azra Ghani is
going to follow on with a more statistical point of view and I am going to
after a very brief introduction talk about the illness and its diagnosis, deal
with some important questions and then turn to human transmission before
passing on to my colleague.
So, a brief introduction, I am not going to go into all
this in detail because obviously everybody here is familiar with this, but I do
want to stress that I am going to talk about CJD essentially and really variant
CJD.
These are the underlying assumptions that I will take as
given, that the key molecular event is
the post-translational change of the PRP protein from the normal
cellular form to the abnormal
disease-related form, that t his is going to be deposited in tissue and that
this is associated with disease and associated with infection but I am going to
pass over the difficult and controversial issues as to the precise nature of
that association and what is more and it is important of course, misconcepts
that while the disease is limited to the central nervous system the deposition
of the abnormal protein may not be, and as you have already heard about this I
will pass over it quickly but the prion
protein gene is of critical importance and in particular the common polymorphism
at codon 120 and here you can see that people can codify the methionine or
valine. Therefore all of those are either MM homozygotes, VV homozygotes or
heterozygotes and the significance of this is that this to some extent may
affect susceptibility to these diseases. It may affect the incubation period in
he quiet forms and it can also affect the clinical pathological features of the
resulting illness.
This is the normal UK population. Just over one-third of
those are methionine homozygotes, about one-half MV heterozygotes and the rest
valine homozygotes. This does vary from country to country with roughly an east
to west drift so that in Japan over 90 percent of the population are methionine
homozygotes.
This is variant CJD, and you can see straightaway that all
tested cases to date, 154 in total have been methionine homozygotes.
So, I will turn now to the illness and this diagnosis and
we have identified 158 cases to date in the UK. You can see it is a disease of
the relatively young. The youngest age of onset so far is 12. The oldest age of
onset is 74, median duration 14 months although it can be very short and we
have one individual who is still alive at well over 40 months. Apparently more
men are affected but this is not a statistically significant difference and at
any stage we tend to have a few people alive with the illness in the UK and at
present we have seven.
This is just the background and I am not going to discuss
it in detail but these are the three elements in the theory of variant CJD and
as you go down the line the color blue becomes lighter because the evidence
becomes thinner.
Certainly the diseases do appear to be caused by identical
agents although of course we haven't
characterized the agent and therefore all the evidence is indirect. It
does not appear to have passed from a third animal or somewhere else into
cattle and man. It does appear to have gone from cattle to man and it does
appear to have passed in diet. We don't have any other reasonable
theories. Our observations in the UK do
not suggest any other plausible route and indeed our case-controlled study has
now started to produce evidence that modestly but does support the dietary
theory.
This is a rough outline of what we think happens.
Infectivity from cattle enters food. Food enters the human gastrointestinal
tract and then enters obviously the human being in general. There appears to be
an important lymphoreticular phase. These are the tonsils, the spleen and of
course the appendix and they Peyer's patches in the intestine and after some
period apparently by a neurological route the infection enters the brain.
It may be through nerves in the gut going into the spinal
cord and descending northwards. It may be the vagal nerve going directly into
the brain stem. It may be through the trigeminal or glossopharyngeal nerve into
the brain stem, then into the brain where disease results, and this is a
probably pattern of tissue infectivity in humans, infection, a rise infectivity
in the lymphoreticular system which then plateaus and later rising of
infectivity in the central nervous system and at some point the beginning of
clinical disease with central nervous system infectivity being significantly
higher than that found in the lymphoreticular system.
This is just to illustrate the points about preclinical and
subclinical infection as I am going to use them. You may become infected. There
may be no evidence of an infectivity and then there may be lymphoreticular
colonization. Then there may be neurological disease and the incubation period
is the time to neurological disease followed by clinical illness and death from
variant CJD.
In subclinical infection you may get nothing to start with
and you may get lymphoreticular colonization but you get no variant CJD and die
from another cause, and why would that happen?
One thing is the incubation period may be so long that it
exceeds the life span of that individual either because the incubation period
is longer than the normal human life span or because this individual dies for
another reason before they have a chance to develop disease.
It may be there is a genuine subclinical state whereby no
matter how long somebody lived they would actually never develop infection.
The difference between these two situations is of course
rather theoretical at present. I don't know any way of distinguishing between
them in human beings.
So, that of course brings us on to the incubation period of
this disease and I think Azra Ghani is going to approach this in a rather more
rigorous form but just to outline it in general we think the minimum incubation
period is likely to be around about 5 years, the mean somewhere around 10, but the maximum may indeed be
very long indeed.
Now, when you look at prion diseases there are certain
factors which have been called determinants of the clinical pathological
features but they may in fact be
associations. I will pass over that point, and they are first of all cause,
secondly route where these are acquired, thirdly, agent strain, a rather
complex and controversial issue but nonetheless these agents do appear to exist
in strains with different biological behavior, the type of protein found in the
tissue and the 129 genotype, and if you look down at variant CJD there is
apparently one cause at present, one route at present, one agent, one protein type
and one prion genotype and therefore it is hardly surprising perhaps that in
the United Kingdom and elsewhere this disease has been very homogenous from a
clinical and pathological point of view which is rather unlike what you see in
some other forms of prion disease, but certainly from a surveillance system
point of view the critical factors that you change any of these factors like
have a route other than the oral or you have a different genotype, then it
might be that the resulting picture would be different and we might have to
look out for a new variant CJD.
The illness tends to present with psychiatric and
behavioral symptoms rather than the typical neurological presentation of many
of these diseases. You may get other symptoms but they are often non-specific
and taken as part of the psychiatric picture,
and neurological signs appear usually around about 6 months into the
illness and this is an illness of median duration of 14 months.
So, these people present with multiples symptoms with a
psychiatric flavor without neurological signs and early neurological diagnosis
is really very difficult indeed. There is no simple clinical diagnostic test at
present.
The diagnosis therefore requires neuropathology if you want
to be certain and this is a critically important point if you really are
wanting to know for sure about variant CJD in the population. You need good
neuropathology with effective autopsy rates and that does not happen in many
countries.
A clinician approaches this by suspecting the disease in
the first place which requires a suggestive clinical picture and for the
clinician to understand of course what the picture looks like. They have to
exclude alternative diagnoses and that I should stress includes other forms of
CJD and so you need a knowledge of clinical neurology and of CJD in general and
there are supportive tests which while not absolutely diagnostic are helpful if
you understand their role and one particular very useful test is the MRI and
what you see in variant CJD is this high signal in the posterior thalamic
region, the pulvinar sign which is present in over 90 percent of our cases if
you use flare sequencing and of course if you use certain standard techniques
you do not find the abnormal form of the prion protein in lymphoreticular
tissues in other forms of illness but you do find it in variant CJD and so
tonsilar biopsy is sometimes potentially diagnostically helpful.
Now, I mentioned the differential diagnosis and it may seem
perhaps a bit odd to anyone who has seen some cases of sporadic CJD but they
could be confused with variant, but some genetic forms of prion disease may
look like variant CJD and there are atypical sporadic CJD cases that may be
atypically young with unusual even psychiatric presenting features with an
atypical clinical course and an unusually long duration and in the United
kingdom the main differential diagnosis of variant CJD is sporadic CJD and
throughout the world we get notified every now and again of cases that are
thought to be variant CJD occurring for the first time in a new country which
are in fact atypical sporadic CJD cases and I think that I would stress again
the importance of autopsy and stress also that if you are really interested in
surveillance of variant CJD you need to have an effective surveillance system
for all forms of prion disease.
How would you tell
variant from sporadic apart? The MRI appearances can be very useful but they
are not completely reliable. Tonsilar biopsy is certainly a possibility but a
negative tonsilar biopsy can't exclude
the illness and it is a relatively invasive
test.
The histological appearances of course are important and so
is protein typing but they require of course brain material. In the end the
final arbiter at present is experimental transmission characteristic, i.e., you
take material put it into laboratory animals and you look at the incubation period
and the neuropathological lesion profile. However, that is clearly difficult and expensive and is only done in
particularly important and difficult cases and just to finish on this topic
this is the US CJD collaboration
showing the standardized mortality ratios which of course should be around one
and the countries in yellow are those countries that have mortality ratios that
are not significantly different from one. The
ones in blue, Slovakia and the United Kingdom are countries which have
statistically lower mortality rates and I have no idea exactly why that is and
two countries, France and Switzerland that have statistically higher mortality
rates and again I am not sure why that is and certain countries like for
example, Switzerland have shown a significant increase in identified sporadic
CJD cases recently.
The explanation for this is not clear but there is a lot of
collaborative research going on within these countries and all I can say at
present is that there is no evidence that these differences or changes are due to unexpected infections with BSE.
So, that leads to questions, the relative youth, the
numbers of cases, other genotypes, other countries and then going back to the
preclinical, subclinical issue.
This is the graph showing the age at death or the present
age if they are still alive of cases in the UK and you can see that they mostly
fall in this 10 to 20 age group and what is more striking is that over the
whole period of the epidemic in the United Kingdom this age of onset has not
changed which is a big curious for a disease which is supposed to have been due
to a limited time exposure of infection and stands in need of some explanation,
and the three explanations that I have heard put forward are one, different
age-related exposures, two, age-related incubation period, and three,
age-related susceptibility and all I can say is that from my UK data we do not
think that age-related exposure is likely to be a major factor, and therefore
it is likely to be one or both of these and indeed of course they may in some
way be related.
These are the numbers of cases. These are onsets in the United Kingdom showing a rise
and then a fall although the figures for 2003 and 2004 are incomplete and you
can see that there almost appears to be a rise again in 2004.
Mick Andrews of the Health Protection Agency produces
curves to fit these data and the best curve at present is a quadratic curve.
These are deaths showing a peak in deaths in 2000 with a subsequent decline.
However, these profiles relate to dietary and codon 129 MM cases and of course
the numbers and predictions will be dealt with in more detail by my colleague
afterwards.
So, will there be non-MM cases? The only thing that I can
say is that it is virtually certain that there will be non-MM cases and why do
I say that? Well, first of all if you
look at other prion diseases, iatrogenic CJD or kuru, other genotypes are
affected. Secondly, one of my colleagues in collaboration with other colleagues
in Edinburgh is looking at the human transgenic mouse model and while I can't I
am afraid disclose the results of this experiment in detail the
experiment's preliminary data suggests very strongly that other genotypes will
be affected by BSE infection and of course we do have a case report of lymphoreticular systemic
involvement in an MV blood recipient. This of course was not variant CJD itself
and presumed to be an infection related illness rather than a dietary one but
nonetheless it does show that and MV
individual can have BSE infection.
If all this is true what we expect is first of all that longer incubation
periods will be apparent for these genotypes which is perhaps why we haven't
seen them to date. There is also some
reason for believing that you might get more subclinical infections in these
non-MM types and certainly that is evidence that is coming
again from these human transgenic mouse experiments and the clinical
pathological phenotype might be different and again, the human transgenic mouse
experiments are beginning to suggest that the clinical pathological phenotype
in non-MM cases might actually show some significant differences which is an
important point for surveillance.
Well, now, aside from the UK these are the figures and you
can see that France is next in the lead with 15, Republic of Ireland 4 and the
rest of the countries single cases only.
The dark blue countries here are those countries in whom
the cases are thought on good grounds to be intrinsic to those countries. They
are cases in those countries who were infected in those countries. These colors
here are those countries in whom they have had cases but it is thought that
they were infected during stays in the UK and you can see here for example the
USA case is considered really to be a UK case.
Saudi Arabia, the status is uncertain but I think it is
likely to be an intrinsic case to Saudi Arabia. The Japanese case you have
heard already is attributed at present to the UK. It is very difficult. The
decision was a problematic one since they
stayed for less than a month in the UK but it was thought that it was
very unlikely that they would have gotten the infection in Japan intrinsically.
It was also felt very unlikely that they would have gotten the infection during
the 1-month stay in the UK but the probability that it was in the UK was
marginally higher than it was for due to Japanese intrinsic infection.
Now, I will move on to preclinical and subclinical and we
do have definitive evidence that the lymphoreticular system can be involved
preclinically. These are two cases, one with onset of disease in 1995, and one
in 1998 both of whom had their appendix removed due to routine surgery 8 months
and 2 years prior to onset of disease and in both of these cases the appendices
were examined and found to be positive.
So, the appendix certainly can be positive at least 2 years
prior to clinical onset of disease. We, also, of course, have two cases of
probable transmission by blood donation from individuals who at the time they
donated did not have variant CJD. They were preclinical cases and therefore
infectivity implies infection. So, these individuals must have had some form of
preclinical infectivity and there is also of course the case of the
lymphoreticular positivity in a blood recipient who did not have variant CJD
and therefore again was some kind of preclinical or subclinical case and we
have the UK appendix study.
Now, this is something you have already heard referred to.
This was undertaken by David Hilton and James Ironside and others and they
looked at surgical specimens from across the whole of the UK population. We
don't know anything about the genotype of these individuals who had their
appendix removed and presumably unless there is something peculiar about the
prion protein and appendicitis they should represent a cross sample of the
normal human population.
They were tested for PrPsc and nearly 13,000 appendices
were examined and three of them were found to be positive. Now, if you
extrapolate this data across the UK population then it would suggest that 247
per million of the UK population have appendix positivity. Of course, the 95
percent confidence intervals are wide. Most appendectomies are done in the 10
to 30 age group in the UK. So, if you adjust for that that would suggest that
in the 10 to 30 age group in the UK nearly 4000 people have positive appendices
for this abnormal protein, again with wide confidence intervals.
Now, you have heard there is a discrepancy here and indeed
there is. If you say in this age group here there are nearly 4000 people with
lymphoreticular positivity bearing in mind the wide confidence intervals yet
within this age group we have only noted 92 cases of variant CJD and variant
CJD in the UK appears to be in decline; so, what is the explanation for this?
Well, people have suggested that there could be false
positives in the appendix study. I am not a neuropathologist, but I am given to
understand that this is extremely unlikely. Of course, we don't know if the
codon 129 genotype of these three positive appendices. They are being studied
but I cannot tell you the results at present.
Of course, all the cases so far have been MM and it may be
that the appendix cases are non-MM and of course it also might imply as indeed
most people are beginning to think that there may be substantial numbers of
subclinical cases of BSE infection in the population which is very reassuring
to a neurologist but not very reassuring to a public health doctor.
So, that is it really in the UK. BSE is controlled at least
in the UK. Diet is controlled, at least in the UK. So, we are awaiting the
outcome of this terrible accident to see what happens, but of course in the
meantime there could be secondary iatrogenic spread particularly if there are
preclinical or subclinical cases and that leads on to the concern of surgery
and blood, and I am going to close by just talking a little bit about
human-to-human transmission via blood.
So, first of all there are opportunities for this. It
should be possible to avoid clinically ill people being donors. At least I hope
so. Therefore the exposure will come either from the incubation period which of
course may be very long or even more
worrying from subclinical infectivity which may extend through the whole lifetime
of the individual especially in the absence of a simple diagnostic test.
If we are to consider this issue we have experimental
evidence and we have epidemiological evidence and I am not going to review the
experimental evidence at all except to comment on the sheep blood
experiment which had most relevance, at
least by Nora Hunter and her colleagues BSE was given to sheep. The sheep then
act as blood donors and other sheep are intravenous recipients and just to
summarize the present status of the study there is transmission of BSE by whole
blood or by buffy coat, if transmission by intravenous route of a unit of blood
it so parallels the human situation. Transmission has been successful with
clinical phase donations and preclinical phase donations. So, there is evidence
of preclinical infectivity again and the whole blood transmission rate at
present is around about 25 percent but because of the methodology of this
particular experiment this equates probably to a successful transmission of
about 40 percent.
So, this is concerning but people always say can you really
go from animals to humans. So, we don't experiment with humans but we observe
them and the transfusion medicine epidemiological review was set up in 1997
between our unit and the National Blood Services and in outline for this particular
topic what we do is we identify cases of variant CJD. We give their names to
the national blood authorities. They look to see if they act as blood donors.
If so they identify the recipients. They give the names of the recipients to us
and we check to see whether they have appeared or in the future appear on our
register and there is of course a reverse study whereby we traced the donors of
blood when variant CJD cases report being recipients and there is a parallel
sporadic study.
The data are present.
When there were 157 cases in the United Kingdom we had 23 that had got
donor records and the numbers from which the components were actually issued
was 18 and the recipients were 66, so, essentially 66 recipients potentially at
risk.
In addition 9 variant CJD individuals donated to 23 plasma
pools which were identified as going on to make plasma products. What has
happened to these 66 people? The first thing you note is that most of them have
died. Forty out of 66 have died already
and I suppose the reason for that is
simply that if you have to have a blood transfusion you are ill and if you are
ill you may die from that illness and you can see the majority of individuals
actually died within 1 or 2 years,
i.e., within the time period of the incubation period as we expected. In other
words they would never actually have had a chance to develop variant CJD.
The ones who are still alive, 26 of them, there are a
number that are in a short period of time from transfusion and one would not have expected them yet to
develop variant CJD if they were going to. There were a significant number in a
kind of high-risk period. A few have lived beyond 10 years although of course
we don't know what the maximum incubation period for this disease is.
This is just to illustrate that it is no longer a UK
problem. These are variant CJD blood donors by year of disease onset and you
can see that it was a UK problem until recently.
The Saudi Arabian case had been a blood donor. Some of the
French cases have been blood donors. Spain and Ireland have had blood donors.
So, if variant CJD occurs in other countries clearly the
risk exists there as well. We, also, identified two individual cases and I want
to discuss them in a little detail.
The first instance occurred in 2004. An individual donated
blood. Three point three years later they developed variant CJD which was
neuropathologically proven. One unit of non-leuko-depleted red blood cells was
given to a recipient who 6-1/2 years had variant CJD and died after a fairly
typical illness neuropathologically confirmed.
There were 68 slightly older than the usual case of variant
CJD but they were still codon 129 MM. Now, of course, this individual had lived
in the UK throughout the risk period and therefore had been exposed to diet and
the question was couldn't this just be an accident. Well, the figure you heard
earlier on of 1 in 15,000 to 1 in 30,000 my understanding was that it was not a
prediction for the whole population but an analysis to see whether of the
people that we knew who had been recipients of variant CJD blood what would be
the chance that they had developed variant CJD by diet simply by accident, by
coincidence and the answer in this particular analysis for this patient it
would be about a 1 in 15,000 to 1 in 30,000 chance that they would have
actually developed variant CJD through diet rather than through blood. In other words, this was very unlikely to be
a coincidence and therefore a probable case of transmission.
In the second case a donor gave blood and 1-1/2 years later
developed variant CJD, again, proven. An individual received non-leuko-depleted
red blood cells and 5 years later died of a non-neurological illness. They
didn't have any symptoms of variant CJD and neuropathologically there was no
evidence of variant CJD.
However, at autopsy they were found to have the appropriate
form of abnormal prion protein in the spleen and in the cervical lymph node.
So, they had evidence of BSE infection and interestingly they were an MV genotype.
What is quite interesting about this case is that although
the spleen and cervical lymph node were positive the tonsil and appendix were
negative and of course I don't know why that is. It could be that because they
were MV they have a different tissue distribution. We don't know. It could be
because this is a blood transmission case rather than oral transmission case.
There might be another reason. We don't know, and just to finish on the reverse
study we have six variant CJD cases who have records of having received blood
in the past.
Two of them the timing was just wrong. So, it couldn't have
been that they got infection from the blood. In the remaining four one was the
case I have described to you, the probably transmission of variant CJD with the
time interval indicated here.
The other three cases we don't know. As far as we know the
donors did not have variant CJD and have not developed variant CJD yet.
In one instance this individual here received a total of 106 components during her transfusion
for a very serious illness. The intervals as you can see at present are running
about 5 to 6 years.
So, just to conclude the UK is showing a decline in variant
CJD, but there are lots of concerns. First of all there may very well be MV and
VV cases to come. Secondly, more countries are being affected and some of these countries are not entirely
predictable countries. There is increasing experimental evidence of blood risk
and there are now two instances of probable actual human blood transmission, one
of them showing evidence of blood infectivity at at least 3.3 years
preclinically.
The magnitude of the blood risk clearly must relate to the
prevalence of infection and this is particularly important with increasing
concern over the whole issue of preclinical and even subclinical cases and the
UK TMR study continues to collect data
and obviously various precautionary measures have been taken, but what I will
do now is hand over to my colleague, Azra Ghani who will address the issue of
prevalence in the population in a more rigorous and scientific manner than I am
capable of.
Agenda Item:
Azra C. Ghani, PhD, London School of Hygiene and Tropical Medicine
DR. GHANI: Okay, thanks very much. Hopefully I will follow on from Rich's talk
and that has given you most of the background and I am going to very much focus
on a more quantitative aspect which is the mathematical modeling work that I
have been involved with over the past 8 years and that other groups are also
developing which really focuses on the first part of Steve Anderson's
presentation in terms of trying to estimate the prevalence of variant CJD in
the UK, and all of the work I am going to present today is work that I have
been involved in but which over a period of time would have come from Oxford
University and the Imperial College and now the London School of Hygiene and
Tropical Medicine.
There are other papers published by other different groups.
The predictions that we are all getting now are very, very similar and the
basis of the models is also very much alike.
Okay, all the models to date have really been sort of risk assessment based on primary
infection and by primary infection I mean ingestion through consumption of
BSE-infected material and this schematic just shows the general process one
might want to go through in trying to understand the potential for variant CJD
cases arising through consumption of BSE-infected material.
So, at bottom here you have some sort of profile of the BSE
epidemic in cattle and this is very well estimated. Certainly in the UK we have
very good records of the clinical cases of BSE and mathematical models have
been used to translate those clinical cases into estimates of infected animals
slaughtered for human consumption over time.
It is important to note that current estimates suggest that 3 to 4 million
animals were infected and slaughtered for consumption in the UK over the course
of the epidemic.
So, there was widespread exposure to the BSE infective
agent. There are a number of steps then that BSE infected cattle will go
through prior to being consumed by a human.
Very little is known about the production in particular
types of tissue used for the food or indeed the effectiveness of certain
precautionary measures that were put in place notably a specified bovine offal
ban which removed the riskiest material from the human food chain in the middle
of 1989.
Consumption patterns are also thought to vary and there
have been studies looking at dietary data. Dietary data obviously is fairly
difficult to analyze. Typically there will be some sort of recall bias,
particularly when you are trying to ask individuals about what they consumed
over a long period of time, but it is likely that there was some heterogeneity.
These to date and these have been included in some other mathematical models
have really focused on age and
certainly for the UK the dietary data do not support an age-dependent exposure as being the main reason why we are
seeing the majority of cases in young individuals.
There is then the infection process. Infectivity obviously
varies by different tissues that were consumed and some being riskier than
others, also, by the incubation stage of the cattle and it is thought that the
riskiest cattle would be those up to 1 year prior to clinical onset or onset of
clinical signs.
There has been some discussion earlier about the dose
response. In all of the models so far we have assumed a linear dose response
and this is very much the simplest type of response to include in these types
of models but obviously it is possible that there are some other forms of the
dose response curve.
Heterogeneity and susceptibility are very much focused to
date on two factors, variation in age-dependent susceptibility and I will go on
to show how estimates about age-dependent susceptibility arise from these
models and also genetic susceptibility and all of the models to date as has
been stressed earlier have really focused on trying to predict what is
happening in the MM homozygous population. So, that is approximately 40 percent
of the UK population.
The reason for making that assumption is not so much that
it is an assumption but all clinical cases have arisen in MM homozygotes and so
it is very difficult to predict anything in the other genetic subgroups because
we haven't seen any clinical cases.
There is then of course the species barrier very much an
unknown quantity and then we have an incubation period in humans. Once an
individual has become infected there will be a long and variable incubation
period. This again could be dose dependent. No models to date have actually
included a dose-dependent incubation period really because it is mathematically
quite difficult to do. It may be age dependent and genotype dependent and
earlier models t hat we looked at with age-dependent incubation periods showed
a shift in age profile over time. So, it would suggest that the average age of
those coming down with disease would increase over time and that is
inconsistent with the data that Richard has shown in his previous talk and so
most models now only consider age dependent susceptibility and exposure.
It is also of course important to include survivorship for
diseases with long incubation periods. People will die of other competing
causes of mortality and so this is a schematic that was used to relate
estimates of BSE-infected animals to what is happening in variant CJD cases.
So, the process that the models go through is to try to
incorporate all the various uncertainties through this process to generate
potential epidemics and then we look at those generated epidemics and say how
well do they match what we have seen so far and we can exclude statistically
those that are way out and those that match very well are our best estimates.
So, this is really the only equation which is the
fundamental equation of the process that is being used for mathematical
modeling in this area and it is an equation that arises from a technique known
as back calculation which is used very much for HIV and was developed for HIV
in the mid-1980s.
What you are basically trying to do is relate the number of
people who are becoming infected at certain times to those cases that you will
observe at a later date. So, you are trying to relate numbers infected to the
cases through multiplying this by the potential for the incubation period. So,
it is really a method very much developed for long incubation period diseases.
So, mathematics is a little bit more difficult to interpret
for most people. So, this is the same method simply expressed in words. Suppose
we have a case of disease that we have observed in 2005. Then under this very
simple model we would say that the probability that we would observe this case
is equal to the number infected in 2004 times the probability that their
incubation period was 1 year because if they had been infected in 2004 and the
onset of disease was in 2005 they would have an incubation period of a year.
We then sum that with the number infected in 2003 times
probability that the incubation period is 2 years and so on and we would go all
the way back and in these models infection risk starts in 1980, and so that
would be the probability for having an incubation period of 25 years.
So, that is the basic process these models are going
through.
All of the models to date have a number of parameters and
these parameters are uncertain and the approach to this uncertainty is to try
to generate lots and lots of different scenarios to different sets of
parameters and see which sets of these parameters are consistent with the
variant CJD cases we have seen so far.
The first important one is some sort of measure of the
exposure which is always estimates of numbers
of infected animals entering the food supply by time and by disease
stage at slaughter. So, in all of our models we assumed that those animals that
are close to onset of clinical signs are more infectious than those early in
their incubation period.
They all have an incubation period for humans which is
either the time from infection to onset of disease or death. The term
"incubation period" is used a little bit more loosely in the models
dependent on whether the model is being fitted to the onset or the deaths.
They have some sort of age dependent susceptibility or
exposure function which allows younger individuals to be at higher risk and
that is a function that can be varied and we can try to see what function best
explains the current data.
They all include the effect of control measures and most
notably the specified bovine offal ban in mid-1989 which would have removed the
highest risk materials from the food supply but we very much suspect it wasn't
100 percent effective.
Finally they have a transmission probability. That is the
probability that someone who consumes infected material develops infection and
so that is really dependent on the species barrier and finally competing
courses of survival and birth cohort size are taken from census data. So, they
are fixed quantities.
So, predictions of future clinical cases or deaths, this is
what most of the models really have been set up to produce and models are able
to produce fairly statistically robust estimates of future cases once the
epidemic has peaked and that is a feature really of the methods, that these
methods are helpful once you have seen
a peak in an epidemic. Prior to the peak as you will see from the sort of
predictions that were made prior to 2000 you get very wide uncertainty in any
predictions.
So, there was variation in the different predictions that
were made prior to 2000 by the different groups and these were just really
dependent on slightly different assumptions about the parameters or slightly different model structures but they
now all give very much similar estimates.
One important thing to note is that the predictions really
are only valid within the populations that are being studied. So, to date all
the UK models include the UK cases but do not include any of those cases that
were assigned to other countries but were probable UK acquired infections, for
example, the US and Canadian cases.
They consider all the cases but one to be acquired from
consumption of BSE-infected beef. So, we are assuming that all these cases that
we have seen so far have been through consumption of BSE-infected materials and
for example cases arising through blood transmission.
For reasons I have already explained we only considered the
MM homozygous population to be at risk and related to that they all assume what
we call a unimodal incubation period so that the probability of coming down
with disease after a certain time period increases and then decreases. So, we
couldn't potentially see two peaks and situations in which we might see more
than a multimodal incubation period really would be if we were trying to model
wider genetic susceptibilities and we could see peaks coming in other
genotypes.
The majority as I said, assume no age dependency in the
incubation period. So, the cases I am going to present in the next slide are
based on the models that are fit both to the time and age specified variant CJD
deaths and the most recent predictions are based on cases up to the end of 2004,
and importantly they also fit to the results in this appendix survey, so, the
prevalence estimate that you will have seen in the previous talk.
To do that we need to include some sort of carrier state,
subclinical infection. The terminology effectively mean the same thing so that
we have a portion of individuals who become infected and are detectable having
detected PRPSC in their appendix but do not go on to develop clinical disease
and I will show estimates of how that is obtained in the model later.
They exclude the one patient thought to have acquired
infection via blood and again they were only in the MM homozygous population.
So, this shows you the long-term estimates and bounds or
prediction intervals for variant CJD mortality that my group have published
over time and we started fitting these actually back in 1998 and this shows
just how the uncertainty has decreased and really critically. There was a big
jump after 2000 from 2000 to 2001 when the epidemic started, the clinical cases
started to decrease.
So, current projections are for fairly low numbers. So, the
best estimate at the moment would be that there would be 37 future cases with
confidence bounds that have of course decreased as well so showing decreased
uncertainty.
So, these are just saying that the projections of future
clinical cases in the MM homozygous population in the UK are fairly low. We are
seeing a declining epidemic.
By doing those and producing those projections you can also
get some estimates of how age-dependent susceptibility and exposure relates to
the age distribution of the clinical cases and the best distribution looks
something like this so that those aged really between about 5 and 25 appear to
be at highest risk for acquiring infection.
We can't distinguish in these types of models whether that would be due
to exposure or due to some sort of biological susceptibility and very similar
patterns are reported from other models.
We can also obtain our best estimates for the mean
incubation period and this is the incubation period defined as the time from
infection to death rather than to clinical onset and that gives the best
estimate currently around 11 years and you can see a tail here. The tail
actually cuts off quite quickly but of course this aspect of it is less well
fit by the model. There is more uncertainty in the tail simply because we won't
have seen those cases arising with long incubation periods. So, there is
uncertainty in that tail.
Okay, moving on then to estimates of prevalence of
infection I think the most important point to note is that these models cannot
estimate the prevalence of infection. You are taking models looking at the risk
from BSE and trying to relate them to variant CJD cases.
All your information in this model is coming from those
clinical cases. So they are quite powerful in predicting, making short-term
projections onwards for those clinical cases but they can't say anything about prevalence because we could simply
scale up and down the prevalence and increase the tail on the incubation period
and we would get very similar
projections in terms of what is happening with clinical cases.
So, if they are fit to the clinical cases alone we are
unable to make any estimate of prevalence of infection. One way we can try to
understand the prevalence of infection is to also fit the models to this data,
the appendix survey data because that then constrains the prevalence at a
specific point in time. So, those appendix tissues were removed between 1995
and 2000 in a specific age group and we could therefore constrain our model to
match that prevalence as well as the clinical cases.
The useful thing from the models is that we can then say
that given the age distribution of the clinical cases and given that we have
found this prevalence in our highest risk group, the 10 to 30 age group what
would we expect the wide equivalence to be elsewhere in the population; so it
is quite powerful in terms of extrapolating those survey results.
For the clinical case and survey to be consistent in any
model that we fit we need to include the possibility of a carrier state or
subclinical infection and just a technical point. The survey results only apply
to the MM population when we enter them into the model because our model is
only looking at the MM population.
So, including this carrier state this is our sort of
estimates that we get. So, we get estimates that only 10 to 15 percent of
infections would go on to develop clinical disease. So, we are saying that 85
to 90 percent of those that appear infected or have detectable infection in
their appendix will actually be subclinical infections that would never go on
to develop clinical disease.
Just to stress that this is just an estimate from a model,
it is not saying that subclinical infection does exist. This is one plausible
hypothesis for why we get this discrepancy between the appendix survey results
and the clinical data. It doesn't say that this is the only reason. This is
just the reason that we have come up with that best fits the data at the
current time.
The model then can also be used to then extrapolate and
give estimates of prevalence by age group and these sort of data that are now
being used to try to focus testing of tonsil tissues that have been collected
in the UK.
So, there is a storage of tonsil tissues that started 2
years ago in the UK and we are now looking at ways to best test those tissues
to try to detect infection and age is one aspect of that.
So, you can see also how we might see past, current and
future prevalence coming out of these models by age. We would see a cohort effect so that infection in those that were
young in 1997 will gradually move through the cohort.
So, this is just saying that a specific cohort was at highest
risk. Going on finally then to
genotypes we have gone through a lot of this information already on the
genotypes. So, one aspect that we wanted to look at was if we were to see cases
in non-MM individual although we can't constrain epidemics in this group what
can we say about the potential scale of an epidemic in the non-MM individuals
based on what we have seen in the MM individuals and we know that they have
either to have not seen any cases to date they would have either had to be less
susceptible to infection and/or have longer incubation periods. So, we can do a
sensitivity analysis say if we have an incubation period that is up to 5 years
longer and if we have a reduced susceptibility what would this do to our
projections?
So, I will just skip that. So, these are the sort of
results that we would get in terms of cases in non-MM genotype. So, what this
figure is showing is the scaling of the incubation period distribution in the
non-MM genotypes. Because we
don't have very much data we haven't distinguished between the VVs and the MVs
here. For example, here we would be saying that the incubation period in the
non-MMs is twice as long as that in the MMs and here we have the relative
susceptibility. So up here we would be saying that they are as susceptible but
they may potentially have much longer incubation periods and as we go down we
are saying that the non-MMs are less susceptible.
So a value of .5
would mean they are only as half as susceptible to infection and the colors
here are denoting the potential sizes of the epidemic. So, of course, our worst
case scenario would be if they were almost as susceptible as the MM genotypes
but have much longer incubation periods because that would suggest we have an
epidemic that is going to occur later in time that we are waiting to see, but
this sensitivity analysis did also suggest that future case estimates could
really only be up to about five-fold higher because this depends on the
relative frequency of the MM and non-MM genotypes in the population, also, that
it is unlikely that we would have greater susceptibility. The biology doesn't
really suggest that the non-MMs would be more susceptible but have much, much
longer incubation periods.
Okay, finally I wanted to talk a little bit about blood
transfusion. I will skip these couple of slides because they have been covered
by Richard in his previous talk.
One question of interest at the moment is what the
potential for an epidemic arising through blood transfusion and this is really
the main concern because we have obviously seen cases arising through this
route.
So, just to go through what actually determines the
potential scale of a transfusion associated transmission mathematical models
typically deal with this quantity called the reproductive number of R
naught and this is basically saying how
many on average, how many new infections are on average generated by one
initial infection in an almost entirely susceptible population.
So, diagrammatically here we have the first person infected
through the dietary route and that person donated blood and that went on to
infect this second person and that second person could then possibly donate
blood that was given to two more individuals but only infection occurred in one
of those instances and so we could see this expanding tree of infections and
the critical quantity is this factor R naught, the average number of new
infections generated by each individual in this chain and if that is more than
one so each individual is on average transmitting on to more than one other
individual we will see that this chain is expanding and we will get an
expanding epidemic. If it is less than one, so on average each new first
infection generates less than one new infection then the epidemic will die out.
It won't persist.
So,
this is a quantity that we have been particularly interested in. This quantity
R naught is really telling you whether you can get a self-sustaining epidemic
and a self-sustaining epidemic is obviously something we want to avoid.
So, this just shows you diagrammatically some very simple
models, the types of picture you could get. Here if you have an R naught on two
so on average each initial infection gives rise to two new infections, then you
will see an epidemic appearing in this sort of form. It will become endemic and
you will reach a steady equilibrium state of prevalence and over this time you
will be accumulating new cases and you could see that cases could rise very,
very rapidly for a R naught of this value.
For an R naught of less than one we see that the prevalence
will die down and decrease and eventually we won't have infection in the
population and so there is a lot of focus on keeping R naught less than one for
all epidemics but I think it is very important to note that this does not mean
that there aren't substantial numbers of cases arising. You can still get a
substantial number of cases arising even if on average the epidemic is not
going to be self-sustaining.
So, these principles really hold not just for the blood
transfusion associated epidemics but also for transmission occurring via
surgical instruments. So, what are the factors determining R naught? Most
important obviously is the infectious dose. So, what is the probability that an
individual given say X units of infected blood would become infected, and that
is something that we realize is highly uncertain. We would never be able to
really put any bounds on that value but we could potentially look at scenarios
in which we vary this infectious dose right up to the value of one so that
anybody given an infected unit of blood becomes infected which is a plausible
value but also not just the infectious dose but also the numbers of donations
recipients of transfusion really determine this R naught value. So, it is the
magnitude of that blood supply and this just gives some figures for the UK and
for the similar figures available in the US from the national blood service
figures for 1996-97. We had 1.9 million donors donating just 2.2 million units
of blood. We also have some good data on red cell transfusions so where the
blood is actually going to and that gives estimates of the units received per
100,000 population per year. It,also, gives good estimates of the age
distributions and this is a final point I would like to stop on.
This is the age distribution of the recipients and the
donors. So,you can see that blood
donors are typically in the 30-to-50 age range but as we all know transfusion
recipients are very much older individuals and this age distribution is also
very, very important for this concept of a self-sustaining epidemic because if
these were the primary infections and we do see infections in that age group
they might go on to donate blood that is used and infects individuals in this
age group but it is then fairly unlikely that we would get infections going
back into this population simply because of the age distribution but those
receiving red cell transfusions are unlike to then themselves donate blood.
They are in a much smaller probability.
So, these age distributions are very important both for
blood transfusion and also for surgical instruments in determining the
potential scale of an epidemic by these routes and this is work that is
ongoing.
So, in summary then the variant CJD clinical cases remain
low and the current predictions are also low based on either fitting into
clinical cases or including a subclinical or carrier state.
The prevalence estimated from the appendix survey is higher
than would have been expected from the epidemic observed so far if we didn't
include any sort of form of subclinical infection and then this inclusion of
this subclinical infection or carrier state to explain this discrepancy between
the two data sets gives rise to an estimate that approximately 20 percent of
those infected will become clinical cases.
There is of course still uncertainty in the genotypes and
Richard already covered some of this. Worst case scenario is where the non-MM
genotypes have similar susceptibility but much, much longer incubation periods
and this could result in a five-fold higher estimate of future epidemic and the
big remaining uncertainties are blood transmission and potentials for secondary
epidemics.
Okay, I would like to acknowledge my people who have helped
with work and finally I have put a few of the key model references down for
people to look at.
Thank you.
DR. PRIOLA: Thank
you very much, Ghani. Will you and Dr. Knight be here for the rest of the day?
DR. GHANI: Yes.
DR. PRIOLA: Okay,
so, you will be available for questions.
I think we will take a break now for about 15 minutes and
reconvene at ten-fifty-five.
(Brief recess.)
DR. PRIOLA: Once
again I would like to remind the Committee because I know this is tough to sit
through these talks without asking questions but to keep in mind the questions
that we are supposed to address as we listen to these talks so that when we get
to the discussion we can get through the 10 questions we have to discuss early
this afternoon.
So, our first speaker for this next session is going to be
Alan Williams and he is going to talk to us about modeling the risk of variant
CJD in US donors.
Agenda Item:
Modeling Risk of vCJD in US Donors – Residual Risk and Efficiency of
donor Deferral – Alan Williams, PhD, OBRR, CBER
DR. WILLIAMS: Thank you.
Combined with laboratory testing the screening of blood donors by
medical history and other screening questions is a powerful adjunct to helping
to maintain the safety of the blood supply but there are a handful of
situations when safety of the blood supply is wholly dependent on the screening
of donors because there simply isn't an available laboratory test and variant
CJD is one of those instances.
Most of you have
seen a pie chart similar to this in the past but this is a representation of
the overall risk burden in the donor population prior to the initiation of any
interventions, any donor screening for
dietary exposure.
One can see that the major risk component is dietary
exposure within the UK, components related to travel residence in Europe, a
portion of the donor population that was imported from Europe at the New York
Blood Center and something relating to the second set of deferrals was the
exposure to UK beef on military bases.
The first set of recommendations was issued in November
1999. I am not going to go through the details because Steve covered those in
this talk and you had those in great detail last October but basically the primary deferral was related to time spent in the United
Kingdom for 6 months or greater and a major consideration during that policy
determination was the impact on the blood supply.
If one deferred everyone who had a contribution to that
original pie chart one would lose more than 35 percent of the blood supply.
Obviously that would not be tolerable. So, with the first recommendation there
was an estimated loss of 2 percent which was tolerated and left this as the
fractional component of risk proportionally a larger component from the base
exposure. So, it was a sizeable
component 32 percent from UK travel and then the Euro blood and Europe
exposure.
Then in January 2002 the second set of recommendations
issued which tightened the deferral for UK travel added base exposure and this
is the representation or the impact on that second pie chart. The total risk
burden reduction was estimated to be about 91 percent from that original pie
chart and one can see here the representation of the DOD exposure removed by
the deferral, the DOD exposure left in because of time that was lower than the
time period of the recommendation.
UK exposure cut not quite in half with a little bit of UK
exposure left primarily due to individuals who traveled less than 3 months and
similarly for European exposure.
Now, this gulf
really I think shows the two elements that are incorporated into the model. The
white areas were risk is removed what we are going to be looking at in a major
component of my talk is what is the efficiency of those donor screenings; has
everyone in fact with that risk been taken out of the blood supply or is there
a false-negative rate for the donor screening questions? The segments of the pie that are left there
represent the shorter term deferrals, those who have been to Europe for just a
couple of days or a week and are not subject to the deferral but may well have
had dietary exposure throughout this period and represents quite a large number
of donors.
So, just to reiterate factors related to the current donor
screening procedures are considered in the proposed FDA model that Dr. Anderson
described. The first is periods of dietary BSE/vCJD risk among donors that are
less than the current deferral criteria. These are estimated from the original
donor travel survey data and estimated as about 9 percent of the total risk
burden prior to any implementation of donor screening.
The second factor included in the model is the
consideration of the sensitivity of current donor screening procedures to
exclude those donors with deferrable risk when they appear for donation.
FDA is proposing that in the absence of empirical measures
the proposed FDA risk model should incorporate an estimate range of 90 to 90
(sic) percent sensitivity to occur in donor screening procedures to exclude
that deferrable risk.
The second point, due to the donor population size, the
limited other risk-reduction measures
and the fact that the donor population
dietary risk really is the risk contribution to the model the impact of this
factor of sensitivity on the model is quite large.
So, the balance of this presentation will concern the
rationale behind the 90 to 90 percent sensitivity estimate for the questions.
I think one thing to understand is what are the different
components of donor screening. A policy
is developed which is a combination of regulatory policy and industry standards
and local blood establishment policy and this is generally made known to
potential donors through educational materials, web sites, donor calls with
questions. Often they get a little
prescreening over the phone.
So, the elements that contribute to donor screening are the
reduction of entire population subsets such as occurred in the past. Paid donors are eligible for donation but in
the whole blood segment those units need to be labeled as being from a paid
donor. Prisoners for some time have
been ineligible for blood donation.
Then through education there is a large component of
self-deferral before a blood drive. This is the group that Dr. Anderson
mentioned that are aware that they are not eligible and simply don't appear at
the blood center.
A second self-deferral is folks who appear at the blood
center. They may not have been aware of it beforehand that they are not
eligible but they see the materials while they are sitting waiting to be
interviewed and determined that they are not eligible and leave.
There are also those where it is very hard to get any sort
of empirical measures of how many donors actually do that because they are not
available for study. The highly visible
area of donor screening is a deferral by staff during the medical history
interview process and I will say more about that in a moment and then finally
if the donor proceeds with donation and that risk factor is not appropriately
elucidated sometimes additional information comes back to the blood center and
we find out about that risk after donation and in instances when that unit has
been issued for transfusion that would constitute a biologic deviation and be
reportable to FDA.
So, there are limited data available but that tends to be
somewhat a passive reporting system. So, again it is hard to get rigorous data.
I mentioned the deferral on site that I would say more
about. The 1999 recommendations there was an estimate of 2.4 percent of
deferral among the blood donor population and 2002 about 5 percent, a little
bit over 7 percent overall.
You can see that the on-site deferral experience and these
have been presented through the years by Red Cross and other blood establishments,
the current deferral is 3 to 4 per 1000 overall, most of this representing not
first- time donors because the definition of first-time donors gets very
complex but Red Cross has considered this as donors who have no previous onset
exposure to the variant CJ question. So, although they may have donated
previously it was in a time before the deferral was put into place.
So, you can see that the bulk of those deferrals are those
who had no previous administration of the question and about 7 per 10,000, those
who had a previous experience of the question may have traveled since that time
but may have been missed in the earlier question administration.
A small proportion but when looking at about 14 million
donations per year it can constitute a sizeable number of individuals and then
similar data among the source plasma population, about 4 per 1000 deferral
among candidate donors. These are donors whose plasma has not become part of
the plasma pool because they are not yet qualified donors and if they a positive
question response their donation is removed and the ongoing rate about 4 per
10,000,not incompatible with the whole blood donor population but there are
probably other factors such as level of education, materials that are
encountered and demographics that in fact probably account for some of those
numbers in the underlying rationale.
So, how does one assess the sensitivity of donor
screening? The things that we would
really like to get at but we can't for variant CJD are changes in donor
seroprevalence, reduction in adverse events to recipients or comparisons with
risk levels in the general population.
Now, we can't get at any of this for variant CJD. So, the
approach that we took was looking at some non-agents and some extrapolations
from analogous situations with other transfusion transmitted disease risk
factors, and then I also wanted to be sure to mention that there has been a lot
of recent work in the questionnaire process itself. The Blood Products Advisory
Committee has worked closely with FDA and the blood collection community so
that the questionnaires currently being used for donors now have been
cognitively assessed for understanding by donors, a lot of this work by the
National Center for Health Statistics.
So, really for the first time we have some confidence that the questions
have been through a rigorous qualification process.
So, to look at some of the comparisons, first looking at
marker prevalence and although I am not showing data for incidence presumably
data should be available to make some similar comparisons using incidence of
infectious disease markers.
So, here we are looking at comparing the general population
versus first-time donors. First-time donors have not donated. They have not
been prescreened. It is the best population to try to correlate with general
population data.
So, looking at HIV seroprevalence, a report by Jerry
McQuillan which is the Dallas County Household Survey found a little less than
1/2 percent HIV-positive in donor age general population subjects in Dallas
County. That can be compared with about the same time frame HIV seropositivity
of .03 percent in first-time donors. So, the difference between those two
should be the impact of the education, screening on the donors and results in a
93.6 percent reduction in HIV seroprevalence.
Similarly one can make that comparison by looking over time
and this I would say is the classic graph developed by Dr. Mike Gershon and his
colleagues in the early 1990s.
This was a combination of looking at Irwin(?) Memorial
Blood Center seroprevalence data together with some of the prevalence data for
targeted studies within the San Francisco area and the NHLBI transfusion safety
study, and this graph was produced to show the risk of HIV transmission per
unit of blood starting with the earliest days of the epidemic through 1985
which was the development of specific screening.
It shows that the epidemic was under way for several years
before initially recognized, then recognized by clusters of Pneumocystis
carinii and other clinical syndromes and then the first post-transfusion AIDS
case report and the recognition of high risk donor subpopulations which were
then subject to deferral and self-deferral, and a lot of self-deferral took
place so that by the time the test actually became available the risk in the transfused blood had been
reduced about 90 percent solely on the
donor screening aspect.
Similar comparisons, we started looking at seroprevalence,
and here we are looking at risk from accepted blood donors and there was a
study published by the University of Chicago showing that in the general
population of the country there is about a 4.1 percent prevalence of males who
have had sexual contact with other males in the past 5 years.
Compare that with survey data and I think the publication
was shared with you a little more than 1/2 percent of that risk, males who have
had sex with males since 1977 in accepted male donors, so, again, general
population versus the male donor population about an 86 percent reduction and
then one last example comparing intravenous drug use risk. Again, the Dallas
Household Survey documented a little under 4 percent IDU since 1978 in the
general population versus 1/2 percent intravenous drug use ever among accepted
donors, again about an 86, 87 percent reduction.
Now, those show the positive impact of screening but I
think there are also data which show quite convincingly that there is a
false-negative aspect of screening and this comes from several different types
of observational studies but basically data collected from donors after they
are accepted for donation may identify behavioral risks that should have
prevented their donation and that is what is being called deferrable risks.
I think again some of the classic data come from interviews
with HIV seropositive donors, many of these studies sponsored by the Centers
for Disease Control. For the period of the late 1980s and then another study in
1997 for both males and females when a donor is found HIV seropositive and
subject to one-on-one interview one clearly sees risks that should have
resulted in the deferral of that donor including MSM risk in males,
heterosexual contact in a small
component of injecting drug use and then similarly for women a much larger
group with no reported risk but again others with non-heterosexual contact and
one can see those types of data whether it is interviews with donors who have
been identified with hepatitis infection or HTLV. One commonly sees risks that
should have resulted in deferral and then similarly the Red(?) study did a
post-donation anonymous survey of risks among accepted donors. This was
published in JAMA in 1997 and then repeated in 1998 and also published with
very similar results but a wider range of risks assessed and this shows that really
for all the risks that are being screened for there is some false negative that
gets through into the accepted donor population.
Just one anecdote that I happened to look at and didn't
make it on the slide but males who trade drugs or sex for sexual contact there
is a general population figure for that, I think, again, the Dallas Household
Survey reported 11.6 percent in the general population versus 1/2 percent in
blood donors. So, here we are seeing about a 20-fold risk reduction there as
well.
So, you can see we are looking at general ballpark of risk
reduction ranges.
From a behavioral science perspective one can
understand why there are difficulties
both in screening individuals for histories as well as trying to get rigorous
data to look at efficacy.
Information about personal behaviors is inherently
difficult to collect. One big thing is the social acceptability of information
and clearly for injecting drug use and MSM that would probably be a larger
factor than for travel history.
Response rates on behavioral surveys tend to be low. There
tend to be missing data when someone completes a questionnaire and
inconsistencies are frequent.
Now, keep in mind that blood establishments are regulated
and they simply need to have all the blanks filled in. So, that is less of an
issue within a regulated blood collection environment but it is a background
problem with history taking.
People tend to avoid careful reading. I think for the donor
setting there are those who are convinced that a video presentation or a
one-on-one interview is better than simply giving somebody two pages of
educational material to read but still the community is very dependent on
reading material.
It is known that there is an educational effect of donor
screening that even if a donor has missed the first time they are in there is a
likelihood that they will be caught the second, third or fourth time that they
are in.
So, there is a reduction in deferrable risk with subsequent
donations and the Red study has shown some of that information for some of the
major screening factors.
What happens when a donor determines that they are in fact,
the individual that is being talked about in that screening questionnaire?
There can be an aspect of denial and there can be quite a proactive lack of
respect for policy if you have an individual who is knowledgeable and feels
that the donor screening is out of line that in fact out of lack of respect
they simply will not identify
themselves as the subject of that policy and fail to self-defer.
There can also be external factors such as secondary gain
for donation be it peer pressure coming to the donation site with a group of
friends and not wanting to appear to stick out by being deferred. Plasma donors in the country largely are
paid for their donations. So, peer pressure, other secondary gains and the
environment, what is the privacy of the donor screening procedure; can one in
fact give a socially less acceptable answer and be assured that it will remain
confidential? And then finally, the
aspect that has been looked at recently with respect to the questionnaire is
the issue of comprehension of the donors and question complexity. Both of these
are an acknowledged problem for the travel histories where one has to think of
the cumulative travel history and determine whether or not that exceeds a
3-month period for the UK. I think there are probably those, a few of those in
this room who would have some difficulty doing that if they are not current
blood donors.
So, in conclusion based upon limited data from analogous
donor screening situations we believe
that a 90 to 99 percent estimate of screening sensitivity is bound, is
realistic. The 90 percent lower bound supported by screening experience with
other transfusion transmitted infections, the 99 percent upper bound supported
by behavioral factors, the lower likelihood of travel among plasma donors and
the high proportion of repeat donors, I mentioned that qualified donor aspect
for source plasma donors and in fact all donors now it is an industry standard,
are prequalified so that de facto all donors for source plasma are repeat
donors.
There may be other ways to get at the predictive value and
sensitivity of the questions but the work hasn't been done. There could be
targeted follow up of the reasons for the post-donation information reports.
There could be on-site attempts at validation and there could be comparison of
results from different donor screening modes such as post-donation interviews
or surveys to help continue to study this aspect.
So, I remind you that the TSE Advisory Committee in fact
gave a mandate for the initial collection of survey data which you have heard
about now many times so that if there is a key area of data collection I urge
you to identify that and make it known most likely to the National Heart, Lung
and Blood Institute which funds these types of studies and would be capable of
carrying that out.
Thank you.
DR. PRIOLA: Thank
you, Dr. Williams.
We will move on to the talk by Dr. David Asher who is going
to tell us about estimates of variant CJD infectivity in plasma.
Agenda Item:
VCJD Infectivity of Plasma – Estimates from Experimental Models – David
Asher, MD, OBRR, CBER
DR. ASHER: Thanks.
First, I want to say that to comment on the loss of Al Jenny so soon
after Beth Williams, they were two of the people that I have relied on for
years for expert advice besides being two of the nicest people that I can think
of and I, personally, feel a tremendous sense of loss at their deaths.
We are asking the Committee to comment on several
assumptions used in FDA's provisional
variant CJD risk assessment for plasma derivatives. We have attempted to use
very conservative assumptions about infectivity in plasma. We have assumed the
infectivity to be present in blood throughout incubation period although we
certainly that that won't prove to be true.
The maximum and minimum incubation periods of variant CJD
are not known. Depending on how you estimate the minimum incubation period somewhere
between 5 and 12 years after oral exposure seems reasonable and the one case of
transfusion transmitted vCJD 6 years.
About infectivity how much infectivity might be present in
human blood during various stages of the incubation period, the shorter answer
is we don't know. All we can say with any confidence is that two units of non-leuko reduced packed red blood cells
each contained at least one human intravenous infecting dose which translates
into something like .005 doses per
milliliter minimum.
However, it seems likely that there is more infectivity
than that and we have taken provisionally 0.1 dose per milliliter as a
reasonable minimum.
The rest of the model is based on what we know from
experimental studies in rodents and 10 infectious doses per milliliter has been
taken as an approximation of a common result.
We took 310 as the maximum dose because that is the maximum
reported anywhere in the literature for animals although as you will learn that
number is not really well supported.
In the 8 minutes or so that remains in this talk I can't
review much of what we know about TSE agents in blood but I do want to remind
you that for sporadic CJD attempts to
transmit disease by inoculation of patients' blood into non-human primates even
whole units into chimpanzees have failed. Claims of transmission of CJD from
patients into rodents have not been confirmed.
Those observations are consistent with the epidemiological
studies that failed to show blood transfusion or exposure to blood products as
a risk factor for sporadic CJD and especially the surveillance of more than 100
recipients of labile blood components from donors who later got sporadic CJD
presented here found that no recipient has ever been recognized with sporadic
CJD, quite a different situation from that that we see with variant CJD as you
know.
Studies of animal TSEs revealed similar difficulties in
detecting agent in blood but when those
difficulties were overcome a troubling consistency in detection of small
amounts of infectivity in blood of animals during the incubation periods of
TSEs was seen.
For many years William Hadlow and Carl Eklund hypothesized
that there might be a blood-borne phase of infection in scrapie. They tried and
failed to transmit the disease from sheep and goat and mouse blood into mice.
Several years ago Hunter Houston and colleagues succeeded
as reviewed by Richard Knight earlier today, succeeded in transmitting natural
scrapie to sheep by transfusion demonstrating the previous failures had
probably been limited both by the species barrier of the assay and by the small
amount of blood that it was possible to
assay in experimental animals by intracerebral inoculation.
Shortly before the scrapie transmission by transfusion was
demonstrated by Hunter and colleagues the same investigator succeeded in
transmitting sheep adapted BSE by transfusion to scrapie-free sheep.
Those experiments did not permit estimates of the amount of
infectivity in blood but experiments with the BSE agents adapted to mice suggested
that the amount of infectivity in mouse blood must be very small; a published
incubation time assay and I will comment about that in a minute was about 5
intracerebral infectious units per ml of mouse blood.
Most work in estimating the amounts of infectivity that
might be present in blood has been performed using other models of TSE adapted
to rodents which was first demonstrated by Elias and Laura Manulites who
demonstrated convincingly in 1978 in blood of guinea pigs infected with a
strain derived for a CJD patient. Soon
after that Koroda and Gibbs in 1983, reported similar findings in mice infected
with a strain adapted from the brain of a patient with a familiar TSE later
identified as Gershner-Streisler-Shankar(?) syndrome.
A particularly popular model has been the 263K strain of
scrapie agent adapted to hamsters and I will present some of the work of Bob
Rohwer who is here to participate in the next session but who kindly lent me
several of his slides. That model was first reported by Heino Diringer shortly
after that by Petricio Casachia and Mauricio Pochiari after hamsters were
inoculated intraperitoneally with scrapie.
The results of that study were reworked recently by Phil Colmer and his colleagues at Detnar Scarveratosh(?)
to estimate the average of 310 50 percent infectious doses per ml of blood
during the first part of the scrapie incubation period and I want to note here
that those results have at least two serious problems. First the pattern of
blood infectivity which in their studies was present only in the first part of
the incubation period has not been confirmed in later work and does not appear to be predictive of what we have seen for variant
CJD.
In this panel prepared by Bob Rohwer I will show you what I
mean if the cursor comes on. Okay, the
cursor didn't come on. Okay, and I
don't know where the pointer is. Okay, Heino Diringer demonstrated infectivity.
The red stars are successful isolation of transmission attempts and the open
circles are negative attempts, failures. In the first part of the incubation
period they stopped looking at 40 days. Casachios showed infectivity on through
90 days but failed to demonstrate it after that and found no infectivity at 120
days when the animals were sick with scrapie.
If you look at other studies this is Laura Manuilitis's
study in guinea pigs and you can see that after a little infectivity during the
first couple of weeks potentially coming from the initial inoculum a number of
weeks went by with no infectivity and then periodic detection of infectivity
and infectivity detected in some animals on into clinical disease and the work
of Karoda and later Paul Brown and Delores Achevanukova no infectivity early.
Infectivity appears later in the incubation period and on into clinical disease.
So, the Casachio Prochiari work on which that number of 310 is based suffers
from not being predictive for other models of TSE.
Another problem is that they used an incubation period
assay that is highly inaccurate in estimating small amounts of infectivity.
The classical method for estimating infectivity is
titration testing serial dilutions of samples looking for that dilution at
which easy assay unit has a 50 percent chance of being infected. Another way of
looking at it is that it estimates the volume of inoculum that has a 50 percent
chance of containing infectious agent.
As the amounts of infectivity get smaller the incubation
periods get longer and so during most of the range of infectivity incubation
period can be used as a, or the time to death can be used as a rough estimate
of how much infectivity is present.
The problem is that it at the very smallest amounts of
infectivity the dose-response curve becomes non-linear so that in this panel
also prepared by Bob Roy you will see that at the end point there is a very
wide spread of infectivity and animals come down anywhere from oh, I don't
know, 130 days or out to 450 days and if only a small number of animals are
being used those numbers cannot be used to predict accurately what the end
point dilution would have been.
Paul Brown and Lois Achovanukova performed more informative
estimates of infectivity using mice
infected with the Fu-1 strain of GSS, the same one that Kuroda and Gibbs
have developed and they did something approaching a classical titration. They
found that buffy coat contained 44 in one experiment intracerebral infectivity
units and 106 in another. Since in their study an ml of blood contained about a
1/20 ml of buffy coat that means that anywhere from 4 to 10 infectious units
per ml plus the infectivity in the plasma must have been present and that
varied from 10 to 22 infectious doses per ml in the same experiment. So, adding
together the buffy coat and plasma associated infectivity it might be
reasonable to conclude that whole blood probably contains somewhere between 9 and 22 infectious units per ml. Both
of them are here today and would be far better than I to answer any questions. An even more precise, if very expensive
assay method for infectivity has been used by Bob Rohwer called the limiting
dilution titration and it represents an expansion of the classical titration by
increasing the number of assay units near the end point.
For blood that means it assaying an entire volume, large
volume of material and dividing it into aliquots and injecting the whole thing
intracerebrally into hamsters. The
readout is therefore not an ID50 but a
direct measurements of the number of lethal doses present in the whole volume
corrected using the Poisson distribution for the possibility
that some of the animals might have been exposed to more than a single dose of
infectivity.
When they did that on multiple assays Bob and his
colleagues have titrated the blood of a large number of hamsters inoculated
both intracerebrally and orally at intervals after infection, the maximum
amount of infectivity they found in terminally ill hamsters varying from about
2 infectious units per ml to as much as 25 infectious units per ml with both
median and mean about 10 infectious units per ml.
The infectivity was first detected in this series of
experiments just before about day 50 representing something less than 50
percent of the total incubation period rising gradually until the onset of
illness which was of course quite different from the results that Patricio
Casachia had obtained.
At least 30 percent of the infectivity was associated with
plasma in these experiments, 45 percent with buffy coat and 25 percent with red
blood cells although some of Bob's other work suggest that red cells and
platelets may not be intrinsically infected. I am sure we will hear more about
that in the next session.
So, to conclude the provisional risk assessment for plasma
derivatives is proposing as an assumption using a triangular distribution for
the amount of infectivity that might be present in blood of donors incubating
variant CJD a minimum of .1 ID50 per milliliter of blood mostly likely 10 ID50
and a maximum of 310 ID50 acknowledging the uncertainty regarding the assumption.
As I noted the experimental basis for the 310 ID50 per ml
is questionable. However, it does represent the highest published value for
rodent blood. The value is only about a log and a half higher than the mean
value estimated for hamsters and that difference could be considered as a
safety margin.
Perhaps members of the Committee think that we should even
use a higher margin of safety or perhaps you know about information that we are
not aware of.
Until last week we had a preliminary sensitivity analysis
that had suggested that differences of this magnitude were not likely to be
major drivers of overall risk. However, when the values were recalculated
changing some of the other assumptions it appears that the level of infectivity
in blood may not be an inconsequential element in risk although it doesn't
appear to be as important as the prevalence of infection in the donor
population or the ability of the manufacturing process to reduce infectivity.
Thanks very much.
DR. PRIOLA: We will
move on to Dr. Scott for her presentation.
Agenda Item:
Review of TSE Clearance in FVIII Product Manufacturing – Dorothy Scott,
MD, OBRR, CBER
DR. SCOTT: Thanks.
As Dr. Asher just mentioned the amount of clearance in steps used to
manufacture any product really is important for the risk assessment, that is it
is a variable that is found to have a lot of impact. So, right now I am going
to review the publicly available information on TSE clearance by steps used to
manufacture just Factor 8 products.
These are the questions to you. Do you agree with our
proposed approach for estimating clearance of TSEs from Factor 8 products by
manufacturing for use in the risk assessment model and what experimental data
would enable refinement of these estimates and allow comparisons of clearance
affected by various steps in Factor 8 manufacture?
Just to very briefly remind everybody this is how a typical
clearance step is done. You take a TSE infected material. Usually this is brain
because it has a very high titer, but this can also be plasma from an infected
animal and you add that to the starting plasma which would be like a plasma
pool or intermediate material. Obviously this is all done at the lab scale.
Then you take a scale-downed process or a series of processes that you want to
study to see if they result in any clearance and you measure at the end of this
process the leftover infectivity and this measurement as has been mentioned is
typically in logs of reduction.
There are two main kinds of studies that are done but the most
common form manufacturing processes is the spiking studies.
The reason for that is because if you use infected brain
you can demonstrated significant clearance levels because the spike might be 6
to 9 logs of infectivity. Therefore if you end up with three or two you can
show a substantial amount of clearance if it exists.
However, this has been criticized because the physical
similarity to the blood-borne form of TSE agents of brain material is
uncertain. There has been similar behavior demonstrated in some situations,
that is convergence of in general of fairly high clearance for alcohol
precipitations with spiking experiments and endogenous infectivity experiments
but this has particularly been questioned for some other steps such as
filtrations that are size dependent because there may be some forms of TSE
infectivity that are quite small.
At least when the characteristics of blood-borne
infectivity are defined the relevance of spiking preparations can then really
be studied and understood. Endogenous infectivity studies using starting plasma
of an infected animal are certainly more relevant it can be argued but they
cannot demonstrate high levels of clearance because the starting infectivity is
usually on the order of 1 to 2 logs per ml.
Those are very difficult experiments to titrate. So, there
are two ways that we thought of to estimate the TSE clearance in Factor 8
product manufacturing. One is to use the published literature to identify
clearance values from similar steps for Factor 8 or other products and we have
seen this done in other risk assessments but I would point out there is a
probable major flaw in this which is the fact that different clearance levels
are often demonstrated for what appear to be similar steps, but these differences are likely due to product and
process specifics. You don't need to read all of this. This is just an example
of TSE clearance studies. Here is your reduction factor and these all use depth
filtration with some kind of upstream process that allows material to be
filtered.
This is a starting material and you can see this comes from
published information including a package insert but basically the reduction
factors that you get with depth filtration are highly dependent obviously
potentially on the type of depth filter that is used but even not entirely that
and on the starting material and its characteristics which would include
different protein concentrations, pHs, ionic strengths and levels of alcohol or
other things that are used to precipitate.
So, we didn't choose to use this more general method.
Rather we thought it would be better to use product specific studies to
identify clearance values. These are obviously more relevant to the specific
products but they are not available for all Factor 8 products in the US and
even when they are peer reviewed and published many of them have not been
evaluated in detail by CBER.
There are lots of variations in the study methods including
different spiking preparations. Even the brain preparations have different
methodologies and they might be variably clarified, solubilized, sonicated or
filtered and then of course there are microsomal and fibril preparations.
Furthermore the assays for TSE at the beginning and at the
end may be surrogates, that is PRP, scrapie measures or bioassays and these
results can sometimes differ.
I would just point out that the labeling claim that we
offer for TSE clearance is based on demonstration of infectivity reduction at
this time.
Now, what about the Factor 8 products that we look at? I just wanted to mention overall the Factor
8 products that we have and the purity has typically been defined by their
Factor 8 activity and these have been called intermediate purity and you can
see that that has a lower amount of Factor 8 per milligram of protein than a
higher purity preparation or what is called a very high purity
preparation. However, there are lots of
methods used even to produce these intermediate purity products and overall for
all of these products we see cryoprecipitation as a very common feature but
there are also PEG precipitations in some cases, size exclusion chromatography,
ion exchange, monoclonal antibody affinity chromatography and heparin affinity
chromatography.
So, it is more than just cryoprecipitation. All of these
products have a number of other subsequent steps that further purify the Factor
8.
I would like to mention, also, that many of the
intermediate purity products contain von Wiilebrand's factor, and this is very
important for people with von Willebrand's disease obviously.
The potential clearance of variant CJD or any TSE may not
correlate with the classic definitions of purity. It really is process
dependent. So, if you think of studies of TSE clearance and Factor 8 products
one of these is not published. What we did do though is we took six of these reports and looked at the
amount of clearance that we got and basically this is a summary and actually it
is very similar to what PPTA has presented to this Committee in the past that
cryoprecipitations typically do not result in a lot of clearance, that PEG or
glycine precipitation just each step by itself may result in some level of
clearance, maybe slightly higher with
ion exchange chromatography and maybe slightly higher with affinity
purification.
Now, how are our current plasma-derived Factor 8 products
made? There is not a lot of detail here and the reason is because this came
primarily from package inserts and a lot of the processes that are used in the
manufacture are proprietary.
So, I just listed some of these, the heparin affinity for
alphanate, PEG precipitation for Koate and immunoaffinity for these three
products as well as ion exchange for both of these.
So, in other words what I am telling you here is this is
not complete and understandably not because of the proprietary nature of
manufacturing.
Now, this is our proposal for TSE clearance values to be
used in the risk assessment. There is a
range of clearance values that is suggested by the available studies for
different manufacturing steps and the ranges that we would like to select are
consistent with additional data that is available to us which has not been published.
What we propose to do is to run the risk assessment three
times with three different clearance ranges, a likely minimum of 2 to 3 logs
and this would more or less reflect a single step with an intermediate level of
clearance in that 2 to 3 range, a mid-range clearance level of 4 to 6 logs
which would usually involved a single step with a higher clearance level or
multiple additive steps, that is throughput experiments sometimes demonstrate
that if you start and do a number of steps in sequence that you get a higher
amount of removal than you would if you studied just one of those steps.
In other words, they can be additive, and then a likely
maximum of 7 to 9 logs which typically would involve two higher clearance
steps, that is if they are additive.
So, I just put the questions back up again. Do you agree
with this approach for estimating clearance? I think that I hope I have helped
you understand that we do not have a comprehensive data set for these products
and what data would help us refine these estimates because this is an important
risk parameter.
Thank you.
DR. PRIOLA: We will
move on to the last talk by Dr. Weinstein.
Agenda Item: FVIII
Product Usage In Clinical Settings – Mark Weinstein, PhD, OBRR, CBER
DR. WEINSTEIN: As Dr. Anderson mentioned I will talk about
the utilization of Factor 8 products in clinical settings. Utilization factors being considered for the
model include the severity of the disease and treatment regimens.
I will also talk about our proposal to model cumulative
variant CJD exposure per year assuming a linear ID50 dose response.
The first question that we are presenting to the Committee
regarding this topic is what data should be used to estimate how much Factor 8
is used by typical patients. For this estimation we need to know what the
definition of a typical patient is; how much product is used per treatment;
what is the frequency of dosage and what should be the time period to be
evaluated?
To answer these questions I will briefly review some of the
characteristics of the patient populations we are considering and available data
sources for estimates of dosage and dosage frequency.
I will also mention some of the limitations that we have in
our data collection. Regarding the patient populations we are considering
hemophilia A is an inherited X-linked recessive trait. It is caused by a
deficiency of the coagulation Factor 8 related to mutations of the cloning of
the clotting factor gene.
The age-adjusted prevalence of hemophilia in the United
States is approximately 1 in 10,000
males. Factor 8 normally circulates in the plasma bound to a second very
large protein, von Willebrand's factor. I will just point it out in the model.
There is a Factor 8 protein bound to the von Willebrand's factor.
The von Willebrand's factor protects Factor 8 from proteolysis, enhances Factor 8 synthesis
and concentrates Factor 8 at the site of active hemostasis.
Von Willebrand's factor is
also needed for binding of platelets to wound sites. Von Willebrand's disease
is caused by reduced levels of Factor 8 activity and there are several types of
von Willebrand's and subtypes of von Willebrand's disease but we will be
considering in our model type 3 which is the most severe and requires treatment
with plasma-derived products.
Von Willebrand's factor protein occurs in higher
concentrations than Factor 8. In hemophilia A one can have no circulating
Factor 8 but normal levels of von Willebrand's
factor but in severe forms of
von Willebrand's disease with little or no von Willebrand's factor present
there will be little circulating Factor 8 and I will discuss that in the next
slide.
To treat hemophilia A one needs products that contain
Factor 8 but may or may not contain von Willebrand's factor.
To treat type 3 von Willebrand's disease you need
concentrates that contain both von Willebrand's factor and Factor 8.
This chart outlines some of the characteristics of the
hemophilia A population and von Willebrand's disease population that we are
considering. Each of the populations is
treated on average with different total doses of product and at different
frequencies.
Hemophilia A patients with severe disease have less than 1
percent Factor 8 and have spontaneous bleeding predominantly in joints and
muscles. They constitute the largest proportion of the hemophilia A population
and there were roughly 6200 patients in the United States in 2002, our base
year for our calculations for our model that had severe hemophilia A.
Those with moderate disease with Factor 8 levels from 1 to
5 percent have occasional spontaneous
bleeding with severe bleeding accompanying trauma or surgery. We
estimate there are about 3600 individuals in this category or 25 percent of the
total hemophilia A population.
Those with mild hemophilia characterized by severe bleeding
with major trauma or surgery are about 30 percent of the total population or
about 3600 individuals.
Type 3 von Willebrand's disease is quite rare. These folks
have less than 1 percent von Willebrand's factor and 2 to 3 percent Factor
8. They often have mucosal bleeding and
severe bleeding with trauma or surgery. We estimate that there are
approximately 250 of these individuals in the United States.
Regarding product usage the picture is extremely complex.
First most hemophilia A patients we estimate on the order of 70 to 80 percent
use recombinant Factor 8 and this is particularly true in the case of children.
As I mentioned previously von Willebrand's disease patients
have to use products containing von Willebrand's factor.
The frequency of product usage and dosage are highly
variable and depend on the patient's weight, type of bleed and clinical
severity of the disease.
Analyzing data about product usage from different data
sources is complicated because of the variation in how investigators define
terms such as prophylaxis, intermittent or secondary prophylaxis and episodic
or on demand treatment.
For example in some studies prophylaxis has been defined as
receiving a product every other day or twice per week for 45 weeks or more per
year.
However, on the form used by CDC in their uniform data
collection program prophylaxis is defined as receipt of treatment products to
prevent bleeding or to prevent rebleeding. Prophylaxis is further divided into
a category of continuous if products are to be administered indefinitely or on
a regular schedule to prevent any and all bleeding.
Intermittent prophylaxis is defined as the patient
receiving treatment products on a regular schedule for a period of at least 28
days and at least one occasion since the last annual visit but therapy was not
expected to last indefinitely.
Episodic is defined as receiving product only in response
to bleeding complications. You will notice that in this data collection form
that there is no specified or amount of product to be used.
Now, the best quantitative data that we currently have
access to is from a CDC study carried out from 1993 to 1998 on all hemophilia A
patients in six states. These states included Massachusetts, New York,
Colorado, Georgia, Louisiana and Oklahoma.
Data was obtained from patient reports obtained from
physicians, hospitals, clinical labs and hemophilia treatment centers. The list
of information obtained in this study is quite extensive and will be very
helpful to us. It includes the severity of the disease based on the activity
range of Factor 8, the total number of bleeding episodes per year, and very
importantly an estimate of the amount
of product used per year, the pattern of usage whether it is prophylaxis or
episodic, the number of weeks scheduled for prophylaxis and the brand of
product being used.
Possible limitations of this data include that it might not
reflect current usage. Changes in the average weight and activity level of patients
using plasma-derived products may have changed which will affect the average
amount of product used. Extrapolations
to other states in the United States might not be accurate although the
diversity of states in the original study was planned to be representative of
the entire country but unfortunately for our purposes no data was collected
specifically on type 3 of von Willebrand's disease patients.
The second source of information comes from the current
program that was initiated by the CDC in 1998 called the universal data
collection program. Patients voluntarily give information to the survey and we can obtain information
regarding the numbers of hemophilia treatment center patients from the start of
the program, the disease type, whether it is hemophilia A, severe, moderate,
mild and type 3 von Willebrand's disease, the treatment prescription, again,
unfortunately not quantitative but whether it is episodic, continuous or
intermittent and the product brand used by the patients.
No information has been collected about the amount of
product used. We, therefore have to extrapolate the amount of product used from
the survey study. About 85 percent of patients who go to hemophilia treatment
centers are enrolled in the UDC program and from the 1993 to 1998 survey data
about 70 percent of the total hemophilia A population visit hemophilia treatment centers.
The patient population that doesn't visit hemophilia
treatment centers may be different from those who do. For example, they may
have milder forms of the disease.
Also, we know that some patients may use more than one
product brand or type of product.
Nevertheless using a combination of data from the survey and from the
UDC data we have calculated the following information.
Most of the patients who use plasma-derived products are in
the episodic category. Most use monoclonal affinity purified Factor 8.
Of the total 6200 hemophilia patient population in the
severe category about 29 percent use plasma-derived products. Twelve percent of
the 3600 patients in the moderate category use plasma-derived Factor 8 and 6
percent of the 4600 in the mild category use plasma-derived Factor 8.
Of the 189 type 3 patients who receive plasma-derived
clotting factors all were on episodic treatment. Now, as to the amount of
product used we can make some educated guesses based on current practice. For
example, regarding prophylactic use some clinicians have defined prophylaxis as
using 25 to 50 units of Factor 8 per kilogram 2 to 3.5 doses per week and for a
70-kilogram man using 25 units per kilogram for 52 weeks per year we calculate
that that would amount to about 182,000 units per year.
At 50 units per kilogram, 3-1/2 times per week he would use
about 637,000 units.
Again, the term "episodic" is ill defined for our
purposes but just to cite one study in the literature a product was termed
episodic when it was used at doses from 12.5 to 53 units per kilogram and it was infused 4 to 72 times per year.
In this study if we use that frequency wit h our
70-kilogram individual this would amount to receiving anywhere from 3500 to
270,000 units per year and he would receive a median dose of about 45,500 units
per year.
Now, we can get some sense from the literature that we are
at least in the ballpark about the amounts of product used per year from a
study by Linden. She used the information obtained in the 1993 to 1998 survey
study and extracted only the
information pertaining to New York State. Dr. Linden reported that patients
under prophylaxis in the severe, moderate and mild category used about 200,000,
100,000 and 25,000 units per year on average respectively.
Those on episodic treatment who were in the severe category
used 80,000 units, moderates 21,000 units and milds around 3600 units.
Now, unfortunately these data are confounded because the
estimates were combined from both hemophilia A and B patients. However, a very
important point is that we can go back to the original survey data from all six
states and with the very generous help of Mike Souci at the CDC who is in
charge of the database and does much of our statistical analysis we can
separate our data out about the use of product in hemophilia A patients to get
detailed information on product use for each patient.
So, in conclusion regarding clinical use the existing data
are limited and have not been analyzed for estimates of clinical use of
specific brands of Factor 8 products in patient groups. We plan to analyze data
from the ongoing UDC survey to estimate the numbers of patients using specific
brands and the distribution of disease types. We, also, plan to extrapolate
data from the 1993 to 1998 survey in the six states to estimate the total
number of US patients and product consumption per patient with stratification
according to the clinical setting.
If there is inconsistent information from these two
analyses it would be reconciled using patient-based medical records data.
Now, we also know that in the future we may be able to get
more accurate data about product usage from a survey study of inhibitor
formation in hemophilia A patients.
This study is part of a larger data collection effort
called the National Bleeding Disorders Coalition. However, this project is
still very much in the planning stage and it might be a number of years before
we are actually able to get data from this source.
We are, of course, interested in whether the Committee has
further ideas about how we should collect data.
I would like next to turn to the question of whether
repeated exposures to low doses of variant CJD infectivity lead to clinical
disease. The data about risk of cumulative exposure is limited to a few studies
in animals and I will describe one such study by Diringer.
Hamsters were fed one dose of scrapie-infected hamster
brain for 1 day, one dose each day for 10 days or one dose every 4 days for 10
exposures.
There were about 60 animals in each of these studies.
Approximately 1 percent of the animals
fed a single dose died while 8 percent receiving a dose every day for 10 days
died and 4 percent died of those receiving a single dose once every 4 days for
10 exposures. The authors concluded that hamsters receiving a repeated standard
infectious dose several times have a higher risk of developing scrapie than
those receiving a single infectious dose.
In another part of the study the authors fed the hamsters
one infectious dose once. They, also, divided the dose into 10 tenths and gave
one tenth eery day for 10 days to one group of animals and one tenth every
fourth day for 10 exposures.
The animals who received the full dose all at once had 11
percent risk of infection while 8 percent had a risk of infection when the dose
was spread out over 10 days and 4 percent had a risk when treatment was spread
out over 40 days.
The study suggested that there was a smaller risk of
infection associated with longer intervals between feeding.
These findings suggested exposure to repeated low doses of
variant CJD infectious material by the oral route increases the potential for
infection but that increase in the time between doses may decrease the risk.
So, in conclusion the risk of variant CJD infection may not
be linearly related to cumulative exposure. Nevertheless despite possible low
prevalence of variant CJD in plasma donors and limitations to pool size
repeated dosing substantially increases potential risk of variant CJD exposure
in Factor 8 product recipients.
We propose in our model based on these considerations to
estimate the risk per annum in plasma derived or von Willebrand's factor
product users rather than the risk per dose and we are asking whether the
Committee agrees with this proposal.
DR. PRIOLA: Thank
you very much, Dr. Weinstein. We will move on to the open public hearing
portion of the meeting.
Agenda Item: Open Public Hearing
DR. FREAS: As part of the FDA Advisory Committee procedure
we hold open public hearings to give members of the public an opportunity to
make a statement concerning matters pending before the Committee. As
Chairperson at this time I have received two written submissions for the
meeting record, an e-mail from Ms.Sachau and an e-mail from Terry Singeltary.
These e-mails are currently in the Committee members' folders, the public
viewing notebook and copies are available at the reception desk upon request.
We, also, have received three requests for oral
presentations for this morning's open public hearing sessions. The first
requester is Dr. Peter Ostrow, professor and former dean of the University of
Buffalo Medical School on behalf of the CJD Foundation Medical Education
Program.
Dr. Ostrow?
I am sorry, the most important thing before you begin the
Chair must read a statement regarding all open public hearing speakers.
DR. PRIOLA: Both
the Food and Drug Administration, FDA and the public believe in a transparent
process for information gathering and decision making. To ensure such
transparency at the open public hearing session of the Advisory Committee
meeting FDA believes that it is important to understand the context of an
individual's presentation. For this
reason FDA encourages you, the open public hearing speaker at the beginning of
your written or oral statement to advise the Committee of any financial
relationship that you may have with any company or any group that is likely to
be impacted by the topic of this meeting. For example, the financial
information may include the company's or a group's payment of your travel,
lodging or other expenses in connection with your attendance at the meeting.
Likewise FDA encourages you at the beginning of your
statement to advise the Committee if you
do not have any 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.
Now, you can go ahead.
DR. OSTROW: Thank
you. Thanks for the opportunity to present at this meeting, and there are no
financial relationships to report. I am
going to show you a brief preview of a continuing medical education program
about CJD that addresses some issues that are not well understood by health
care workers including physicians and even neurologists. The CJD Foundation
became aware of this information gap through their many contacts with patients'
families and the questions that these people had about the disease, questions
that physicians were often unable to answer.
In some cases the families also complained that the
diagnosis seemed to take longer than it should have, that they felt like they
were in the dark during the workup and that once a diagnosis of CJD had been
made health care workers at various levels were not well prepared to deal with
it and to some extent this is quite understandable. CJD is a very rare disease
and few physicians have had much experience with it and certainly it can be
very hard to diagnose especially in the early stages, and there is also a lot
of misinformation freely available in the popular press.
Our program is intended to provide information to
physicians that will make them more familiar with these diseases, that will
help them in the workup, that will facilitate more useful and supportive
interaction with patients' families and that will help physicians counter some
of the widespread misconceptions about CJD.
I would like to acknowledge three people who are here today
who have starring roles in this production, Dr. Dick Johnson, Dr. Richard
Knight and Florence Kranitz, President of the CJD Foundation.
Our producer, Cathy Nelson is also here to make sure that
this thing works and that I don't speak too long and now I would like you to
see our preview.
(A DVD was shown.)
DR. OSTROW: This DVD which is aimed at physicians and
residents will be available at the end of this year through the CJD Foundation.
We hope to distribute it widely. I should mention that it will also include a
review of the Red Cross Look Back study that the CJD Foundation is
collaborating in to look at blood transmissibility. It is our hope that we will
obtain support to produce a series of these things aimed not just at physicians
but also at other health care workers,
at the funeral industry, at patients and their families and also at the general
public and thanks again for the opportunity to present today.
DR. FREAS: Thank
you, Dr. Ostrow. Based on that preview I will look forward to seeing the full
feature film.
We have two additional presenters this morning. They are
Mr. Mark Skinner, President of the World Federation of the Hemophilia
Foundation from Montreal, Canada and Andy Wertzel from the National Hemophilia
Foundation. They have agreed since we are behind schedule to pool their time
and Mr. Mark Skinner, President of the World Federation of Hemophilia
Foundation will be making the presentation.
MR.SKINNER: Good afternoon. Thank you for having us and I have no financial disclosures. In
fact both the WFH and NHF adopt strict ethical guidelines and would preclude us
from having an investment in any of the companies or products we are talking
about here today.
The issue that we are talking about and the reason that I
am speaking today on behalf of both organizations, the National Hemophilia Foundation
located here in the US and the World Federation which represents 107 member
nations around the world is in fact that the actions of the FDA on this issue
are of vital importance to the global patient population and the actions of the
leading regulatory bodies including the FDA will certainly be heard around the
world and will resonate and have the potential for impact on the use and the
treatment of patients globally.
The World Federation of Hemophilia in fact last October in
October 2004 published our first guidance document or complete guidance
document. We published several before that discussing the assessment of risk as
it relates to TSEs and hemophilia products.
We do believe that it is feasible to counter this emerging
threat in our patient population but we also recognize that it is important
that we balance the issues of safety and supply and we think of risk in this
total context which includes access to treatment and also includes the impact
on the supply of products and certainly actions of the Committee, the TSE
Committee and the FDA in considering this important issue are a clear sign that
the regulators are not complacent.
As a patient population we certainly adopt; we adhere; and
we encourage regulators to advance the precautionary principle when there is
incomplete scientific information which is certainly what we are faced here
with today.
We acknowledge as a patient population that we are dealing
in an area of uncertainty and we don't expect precise and exact answers. We do
appreciate the effort to communicate in an open and transparent manner. That
doesn't always occur. It is in fact occurring here today but there are
certainly steps beyond and before this that are important for us as a patient
population to be involved in and perhaps most significantly the FDA is not the only regulatory agency around the world which in
fact is talking about this subject and
so as regulatory authorities in France, Spain, the UK, Australia have all
opined on similar subjects we are certainly seeing a divergence among the risk
assessments and so the confusion among the patient population globally or the
risk for confusion is certainly growing
every day.
As I mentioned before we published our risk assessment back
in last October and the parameters which we identified as they would relate to
TSE risk for patients using plasma derivatives are listed out here. These are
certainly very similar to the ones that the Committee has been addressing.
What I would say as an aside is that this risk assessment
from the World Federation has actually now been accepted by Vox Sanguine(?) and it will be published in
an article authored by Albert Ferugia, James Ironside and Paul Giangrande and
we expect that to be published electronically in December and in the January
issue of Vox Sanguine.
I am going to start first with the sixth issue because it
is the most important and in the interests of time I can certainly skip over
some of the others but the area in question of risk communication with the
patient population, the clear and unequivocal answer on the part of the patients is that risk communication
is important and the actions of publishing and developing a risk assessment are
very helpful with a couple of caveats, that there is in fact advance
consultation, that the patients do have a right to be informed, that the
patients do have a right to be consulted and that it is vitally important that the leading patient organizations have
an opportunity to be consulted in the development of the risk assessments as well
as our leading clinicians and this doesn't mean simply a consultation in the
context such as this but throughout the development process we need to have an
opportunity for the patients to
interact, to understand the kinds of issues t hat are going forward because
certainly as we move forward and a risk assessment is published it is vital
that the patient population's knowledge and understanding of the issues of
certainty and uncertainty are acknowledged and understood.
If a risk assessment is dropped into laps of the patient
population without adequate information we will see significant harm done to
the patient population and this notion is certainly reinforced from the
experience of the eighties.
One of the conclusions and recommendations of the IOM study
relating to the HIV decision-making process was that it is shared
responsibility and groups such as the National Hemophilia Foundation and other
patient organizations representing the hemophilia community have a right and
should be involved and should share the responsibility of decision making as it
relates to infections such as HIV.
So, we believe the guidance from the eighties is applicable
today and we should continue to monitor and learn from the lessons of the
eighties.
The consequences on the public health for the 5100 odd
patients in the UK that have hemophilia were in fact quite severe. We saw rapid
access denials for patients for dental procedures. We saw denials for basic
procedures including endoscopies in major hospitals around the UK and in fact
those procedures continue today, some out of fear and some out of just simply
the cost on the public health system.
If you are left with little choice but to destroy the
medical instruments afterwards who is going to bear that cost, and so the
hemophilia patient population was rapidly stigmatized because of the
notification process that was not optional but was mandatory in the UK in which
letters were sent not only to their general practitioners but also to their
dentists and it was put in all of their files that in fact they were at risk
for variant CJD.
Now, granted there are several approaches and the approach
that the UK took was one of a general health precaution. So, the patient
population as a group was generalized and they did not adopt the approach of
individual risk assessments for individual patients which of course for the
many reasons we have heard here this morning would be extremely difficult but
we think precisely because of the adverse outcomes that occurred in the UK and
because the patient population for hemophilia and not those with immune
deficiency or alpha 1 anti-trypsin deficiency or in fact for the general blood
transfusion recipient where there is an absolute risk known for transmission of
vCJD, they did not receive the same universal
precautions and as a result they weren't stigmatized but in fact some of
those patients may in fact have a greater risk.
So, we as a patient population were actually singled out
and have suffered great harm to our health care as a result of that. So, we are
hoping that the Federal Government here in the US and other regulatory
authorities have learned from this lesson and understand the importance not
only of advanced consultation which did occur to some degree in the UK but of
thinking through this process and allowing the patient population and our
health care providers, our physicians to work with you to develop the
appropriate response.
So, in summary as it relates to risk communication we as a
patient population do think that we have the right to be informed and
consulted. We strongly support the precautionary approach as it relates to
patient groups. We do think it is important that we need to balance over
reaction and patient stigmatization with the under reaction and the lack of information
and lack of transparency. It is an extremely difficult balance. It is sensitive
and we think through working with the patient groups that we can achieve the
appropriate balance.
Certainly in risk assessment or any guidance that is
offered has to come with counseling, competent explanation and clear
information and you have to acknowledge uncertainty. I mentioned before the
lack of consensus and the confusion between the global risk assessments
certainly is one that will not only confound here in the US because patients do
read the Internet. They do hear about the information happening around the
world but will certainly make it difficult to manage treatment and care around
the world and perhaps have an impact on product supply ultimately around the
world and certainly the patients locally and nationally all need to be treated
the same, that we need to think of this as a global problem and certainly given
that the treatment products on which we rely are in fact global.
I would use just by way of illustration to emphasize the
point of the importance of risk communication just this past weekend we had the
National Hemophilia Foundation Annual Meeting and I had an opportunity to
present on risk communication as it relates to variant CJD.
Following the meeting a young mother with a son of the age
of 12 came up to me and in tears. I mean she is truly worried. She doesn't know
what to do in terms of treating her patient. He has a high titer inhibitor and
he is looking at immune tolerance using the plasma derivative with von
Willebrand's factor to treat his condition but the one thing that she did tell
me clearly and I think this goes right to the answer to question No. 6 is she
said, "I appreciate very much knowing what we do know and what we don't know.
The absence of information is more fearful than knowing what we don't know and
as a mother I appreciate the openness and having a chance to hear it early and
to make decisions with my health care provider."
Just quickly I want to run through a couple of the other
questions and I don't know that these require a great deal of response. I will
point out just one or two instances where our position differs and most of our
answers here in fact come from the risk guidance we published last October.
Similar to the FDA when
there is a doubt and when there
is a variety of estimates in terms of what prevalence should be we adopt a
conservative approach as has the FDA and suggested that we would encourage the
Committee to adopt that as well. Obviously most of the risk assessment will
hinge from this and this is the critical issue which is why you have it No. 1
and we did as well.
The prevalence of vCJD in the US we agree very much with
the donor deferral mechanisms and until there is a clear pathogen reduction or
elimination process that has been validated we have to maintain the integrity
of the donor process and we would encourage the Committee to do that of course
keeping in mind that it needs to be updated as new scientific evidence is
available going forward.
Perhaps this is the area of slight difference with the
FDA's assessment and guidance to date is that we do believe that the larger
animal models are more predictive and we have adopted a similar position of the
UEO and the UK in a one-to-one equivalency between intracerebral and
intravenous routes of transmission. The level of CJD infectivity in human
plasma, again, the similar approach following the precautionary principle
adopting between the two and the options presented of the conservative
estimate.
Dorothy Scott talked about this and we agree
completely that clearance values must
be product and process specific and without analyzing and evaluating each
product it is impossible to have a generalized approach to the Factor 8
derivatives and the other products on which our community depends and part and
parcel to that and assuming that you do agree to go forward with the risk
assessment and communicate it to the community we do believe that it is
appropriate for the FDA to consider actually including a label warning in the
plasma derivative product speaking to variant CJD and while we are not typical
authors of this kind of warning that is done through the regulatory process
there is some language that we have put together and some thoughts that we
believe would be useful and certainly mirrors the experience of similar
warnings for HIV and HCV that have been previously communicated.
Again, we think it is important that it be indicated that
it is highly precautionary,that there are no known transmissions but
communicating uncertainty is an important step in informing the patient
population.
A comment on the
CDC data. We certainly agree that the UDC data, I had been a participant in
this study since its inception, is very useful and perhaps the only available
source. I would remind you as Mark pointed out that there are in fact a number
of deficiencies in this data. There was a reference earlier perhaps
supplementing this data with insurer data and I would suggest that is not the
best option to do given the experience of working with insurer data and
reimbursement and trying to understand treatment patterns. I think that you
would not find that of great use. You may in fact find that some other
countries which have a more centralized health care system you might be able to
find data that would be more instructive as to plasma use treatment and dosage
and duration of treatment that could supplement the CDC data and I would
encourage you to look outside the US before looking to the insurers and payers
within the US.
That question was deleted in the final questions. We do
believe that risk is communicated and certainly from our experience with other
pathogens that the patient populations are dependent upon it and that is
consistent with what the FDA has recommended.
So, thank you.
DR. FREAS: Thank
you very much, Mr. Skinner.
Is there anyone else in the audience who at this time would
like to make a short comment to the Committee?
MR. CAVANAUGH: Thank you. I am Dave Cavanaugh with the
Committee of 10,000. I will be quite brief, no financial interests. We appreciate what the World Federation has
already come to the conclusion of but some of what we heard this morning was
quite disturbing and I just want to speak to it in the hopes that you can
bookmark it in your discussions. The whole discussion of preclinical numbers in
the UK was very upsetting and there was only a brief reference later on as to
the infectivity of persons during that period.
We have a couple of ideas about latter half, former half of
the incubation period. We know so little. It is very much a call to be cautious
and advisory as much as possible.
There was a discussion of the fractionation and reduction
of infectivity as well and every time I heard the figure 90 percent I thought
of 10 percent. That is all it would take and it makes us very nervous. Again,
we need to understand that only in a few spiking studies has anybody been able
to claim an acceptable, putatively acceptable level of reduction. It is not
established. It is transmissible through factor. We have to assume that until
it is absolutely wiped out as a possibility and it certainly is through whole
blood. There is no national association of blood transfusion recipients. The
folks in the blood products family sometimes have to represent that but please
take that into account as well.
On the usage the material that Mark was presenting about
calculating amount consumed it is known that 70, 80 percent of persons with
hemophilia utilize in some degree hemophilia treatment centers but it is often
not those that are mild that don't but those that are severely affected and
have complicating factors like HIV and hepatitis that have to seek out
infectious disease specialists and hepatologists. So, I wouldn't discount that
population. I would at least assume that it is at the same level of risk and
finally I got here at eight-thirty this morning thinking we started at nine.
So, I missed the first presentation from USDA and I haven't heard that agency
mentioned elsewhere this morning but you are linked to USDA. You are our FEMA.
I hate to say it that way but that means rising to the occasion.
We have a motto that we have started. I don't think it is
ready to take it on Oprah yet but the motto is if you eat beef don't give
blood. The item that I wanted to say that I had forgotten in a list of things
that have already been discussed was the post donation information revelations
about true MSN behavior, true IDU behavior. They are catching 1 in 200 donors.
How many get away? I don't know what the estimate is and I would like to talk
to Alan further about it but a lot of people come and they never have that
"aha" 3 days later. So, we do have a risky blood supply.
Thank you very much.
DR. FREAS: Thank
you, Mr. Cavanaugh. Is there anyone else in the audience at this time?
If not, we will close the open public hearing session for
the morning. We will have one in the afternoon.
DR. PRIOLA: I think
with that we will break for lunch and reconvene here at one-thirty.
(Thereupon, at 12:45 p.m., a recess was taken until 1:45
p.m., the same day.)
A F T E R N O O N
S E S S I O N 1:45 PM
Agenda Item:
Committee Discussion and Recommendations
DR. PRIOLA: Okay,
most of the Committee members are back. If we could get started with the
discussion we have 10 questions to discuss but only the very last one that
relates to issue 6 is a voting question. So, the FDA is interested in our
discussion and the recommendations.
So, Dr. Scott is going to present the first question to us.
DR. SCOTT: This is as you have in your sheet of questions
and in the issue statement what estimate should be used to reflect the
prevalence of variant CJD in the UK which of course is linked to the prevalence
of vCJD potentially in donors in the US, and we had proposed using the surgical
tissue surveillance data as the assumed prevalence of vCJD in the UK.
This would be the most conservative estimate that we think
we can make at this time and then we also propose that we run the risk
assessment model again using epidemiological predictions based on diagnosed
clinical disease in the UK as an alternative assumption of prevalence and then
there would be adjustments for possible latent infections during the incubation
period.
So, wait for the Committee's comment on this especially
about using the surgical tissue surveillance data.
DR. PRIOLA: So,
just to remind everyone this was one of the critical parameters that was
pointed out earlier in the presentations and I think it was Dr. Ghani who
mentioned that you can't use the clinical data as a substitution for prevalence
unless you include the carrier state which is what you sort of added on your
slide, right,with the latent; that is the same as the latent, yes.
So, comments from the Committee?
Dr. Geschwind?
DR. GESCHWIND: I
guess one comment I had was my feeling is that the surgical data should in some
ways be the lower estimate and the reason I say that is that it is under the
assumption that the immunohistochemistry is not 100 percent sensitive and PNS
papers so far myself and Stan Prusner and others in February of this year using
the confirmation dependent immunoassay showed that many cases are missed by
immunohistochemistry particularly many parts of the brain.
So, I think that we should be conservative with that.
DR. PRIOLA: Other
comments from the Committee?
Does the Committee agree then in general with the FDA
proposal that both sets of data should be used?
I see lots of nodding heads.
Any other discussion?
DR. BRACEY: Yes, I
think it really is important to use the surgical data because again there are
so many unknowns as far as the incubation period and clearly in terms of the
precautionary principle the idea would be to avoid exposure rather than to
avoid clinical disease.
DR. PRIOLA: Okay,
if there is no further discussion we can move on to the second question.
DR.SCOTT: This is also an issue with a fair amount of
impact on the ultimate outcome of the risk assessment because it has to do with
how many donors in the pool might have vCJD that are not deferred. What is the
residual risk? But the question reads
how effective are current donor deferrals for geographic risk of vCJD and our
proposal is that based on the currently available surveys of unreported risks
for other conditions and allowing for margin of error that we estimate that the
FDA recommended deferral policy has a 90 to 99 percent efficiency for deferring
donors with a specified increased vCJD risk.
DR. PRIOLA: I
forgot to bring up one point with the previous question and that is does
anybody have any comments about the PRP genotype influencing that modeling
because all the modeling or the model that was presented to us was met-met
homozygous with the caveat that if you included the met-val it would sort of be
included with the latent carrier, the sort of subclinical state. Was that correct? I just want to make sure that, is that true,
Ghani? I just want to make sure that point doesn't get overlooked because of
this heterozygous subclinical individual who is picked up.
DR. GHANI: At the
moment the only model, the MM homozygous and if you include allowance for their
being other genetically susceptible groups you increase your estimates of
clinical cases but at the moment the models are assuming that they are behaving
very much the same way so that all genetic groups have potentially a subclinical
infection as well. I just think one important point to note is that the models
are fitting to this data from this tissue survey. So, they are not producing
anything different if you assume that you use the tissue survey data. They are
assuming at the moment that the tests are only sensitive in the last 75 percent
of the incubation period and that we have varied that for the last 50 percent
and that scale is the actual magnitude and that is something that has to be
scaled in terms of the interpretation of the tissue survey as well. The actual
published estimates say, "One hundred percent sensitivity." More
realistically figures are probably around 50 percent.
DR. PRIOLA: Okay,
thank you. I meant to bring up that point, and I forgot.
All right, so, on to issue 2. So, how effective are the current donor deferrals for
geographical vCJD risk and does the Committee agree, have anything to add to
the FDA proposal to model that between 90 to 99 percent?
Dr. Telling?
DR. TELLING: I have a question for Dr. Anderson in this
regard and that is for the input factors for module two. It seems to be
exclusively with respect to travel to the UK but to the extent that this has
been analyzed in other countries and in particular France and I realize that
France is not the same as the US that that aspect had a relatively low rate of
calculating the relative risk of exposure to BSE and a much more significant
determinant was importation of BSE infected animals and foodstuffs and feed and
so on and so forth, but I notice that
that isn't a factor in your calculation for the risk inputs for module --
PARTICIPANT: So,
right now the relative risk rate that we are using for France is .05 or 5
percent of the prevalence or the risk in the UK. I agree actually. We were talking
about that at lunch that it is probably necessary to actually go back and
adjust that number a little but upward because France recently has I think gone
up to about 12 cases.
PARTICIPANT:
Fourteen.
PARTICIPANT:
Fifteen.
PARTICIPANT: Do I
hear 16? Now we are getting more
towards you know, 8, 9, 10 percent rather than .05. It should be more like you
know .08, .09, you know, .1. So, we may consider actually adjusting that
particular relative risk rate. Does that answer your question?
But we are specifically addressing travel to the UK. We
have also got the number of travelers set aside that traveled specifically to
France and then those that traveled to Europe.
DR. TELLING: My question is what is the relative risk of
actual exposure of the US, the North American population actually in general to
BSE materials imported from the UK.
PARTICIPANT: Right,
from domestic exposure to any BSE that may perhaps be here. We have gone ahead
and done those calculations and we determined that risk to be pretty negligible.
So, we will talk about that in the model but it is not absolutely integrated
into the model because the number is so low for the estimate. So, we
acknowledge that that risk is there, but it is just so low that it doesn't
really --
DR. TELLING: I am sorry but that is where the vast majority
of BSE cases, I mean it is three cases, right, but the majority of those three
cases are a result of importation, we presume of feed or cattle or whatever to
Canada and then via Canada to the US. So, it is an important factor.
PARTICIPANT: Right,
but we slaughter. We have got three cases but we slaughter 35 millions a year
for food production. So, in the background of everything it really ends up
being very low risk.
DR. BOLTON; I just
wanted to say that I thought that the data actually supported better a range of
85 to 95 percent. It seems to me that 90 to 99
is a little overly optimistic.
DR. PRIOLA: Why do
you want it dropped in that way?
DR. BOLTON: In the
presentation I think several of the estimates that actually gave hard numbers
were in the range of 86, 87 percent. Plus you have the 2 percent overestimation
of the efficiency due to the false reporting essentially or false
self-deferring.
So, it is not clear to me how the 90 percent as the lower
end of the efficiency of the deferral policy came about. We are talking about issue 2, right? How effective are the current donor
deferrals? I think 90 to 99 percent is
too optimistic.
DR. PRIOLA: Dr.
Williams, do you want to comment on
that at all?
DR. WILLIAMS: I
think it is quite a reasonable observation. I think the rationale between the
85 and the 90 percent is those 85, 86 percent figures were referring to
deferrals for which you know the social acceptability, the answer would produce
a downward pressure on getting a response as part of the screening process.
That said, you know, those are the numbers and I think it is a reasonable
observation.
DR. PRIOLA: Dr.
Leitman?
DR. LEITMAN: It has
been pointed out that the majority of plasma donors for plasma products for
fractionation are paid donors and that population for whatever reason doesn't
travel as widely especially to Europe perhaps as do voluntary donors who donate
whole blood. So, that makes me more comfortable with this geographic deferral.
Having said that paid donors are not always the most honest
group because they are not altruistic. They are donating for self-interest. So,
if a positive answer had financial implications they might not give that so
readily. So, those two things tend to balance themselves.
DR. PRIOLA: So, you
would agree with Dr. Bolton dropping it to 85 percent would be a reasonable
thing?
DR. LEITMAN: No, I think 90 to 99 percent is okay.
MR. BIAS: I thought 90 to 99 percent was optimistic just
because I know the industry has done a lot to clean up their system about donor
deferral but they are paid donors. Those centers are still in places where
people are trading those dollars for sustenance or other things that they might
need and I just thought that 90 to 99 percent meant we were doing it almost
perfect and I don't think that is what is going on out there.
DR. PRIOLA: Dr.
Bracey?
DR. BRACEY: This is
really a request for Dr. Williams. What we are talking about are in essence
projected numbers and we don't have a hard number and since this is an area
where the safety is absolutely dependent upon the screening question I think
that it really would be important for the Committee to send a message to the
funding agencies that we need to acquire more hard information because right
now we can try to draw parallels from other risks that we are dealing with but
they are not the same.
DR. PRIOLA: That
was something Dr. Williams brought up. What sort of other studies would you
want funded to give you the information?
DR. BRACEY: In
terms of just a general design a study that would look at simply the
effectiveness of the screening questionnaires and that is you know these are
very complex sets of questions and there are a number of things that were
discussed such as comprehension, things such as donor motivation. For example,
you know, if you were in the work place there are many donors that we sometimes
consider to be nearly pathologic because they must donate. If they aren't given
the chance to donate they feel as though there is something wrong with them and
that is not the majority of donors but you will find a very small number of
donors that will sometimes not give you all the truth so that they can
participate. They want to feel normal, and those are the sort of things that I
think need to get teased out if you are using a question as your only means for
screening.
DR. PRIOLA: Other
comments from the Committee?
So, is there any major disagreement over dropping that
range to the lower end to take into account
the points that have been raised to go from like 85 and still keep the
upper range 99; you just extend the range and they can do their model in that way? Is that acceptable to the
Committee?
And recommendation for funding for further studies along
the lines of what Dr. Bracey asked. Are there any other comments or can we all
agree that, I mean it is always better to have more information. I don't think
anyone will disagree with that.
Okay, last chance for comments.
Mr. Bias?
MR. BIAS: I would
add to that that I would have that study look specifically at certain economic,
the placement of certain economic centers. I have been to a number of blood
collection centers and one in
particular comes to mind and it was very pristine in Green Bay with a child
care center and everybody was a student and it was very pleasant to visit there
and then I visited one in an inner city area and it was clear to me that folks
needed the income and that is why they were in line and I would gear the study
toward those centers where people are using it as income, needed income for themselves and not doing it for
altruistic ways and the one I visited in Wisconsin certainly they used it for
what they called it was football, beer money which was fine. They were all sort
of you know middle income folks and
stuff but I would be very interested in seeing a survey that looked
particularly at the inner city sites where people are at risk.
DR. PRIOLA: Dr.
Scott, you wanted to say something?
DR. SCOTT: I just wanted to point out that it is a general
believe that plasmapheresis donors travel less perhaps because of their
economic situation but to my knowledge we don't have any real data on that and
it would be nice to have some.
DR. ALLEN: I think
my suggestion would be that to the extent further studies are designed and developed
in this area that they look broadly at the issues of donor deferral and
not necessarily just focus on this one risk. I mean trying to look specifically
at geographic risk when we don't have a
good measure of risk from food intake; you know, we have made some presumptions
here in terms of time factors but we don't have good data. Just to the extent that additional studies
are designed and carried out I think my recommendation to the FDA would be to
look at a very broad scale design that meets the needs of multiple points not
just this one specific one.
DR. BOLTON: I hate to delay these proceedings but this has
been said now several times and I am just curious since this is a science-based
decision-making process I have heard several times now the idea that the
plasmapheresis donors travel less, but Dr. Scott just said that there are no
data. So, the question is where does that come from if there aren't any data in
support of that then why are we bringing it up?
DR. PRIOLA:
Dr.Scott?
Okay, Dr. Leitman?
DR. LEITMAN: There are deferral rates and we know how many
persons in the volunteer collection centers are deferred for a positive answer
to the various demographic deferrals. At my center I can give you exact
numbers. Other centers can give you the number. So, I assume that the plasma
collection centers, paid donors can also give you that data. That assumes an
honest answer and you don't get quite the number of self-deferrals that don't
make it into the center because they know they are not supposed to. I assume
that that is much lower in the paid centers but we don't know about the honesty
of the answers.
DR. BOLTON; So, it really is a question of weighing is the
answer honest given the act that there may also be economic incentives to not
tell the truth versus is there actually less travel.
DR. WILLIAMS: There is one other side to the answer that I
think will hold up scientifically. In the blood donor studies there was a clear
correlation with age and so you are covering a cumulative travel history. It is
clear it is going to be an age-specific rise and it is known that the plasma
donor population is younger. Now, that is corrected in part of the model but
that would apply to the risk associations as well, I think.
DR. SCOTT: I would, also, point out that the amount of
estimated and actual loss of donors in the plasma sector we understood was
lower when we instituted the geographic donor deferrals. I guess mu point
really was that we don't have numbers.
DR. PRIOLA: Okay, I
think given that this was another one of those parameters that was a
high-impact parameter the call for new studies to get those sorts of numbers is
something the Committee is asking for.
So, let us move on then to question 3.
DR. SCOTT: Question 3 is what is the intravenous
infectivity range in ID50? What level should be selected for plasma based on
animal studies and we propose that this model uses statistical distribution of
infectivity with a minimum value of 0.1 ICID50 and most likely a value of 10, a
maximum value of 310 as Dr. Asher explained and we also propose because the
agent in primates may more closely reflect the human situation than rodent
models that we model the IC to IV ratio for infectivity over a range of 1 to 5
based on recent primate study.
DR. PRIOLA: Any
comments from the Committee?
DR. SALMAN: I think using the maximum value of 310 is very
high, that is not justifiable if we follow on the same assumptions and being
even on the very pessimistic side I think it still is very high.
DR. PRIOLA: Dr.
Brown?
DR.BROWN; I would
second that. The notion of a maximum based on a study that you don't believe
strikes me as inappropriate even though it is higher than anything, well, and
also because it is higher than anything that you could possibly imagine. Every
other study has established an absolute maximum of blood infectivity or blood
component infectivity at about a log and one-half and blood consistently, whole
blood consistently ranges between 10 and 25.
I would suggest that as a maximum if one must have a
maximum that it be set at 100, that is 2 logs rather than 320.
DR. PRIOLA: I
agree; 310 is somewhat arbitrary given you don't believe the experiments. You
might as well pick 400, 500, whatever.
Any other comments?
So, the lower end of the range we can agree upon and then
set that upper end at 2 logs, at 100.
DR. BOLTON: This is a range and given new information comes
in it can be adjusted as the model develops.
DR. PRIOLA: Any
other comments?
What about the IC to IV ratio? We heard one of the public
hearing speakers say that they favored a one-to-one IC to IV ratio and this 1
to 5 is based on recent primate studies.
Does the Committee have any comments?
Dr. Brown?
DR.BROWN; One to one is a little pessimistic. Our study in
mice was about 1 to 7. Earlier studies have, an earlier study at least by
Kimberlin was 1 to 10. The primate
study is based on very few animals and I think it is possible that it is a
perfectly valid observation but it doesn't have the impact of the numbers that
the earlier studies do.
So, I would think that somewhere between 5 and 10 is
probably the most appropriate range.
DR. PRIOLA: So, as
a lower end 1 to 5 you would say that 1 to 5 is at the lower end of that.
DR. BOLTON: I will respectfully disagree. I think that it
is important to maintain that most pessimistic 1-to-1 relationship and then the
plan is to study the range of 1 to 1 to 1 to 5. Is that not correct? Right. Dorothy is shaking her head. So, why
not maintain that? I mean if you wanted to go more optimistic perhaps to go
include the 1 to 10 relationship but I would hesitate to make it 1 to 5 to 1 to
10.
You are leaving out that possibility that IV exposure is
exactly as efficient as IC exposure and I don't think we have enough
information to really know that that is true or that it isn't true.
DR. PRIOLA: Dr.
Allen?
DR. ALLEN: The other variable there is obviously the
volume. Generally intracerebral tends to be a very, you know when it is done in
animal studies tends to be a very small volume. If you are getting a whole unit
of blood or packed red cells even, the volume is much,much greater
proportionally. So, I don't disagree with you on the pessimistic. I would think
perhaps extend the range from 1 to 1 to even to 1 to 10 to take in the range of
available data from animal studies.
DR. BROWN: I don't want to inhibit pessimism.
(Laughter.)
DR. BROWN: I was really just suggesting that the most
likely answer is going to turn out not
to be 1 to 1 but the volume point is one that we have been hammering away at
now for several years. If you really wanted an accurate comparison you would be
obliged to inoculate the same volume IC as IV. Under those circumstances I have
no doubt whatsoever that you are not going to get a 1 to 1.
DR. PRIOLA: So, the
Committee would basically like to
recommend a range in keeping with the range previously from 1 to 1 to 1 to 10
which would cover the most likely range IC/IV. Is that fair enough?
If there are no other comments we will move on to question
4 or question 3B.
This is the is there sufficient evidence to estimate when
variant CJD is present in the plasma.
DR. SCOTT: I think we
can go to four. I am sorry about the numbering but that is actually the same
thing and our proposal is that because of the uncertainties about the
incubation periods of food-borne vCJD and the time during the incubation period
at which infectivity appears in humans we propose to adopt a conservative
approach and assume plasma to be potentially infectious throughout the
incubation period.
DR. BROWN: That is really conservative with a capital
"C." There have been actually several studies. I put them all
together on the table for a book that Marc Turner is going to edit and it turns
out that in about half a dozen studies infectivity turns up about half to
two-thirds of the way through the incubation period in each one, very
consistent. That is data from rodents and data from sheep. That is true, also
in the sheep study. The only primate study is actually in humans and there we
know that 5 years in advance at least 5 years in advance of the onset of
symptomatic disease in one case the transmitted case that, or is it 3 years? I
guess it is 3 years but at least we know that.
You know you can model and the more modeling you do, that
is fine as long as we don't come to the conclusion before the story plays
out. Again the likely answer is that
the incubation period from about being conservative halfway through is where
infectivity begins to appear in the blood in those models where it appears.
DR. PRIOLA: Other
comments from the Committee?
So, one of the things I see about that data depending upon
the study you get infectivity early; then it goes away; then it is late. It
starts in the middle. Then it goes away.
DR.BROWN: it is not that inconsistent, Sue.
DR. PRIOLA: It is
not?
DR. BROWN: The early infectivity is almost certainly due to
residual infectivity from the inoculation. If you sort of take away that first
week or two then consistently infectivity doesn't begin before halfway through
the incubation period and usually about two-thirds of the way.
DR. PRIOLA: So, you
would recommend basing the model on the appearance of infectivity one-third to
one-half of the way through the incubation period?
DR. BROWN: Yes, I would recommend the last half of the
incubation period as being pretty conservative.
DR. PRIOLA: Other
comments from Committee members?
Mr. Bias?
MR. BIAS: I just
wonder if that is the most conservative we can be since we are talking about
plasma and people who are taking it on a regular basis. Doesn't that make us
want to go toward the lower end? I am not exactly sure of the science. I will
leave that to others but I am just a little concerned about that.
DR. BOLTON: I can't imagine if I were the one running the
model that since it is just a model that I wouldn't include the entire
incubation period just to see what the answer was. It is sort of an exercise in trying to figure out what the
parameters are and which parameters given the biggest risks or uncertainties
and it seems to me that it would make sense to again cover that range, the
entire incubation period, half, maybe even the last third and see what that
does to the model.
DR. PRIOLA: Dr.
Anderson?
DR. ANDERSON: We can do it both ways and we have done that
with particular models I think with Creutzfeldt-Jakob disease and the
predictions at least come out. It is not a huge influence on the model. It
probably predicts about twice as many cases if you go through the entire period
versus the last half.
So, I think what I said before was that we are introducing
a fair amount of uncertainty doing just the last half just because we have got
to make some assumptions about incubation period and some other factors.
The good thing about using the entire incubation period is
that you can then say that it can't be any worse than this with regard to that
factor.
If you say that we are only assuming the last half then
there is always the suspicion well, you didn't include the first half. So, what
does that do to the outcome?
In the other case it certainly can't be any worse than
that.
DR. ANDERSON: Right. It is a very conservative approach.
DR. PRIOLA: But you
said that it wouldn't affect the outcome that much actually if you --
DR. ANDERSON: It is not going to affect the outcome as much
as other factors in the model.
DR. BROWN: One of the bad things about using a broad range
which I don't disagree with, David at
all is that they tend to get through a
process of inertia factored into the final risk assessment no matter what the
answer turns out to be. Somebody is always going to say, "But you know you
didn't include the whole incubation period. You had better do that," and
when the data as it exists simply doesn't jibe with that I think you are
obliged to set the limits for which you have science.
DR. PRIOLA: Dr.
Salman?
DR. SALMAN; I am in
agreement with what Paul is saying. If we use the model only as a game we don't
need it. We have to try to as much as possible to have the model to mimic the
infection status of what we know with the science we know.
I will question like any of these diseases, any of the
diseases we know that the infection starts on the day one of the incubation
period which diseases we know about that, I mean. So, we need some credibility
for the model. Otherwise it will be a game.
DR. BOLTON: Let me
say this. I think one thing that we do know is that from the day of infection
the agent is present. It is present in the body somewhere. It may very well be
in the blood and the plasma. It may not be in amounts that are easily detected,
but given some of the studies and especially the recent paper from Rocky
Mountain Lab that is published in Nature about the multiple injections over
time I think that we have to now suspend our belief in the linear relationship
between the LD50 and outcomes, in other words multiple inoculations of very low
titer in fact below 1 ID50 dose will in fact result in a very high proportion
of infection.
So, science based, yes, but we do know that once an
individual is infected the agent is there somewhere and one of the problems
with some of the animal studies is that the route of inoculation is important.
The type of agent, the strain of the agent is important and the host is
important and I am not sure. I was going to ask Paul this question before but
again I don't want to make these things go on too long, but in the table that
you constructed, Paul how do those studies look in terms of the peripheral
nature of the early part of the infection anyway? I mean are those studies that
used agent strain combinations that have peripheral distribution that mimics
variant CJD or are they like some of the other models that are primarily CNS
based?
DR. BROWN: I suspect none of the studies were full autopsy
studies in a time course manner but I can tell you that the studies that I am
referring to were studies of hamster-adapted scrapie, GSS-adapted mice, vCJD,
mouse adapted vCJD, sheep-adapted scrapie and sheep-adapted BSE. So, it is a
fair range.
DR. PRIOLA: So, let
me ask the Committee maybe just since we have two it seems like primary points
of view, both of which I can understand, actually, does the Committee have any
preference for this assuming infectivity present throughout the disease course
or basing it on where we do have scientific data and that is saying from about
halfway on?
Any preference for modeling based on infectivity, oh, hold
on.
DR. EPSTEIN: I do have one suggestion. There is the
question of what parameters to put in the model and there is the question of
how to do sensitivity analysis and one pathway here would be that we use 50
percent of the incubation period to generate the estimate and then report out
the results of the sensitivity analysis looking at infectivity throughout the incubation period and that I think has
the virtue of getting at both sides of the argument without biasing if you will
the model itself.
DR. PRIOLA: David,
do you like that idea?
Mr. Bias?
MR. BIAS: It works for me.
DR. PRIOLA: Okay,
nice compromise. Okay, if we have no other comments let us move on to the next
question.
DR. SCOTT: Does the Committee agree with our proposed
approach for estimating clearance of vCJD infectivity from Factor 8 by manufacturing
processes? We proposed to model three
clearance ranges to represent a likely minimum, 2 to 3 logs, midrange 4 to 6,
and maximum 7 to 9 logs of clearance of the vCJD agent from products
manufactured in a variety of ways.
DR. PRIOLA:
Comments from the Committee?
Paul?
DR. BROWN: Is there any particular reason that you had for
and again here we are playing games in terms of modeling but we already know
that if you have a guaranteed 3 log
per ml
clearance as a concentration clearance you have done the job and 4 to 6 logs is nice; 7 to 9 logs is just
insane. I am not sure why you are going to do that
DR. LEITMAN: For clarification just the 20,000 to 60,000
pool already gives you a log reduction, well, a 4-log reduction in
concentration. So, this is over and above the effect of dilution in the pool.
This is specific processing whatever that is, precipitation, filtration. So, is
that beyond the several logs just by dilution?
DR. SCOTT: I guess that would be but I think the whole
dilutional thing is another topic altogether. So, if you start out with 10
infectious doses per ml of plasma and
you have 800 cc's of plasma of 8000 infectious doses that is going into
a pool of 20,000 but that is still, if just one of those is enough to infect
somebody you still have 8000 infections. Do you see what I mean?
So, you might want to have more than a few logs of
clearance actually or that is one of the ways of thinking about it.
Now, in terms of how we selected these numbers we really
used a combination of the data that is available to us to try to identify types
of steps that are likely to result in greater or smaller amounts of clearance.
This is a very sensitive parameter. At least it was in the Factor 11 risk
assessment and we felt it was important to run this range to really see what
happened and to see whether or not this made a difference in terms of the
products.
DR. BROWN: We need I think to understand are you talking
here about concentration or total mass?
Are you talking about 9 logs of clearance in a unit or are you talking
about a 9-log clearance per ml?
DR. SCOTT: Actually, Paul when I was talking to Dr. Leitman
I was just making an example but usually we talk about per ml is my
understanding.
DR. BROWN: Again, I don't understand the reason for the
higher values in terms of are you modeling again or have I missed a beat here?
DR. PRIOLA: Dr.
Epstein?
DR. EPSTEIN: Let me just clarify that the way the model
works dilution doesn't affect the outcome of risk per dose or risk per vial
because in the end you ask how many infective units are in the pool and then
how many end up per vial or per dose.
So, the fact that you may have diluted it initially in the
pool doesn't affect how many absolute infectious units would end up in a vial
unless there is clearance. So, whether you describe the clearance as per ml or
per total unit it doesn't matter. What you are computing is the residual number
of ID50s per vial as mass, as total.
DR. BROWN: It does matter if you are talking processing
reduction because that requires a knowledge of what you are aiming at. Are you
aiming to get 9 logs reduction in a unit or 9 logs per ml? They are different.
DR. EPSTEIN: Okay, the goal in processing is per ml, but
the point I am making is that the dilutional effect of pooling has no effect
whatever.
DR. BROWN: I wasn't talking about pooling at all. I agree.
DR. EPSTEIN: But the earlier question and I forget who
asked it was whether the clearance was above and beyond the effect of dilution
itself because you have 3-log dilution and the answer is we are speaking about
clearance above and beyond any dilutional effect, that the dilutional effect
doesn't affect the risk estimate.
DR. BROWN: Right. As it is stated I agree. It is a
different topic, but my question still stands particularly now if you are
talking about per ml which is a concentration why would be the slightest bit
interested in this 7-to-9-log clearance?
I mean we love to have it but you are not going to because nobody in the
history of the field has gotten a 9-log clearance per ml of anything by any
method.
DR. SCOTT; I think it is pretty hard to estimate a 9-log
clearance actually with the amount of infectivity that you can put into
something but it seems possible. I think that the reason we have a 7 to 9 is
really that reflects more of an 8 which really reflects a combination of two
high-level clearance steps and in fact that apparently has been observed in
studies.
DR. PRIOLA: But
that has been observed in studies using spiked brain material which is much,
much, much higher than you will ever get in blood.
Dr. Epstein?
DR. EPSTEIN: First of all Dr. Scott gave you our answer
which is it comes from combining so-called "orthogonal" procedures
but I think there is another point that needs to come across here which is
whether when you get below 1 ID50 per dose what does that mean; are you now
just talking about the probability that there is a residual infectivity or are
you saying that no one gets an infectious dose, and we don't know really how to
resolve that. So, just to be a little bit concrete let us say that a person,
let us say that the clearance is such
that infectivity per dose is .01 ID50; are we then saying that no on gets an
infectious dose because 1/100 of an
iD50 infects no one or are we saying that the risk of exposure to 1 ID50 is 1
percent and it is the latter model that we are
putting forward and why that matters then is for patients who are
repeatedly dosed.
Remember we are talking about patients who may have
hundreds of exposures per annum and thousands per lifetime and if the probability of receiving an ID50 is low per
single exposure it may on the other hand not be low for cumulative exposure. So,
it matters whether it is a probabilistic model and for that reason very high
levels of clearance if demonstrated may in fact matter ultimately to patient
safety.
DR. PRIOLA: David?
DR. BOLTON: I agree completely but the problem is now not
so much in the model. It is when you take this to reality because to
demonstrate anything more than maybe a 3 log clearance with natural prions in
the natural fluid is going to be impossible and when you do the brain spiking
even microsomal fractions, I am not sure that anybody here that has done those
studies can really believe that they represent what would really be happening
in naturally infected blood. It is just that we don't know. I mean that is one
of the things that if we would ever get
that information what is the natural physical state of variant CJD agent in
human blood that would be a tremendous piece of knowledge to have because when you take a brain homogenate or
brain microsomal fractions and you spike them into a sample of blood to
get a titer of 10 to the 7th or 10 to the 8th it is just we have no idea that that is in fact representing
reality.
DR. BROWN: Well,
you do if you know it is not. It is very simple, but this leads into what I
think is going to be another question coming up. Both exogenous, that is spiked experiments and endogenous experiments
are complementary and you get from one something and you get from the other
something and they both should be done. In other words if you are going to be
talking about optimizing validation studies what you want is validation using
both because the spike study is going to give you maximum range of possibility and the endogenous study is going to
give you absolute relevance so that even if you know you are only eliminating 2
logs in an endogenous study at least you have shown that what you have done
applies to the endogenous infection.
So, there is contradiction and confusion. It would be
terrible, for example, if you got a 7-log reduction in the filtration and then
discovered you didn't get anything in endogenous. I mean I could imagine that
happening if there were some size problem but doing both you have got all of
the information that you can possibly have and you should do both. No one
should ever be satisfied with a spike study for validation today.
DR. PRIOLA: So, in
a way that argument applies to this question as well then as you alluded to
because you can accept that higher
range as being experimentally the most that you can clear using an artificial
system.
So, in that regard this range of logs would be okay. The
low end is the endogenous more realistic one and the high end is the
experimental spiked one and a limit of what
you can do, okay.
Does everybody on the Committee agree with that? Yes, so would the Committee agree based upon
what, I think that is an excellent argument, based upon that argument that we
keep the ranges as proposed by the FDA?
Okay, let us move on then.
DR. SCOTT: It is
actually linked to the last and I think that Dr. Brown was alluding to it. What
experiments might enable refinement of the clearance estimates and allow
comparison of clearance offered by various steps in the methods used to
manufacture plasma-derived Factor 8?
DR. PRIOLA: Okay,
so we can I think use as our basis what Dr. Brown just said that the spiking
experiments are fine as long as they are accompanied by some simulation of an
endogenous spike which it is not exactly clear what sort of endogenous spike
you would use except for blood from a naturally infected animal model.
Dr. Brown?
DR. BROWN: It would be very nice when for example sheep
because everyone is a little nervous about basing human therapy on mice with
cause but when we get another species or two possibly even primates if we are
very lucky if we can get some idea of the concentration of infectivity in the
blood in non-rodent species we will be
much better off in terms of knowing
what really are the maximum levels of infectivity in the blood in endogenous
infections.
Today there is no estimate, no fact, no observation of the
amount of infectivity in any species other than the mouse and the hamster to
the best of my knowledge and that should change I would hope in the next year
or two.
DR. PRIOLA: That is
because that requires titering experiments that are very long term and expensive.
Any other comments as to this question?
I think the issue of using multiple animal models comes up
later as well. If there are no other comments from the Committee we will move
on to whatever the next question is. I
have lost count. I am sorry.
PARTICIPANT: Seven.
DR. PRIOLA:
Question 7.
DR. SCOTT: Only the numbers have been changed, but actually
for this question the proposal has also changed, that is it is really just I think more fully
described and fleshed out. What data should be used to estimate how much Factor
8 is used by typical patients? This is from Dr. Weinstein's slide. We plan to
analyze data from the ongoing UDC
survey to estimate the numbers of patients using specific product brands and
the distribution of disease types that is severe, moderate, mild hemophilia and
type 3 von Willebrand's disease and we also plan to extrapolate data from the
1993 to 1998 survey in six states to estimate the total number of US patients
and product consumption per patient with stratification by clinical setting and
if there is inconsistent information from these two analyses it will need to be
reconciled using patient-based medical
record data.
DR. PRIOLA: So,
basically you have three different routes to this question, right, three
different proposals for this, that you can use all three of these data sets to
address this?
DR.SCOTT: Yes, I
think they are not exclusive. They really ought to be used --
DR. PRIOLA:
Together. So, there is real data to be used which is very nice. Does the
Committee have any comments? Do we all agree with the FDA proposal? It seems
pretty reasonable.
There don't seem to be any more comments. So, let us move
on to question 8.
Oh, hold on, sorry, Mr. Bias, excuse me.
MR. BIAS: I don't know how this might impact but if there
are patients who are on immune tolerance therapy how do you account for them in the model?
DR. ASHER; That is a topic. Actually we didn't bring that
into play here but some of the information is available that is as far as the
number of patients on immune tolerance,
we do have information from the CDC, UDC collection for numbers of patients
immune tolerance. We would also again have to make an approximation from
essentially literature review I think
at this point to get an estimate of the amount of material that would be
used there but those of course would be patients who are using very high levels
of product. There are relatively few of them compared to some of these other
population groups but that is another group that we consider and we would be
able to I think get data probably more
of a, the quantitative data is difficult to get hold of for those patients but
probably with the review of current practices from physicians and looking at
various protocols for treating immune tolerance we could extrapolate that
information.
MR. BIAS: That would be good. I am glad you can get that
and my other question would be occasionally a patient like myself has an
accident in a particular year. Does the UDC data also account for those spikes
in usage? For instance this year my
monthly average tripled for the 6 months I was injured. So, that is a big
spike.
DR. ASHER: There is information from the UDC data. There is
a category of how many times people have been under say a prophylactic
treatment or use but we don't again have quantitative data about the amount of product being used in
those particular situations which is somewhat of a limitation and the UDC data
as it is currently constructed.
DR. PRIOLA: Can you
get that quantitative data?
DR.ASHER: It simply isn't being collected right now. I had inquired in fact whether an
additional question might be put on the survey form of the UDC data and the
opinion was that the information would be not very accurate, that it was felt
that it just may not be sufficient for our purposes. We are going to get more
quantitative data from the survey information.
DR. ALLEN: I certainly think that there are probably
alternate sources of data that could be used on a survey basis to estimate the
extraordinary needs that sometimes arise and I assume also and I forget from
the presentation, but data sources do show recombinant factor usage versus
plasma-derived?
DR. ASHER: Yes, we can get that but of course we are
primarily interested in the plasma-derived materials.
DR. PRIOLA: Dr.
Bracey?
DR. BRACEY; No, I was just going to comment on the
possibility of using alternate sources as well. I think we have heard that
there are probably some very good alternate sources available and if there are
important data elements I think that we should go elsewhere.
MR. BIAS: I am wondering if the delivery industry, if you
have ever tried to use them as a source but some of the larger providers. I
mean there is not a unit of clotting factor that goes out that isn't tracked.
DR. ASHER: The
question that I was uncertain about we had in fact discussed that element here
but I was not certain about whether or not there was a per patient figure, in
other words a delivery system may know in the aggregate, are you talking about
a distributor or a home care company?
MR. BIAS: Yes, they will know per patient. They will know
exactly per patient and they are very happy when it spikes. They produce a
monthly report that indicates exactly how much each person uses and they will
have very accurate figures on whether it spiked.
DR. ASHER: That is a good point.
DR. PRIOLA: Yes,
excellent. Thank you. So, that is another point for data collection for you to
put in the model.
Okay, let us move on to question 8.
DR. SCOTT: The next
question is what is the effect of plasma pool size, that is the number of
donors per final product for Factor 8 recipients and we proposed to estimate
plasma pool size as a range between 20 and 60 thousand donations with a bimodal
distribution to reflect expected source and recovered plasma pool numbers but
we feel that we should or do need to seek additional data from plasma
fractionators to get a better sense of the amount that we have in the lower and the upper range, and I think in
terms of the way the question is worded, what is the effect of plasma pool size
this goes back to Steve Anderson's presentation where he showed the information
or the modeling that indicates more frequent treatment sort removal overall of
the effect of plasm pool size.
DR. PRIOLA: So, you
are proposing this as a starting range really for your model knowing that you
will, assuming that you will be able to get better data from the plasm
fractionators eventually?
This is just a beginning range for you, the 20 to 60
thousand?
DR. SCOTT: The 60,000 actually represents a voluntary
ceiling for number of donors contributing to a pool and 20,000 is based on an
estimate of what we think for the lower end of plasma pool sizes really based
on ad hoc observations.
DR. PRIOLA:
Dr.Leitman, do you want to comment on that at all? No? Other comments?
Dr. Salman?
DR. SALMAN; This is for clarification and excuse my
naiveness. How many donations do you need then of one single pooled unit?
DR.SCOTT: Each manufacturer really has their own unique
batch size but I think the lower limit in the CFR is 1000 or something like
that but typically, I am not sure I understand your question, how many do you
need.
DR. SALMAN: When you have one pooled unit how many donors will
contribute to that pooled unit?
DR. SCOTT: Right,
so the manufacturing pool is comprised is plasma of a lot of donors and if you
want to a 500-liter pool and you have recovered plasma and you have say 200,
250 cc's per recovered plasma you can just do the math and figure out how many
donors that you would need to make up that pool size.
DR. SALMAN: But that will be a very important question for
the model and maybe Dr. Anderson can answer that as we heard like the model
will take that into consideration. So, the number of the donors contributes to
the unit will be unimportant aspect to the model especially when you look on
one of the three slides. You said they are very important and you skipped them and --
(Laughter.)
DR. ANDERSON: Do you want me to actually show those slides?
DR. SALMAN: One of them
you said, "Well, there will be 60,000 donors pool and 10 percent of
those may be contaminated.
DR. ANDERSON: Yes, if you had a disease prevalence of 1 in
500,000 and you had 60,000 donations per pool it would take about, in 10 pools
one of those potentially would have an infected unit, contaminated unit.
DR. SALMAN: If I understand the model and you present it
well I think what will contribute to the contamination is the number of the
infectious donors that participate in the pool.
DR. ANDERSON: That is correct.
DR.SALMAN: So, the number of the donors for that pool will
be an important aspect. Is that correct or not?
DR. ANDERSON: This is an important aspect of the model and
we are specifically modeling it. So, let me just sort of emphasize that and we have one option that we put up here
is we have a range of 20,000 to 60,000. So, we are going between that range
based on the information that we have.
The other thing we can do is we have recovered plasma that
we are interested in and source plasma. We could generate different
distributions for each of those. The problem here is that we have very
limited data by which to make these estimates and what we are doing is we are
saying that we know it is between
20,000 and 60,000 and our anecdotal information is that most pools lie at for the most part at either end of these
ranges. So, we are proposing a bimodal distribution. So, most of them will be
either 60,000 or 20,000 in our model.
So, it is important and it is figured into the model.
DR. SALMAN: But is that reflecting reality like in any
given pool unit? I am just asking the question for people who --
DR. ANDERSON: Manufacturers from our understanding
different manufacturers have different pool sizes from which they make these
products.
DR. BROWN: I think about 6 or 7 years ago when this whole
thing with the FDA and precautions and so forth got going at that time
manufacturers were using 100,000, 150,000 units for a plasma pool, sometimes.
It depended on the product they were
particularly interested in. After this story broke it was proposed that that
was a too high limit and since then I believe in fact I think all
manufacturers, there was a guidance. Is that not right?
DR. ASHER: No.
DR. BROWN: There was no guidance?
DR. ASHER: There is none, not a guidance.
DR. BROWN: There was advice. There was something in the
air, don't go over 50 or 60. Is that right?
DR. ASHER: Sixty. That is again a completely voluntary --
DR. BROWN: Exactly but manufacturers pay attention to
things that are in the air when they come from the FDA and so you can bet your
bottom dollar that manufacturers paid attention to that. I know they did and
virtually the maximum now that is used is 60 and I think this is probably a
very realistic range, 20 to 60 at the moment.
DR. ALLEN: In actual fact from using source plasma donors however, you might have multiple donations from a
single source plasma donor. So, if you had one infected donor there may be
multiple donations from that one donor
that go into a single pool.
DR.BROWN: That is actually an interesting questions. Would
they in fact go into the same pool if they were donating say, I don't know once
every 2 weeks? Sometimes they donate once every 2 weeks. So, they could wind up
in the same pool.
DR. ASHER: And that
is something we can model as well.
DR. SCOTT: I think
part of minimizing the donor pool is
actually trying to use some of the same donors in pooling from certain selected
centers into one pool all the time. You see what I mean? So, it certainly could
happen. It would be consistent with current practice.
DR. BROWN: I think the rationale was to limit the damage.
If you had a pool that was contaminated with smaller pools it would be
distributed to fewer people. I think that was the clear --
DR. EPSTEIN: That is correct for the infrequent product user. The problem that you get into
is that the chronic product user will simply be exposed to more product lots
made from a larger number of smaller pools and so those phenomena offset each
other which is part of our motivation for trying to look at an annual patient
risk but for the rare or infrequent product user yes, a smaller pool would have
a lower probability of having an infectious donor.
DR. BOLTON: I just have a question. Is there a uniform
relationship between the number of donated units and the units of Factor 8 that
are manufactured from that? There is a critical relationship there in terms of
translating donations to product vials.
DR. ANDERSON: Right, and we have that actually from the
literature and manufacturer information. So, we have a range actually for that
and I actually don't recall what that range is offhand, but we actually have
put a range in for that estimate and it is using a yield calculation
essentially.
DR. BOLTON: Is it pretty uniform across the industry or is
there --
DR. ANDERSON: There is a little bit of variability from what
we can see from the information that we have. So, we are incorporating that
into the model.
DR. PRIOLA: Dr.
Leitman?
DR. LEITMAN: This is getting off on a tangent but isn't
there a voluntary hold practice in the
industry so that a donor's plasma is held 6 months until their next
visit to confirm they are not in a window period?
PARTICIPANT: Sixty
days.
DR. LEITMAN: Sixty days. I knew there was a six in there.
So, potentially a donor's unit could get into the same lot 60 days apart?
PARTICIPANT: Yes.
DR. PRIOLA: Okay,
any other discussion from the Committee?
Mr. Bias?
MR. BIAS: It is exactly because of that hold that you can
get several infectious donations into a pool and because there is no rule, hard
and fast rule we don't exactly know how many factors are handling that on site.
We learned from the eighties that it was possible for them to in making batches
leave a little bit of a batch from a previous batch at the bottom of the pool
that would increase the infectivity if that previous pool was infected and
previous batch was infected and therefore instead of 60,000 you had a pool that
suddenly had donations from 120,000 people in there and because there is no
hard and fast rule we have sort of a gentlemen's agreement with the manufacturers that they are going
to lower the pool size. I would be very concerned that that still occasionally
happens because it is a manufacturing process and a manufacturing process is
one that produces a product that produces something they are going to sell and
become income and they are certainly not going to pour it out.
DR. SCOTT: I can say that
that practice is highly discouraged and I, personally, am not aware of
any use of tailings anymore and it is an inspectional issue. Anybody that is
found to be processing things this way will definitely get a problematic inspection.
MR. BIAS: I am sure they are all playing appropriately in
the sand.
DR. ASHER; I want to just make certain it is on the record
that this again is a voluntary system and the 60,000 is voluntary. It does not
mean that there are no manufacturers that have gone above that.
DR. PRIOLA: Okay,
so, are there any other comments from the Committee?
If not do we agree that it seems to me the range that the
FDA proposes is okay?
All right, let us go on to question 9.
DR. SCOTT: Can a cumulative effect from repeated exposures
to low doses of the vCJD agent be incorporated into the risk model and we
propose to allow for the theoretical possibility of cumulative effects by
having the model provide a cumulative risk for a 1-year period for these
different types of patients.
DR. PRIOLA: Dr.
Brown?
DR. BROWN: Yes, that is a good idea. In fact, the good news
or shall I say the bad news first? The bad news is that in our model it can
happen. It has been shown. Now, we were wondering about that for a long time.
The answer is now on the table.
The good news is that despite that fact hemophiliacs are
not dying and that is another way to look at it but absolutely it
is almost more than a theoretical possibility now. It is something that
really has to be included in any model.
DR. PRIOLA: Any
other comments from the Committee?
So, we are in agreement that the 1-year cumulative is a
good idea. I think it is.
All right, let us go on to the final question, question 10
which is the voting question.
DR. SCOTT: I don't think we will have a final solution
today but we do want to understand the Committee's feelings about everything
that you have heard and this is a question that we are asking you to consider
now.
Given the present scientific uncertainties that you have
heard about today in the underlying assumptions of the Factor 8 risk assessment
do you believe that the risk assessment model could provide a useful basis for
risk communication to patients, their families and health care providers?
DR. PRIOLA:
Dr.Salman?
DR. SALMAN: I think the short answer is yes but I will put
a condition like the sensitivity analysis should be done as part of the risk assessment model and that should become part of the
communication with the public.
DR. PRIOLA: Dr.
Brown?
DR. BROWN: It really depends on how well it is articulated
to the patients' families and health care providers. We can't expect them to
understand clearly what has been happening this morning with all the caveats
and this, that and the other thing but the fact is that all the evidence to
date indicates that sporadic CJD No. 1 is not associated with infectivity in
the blood, the evidence to date.
Second, to date we have no cases of variant CJD in this
country.
Third, the infectivity present in cone(?) fraction in the
precipitate already has a low amount of infectivity. In fact, four is that
processing currently in place for Factor 8 is
more than adequate to take out any infectivity that might theoretically have been present.
I think the risk assessment will probably validate this
overall scheme of safety.
DR. LEITMAN; I just want to second that. When you start to
talk to patients and their families about risk assessment they assume you are
talking about very real risk. This is theoretical risk or hypothetical risk
because there has not been a case even in the highest-risk population which
would have been UK hemophiliacs before the screening procedures were put in
place.
DR. ALLEN: Let me concur with the previous comments and say
that I think the FDA needs to move forward with this model development and to look
very carefully at the results that come from it.
The subsequent steps as one tends to want to go public with
the information, however, are to look carefully at how you approach this with
the media because you can't keep it just to patients at risk, providers and the
small community. It is going to and has got to be involved with the general
media and I have got real concerns about that because they like to hype
everything regardless of what the actual risks are.
The experience we had with HIV infection more than 20 years
ago now clearly tells us that we can't just sit on this and wait. I think the
risk is likely to be extremely low. Fortunately we have had enough experience.
We have got much better surveillance systems than ever in the past but the answer
is not going to come down to zero risk. We know that and we are going to have
to look very carefully at how this is communicated so that it is useful and
reassuring and educational rather than frightening.
DR. BRACEY: Again, I concur with the previous statements
and I think the statement that was made earlier was very important and that is
that there are groups already that have been discussing the risk with the
members of that community and I think that rather than start anew it would be
good to try to partner with those individuals to continue the counseling that
has already begun.
DR. PRIOLA: Mr.
Bias?
MR. BIAS: Although I want the risk assessment developed I
have real concerns about how it gets communicated to patients and health care
providers.
I am concerned about the
possible stigmatism to patients as related to not their primary
caretakers at per se hemophilia
treatment centers or someone who is familiar with their background in
hemophilia but their outliers; one of the weaker parts of comprehensive care is
dental care. If their instruments are at risk they may choose not to treat
patients with bleeding disorders. I think that other agencies within the
government have to be alerted and have to, if we are going to publish this
information there has to be some provision so that patients can continue to be
treated and guaranteed that treatment on some level.
States are moving toward preferred product lists where they
are limiting patients to one type of clotting factor and we are fearful that in
some states they are going to select a plasma-based product because it is
cheaper and if that is the case that is going to leave that family without any
alternatives for care.
So, I am very concerned about how this risk assessment gets
applied to the public and any slow news day, we are in a 24-hour-7 news cycle
now. If the earth isn't cracking open this will be the major story of the day
and it will run. If it is a holiday weekend it will run for 3 or 4 days and
what you will have is a group of patients who are without care and without
access to care and without alternatives because the Federal Government hasn't
protected their right to have care or have access to other product choices, if
their state says that this is the product that we have for you.
So, I am very concerned about how this is applied and I
would strongly recommend that before this information is published in any way
that there is major consultation with hemophilia organizations both in the
world and nationally so you can get their perspective and guidance
as you go forward and in addition to that
that we work with HHS to ensure that there are going to be alternatives
for patients to continue to receive care including saying to medical providers,
"You don't treat these patients; you don't have access to Medicaid."
DR. PRIOLA: Dr.
Hogan?
DR.HOGAN; Relative
to that I am sure we are going to be hearing about the results of this model in
this Committee. I think it would be possible and we would ask the FDA for this
Committee to discuss those results relative to how they would be dispensed.
Obviously this is an open forum and the media is here but
we can certainly stress that there are the uncertainties that are involved and
hopefully have some sort of oversight as to what Mr. Bias is talking about.
DR. PRIOLA: Dr.
Johnson?
DR. JOHNSON: I am concerned about the same thing that Val
was talking about and that is the nature of the audience this is being
released. There is a huge percentage of people who are well educated, well
informed in this country who don't differentiate mad cow disease from anything
else and think it is here and the level of confusion they have already
undergone is enormous. Trying to explain something like this on top of it
reasonably is going to be very hard.
I would like to hear Florence's comments on that. She deals
with it every day.
MRS. KRANITZ: Thank you. i totally agree with Val. I could not agree more and as simple as
you may make the explanation or as hard as you may try to show how this risk
model made the assessment and realities of it, you still are going to have some
panic, probably a lot of panic on the part of not only the patient but of the
health care provider.
So, before you take on the project of informing publicly
any part of the population you need to know that you might even have to do risk
assessment on top of risk assessment as to what possible damages you are going
to create by releasing this information.
DR. PRIOLA: So, the
basic point that the risk model could be a basis for communication to family
and health care providers, that is okay, and it is the way in which that
information is communicated that is the biggest concern. Okay.
Any other comments?
DR. BRACEY: This may be a somewhat naive question. I think
it may be a matter, well it is a matter of perhaps economics and a matter of
supply, but you know the entire issue revolves around the current methods for
preparing the product. If we were talking about recombinant products aside of
course from the risk of the albumin that it is resuspended in I think we would
be having a different discussion and so one of the things that I wondered about
and I would like to hear from Mr. Bias or Val about this is if you indeed did
have this risk model that you could address that looked at plasma, recovered
Factor 8 wouldn't that potentially be useful in making an argument to bolster
the use of the recombinant product?
MR. BIAS: It
probably would be but my concern is the reality that we are facing on the
ground and currently we are in a battle state to state to maintain the access
to the care that we have and I am just concerned that without the force of the
Federal Government behind it the publication of this information would not have
the same impact on every patient in every state and there will be people who
will fall through the cracks. There will be discrimination and so on and so
forth. So, my guidance is that if we are going to release this information that
other parts of the Federal Government that are responsible for health care and
health care provision also be prepared to put laws into effect, put statutes
into effect so that we can guarantee treatment for people with bleeding
disorders. This is a disease that we have worked at high cost of lives for many
years to make very livable for people. People are living very full healthy
active lives now that we have gone to recombinant clotting factor and the
plasma products are very clean. It is such a difference from when I was a child
to today.
A child today plays on their school basketball team. I was
not allowed in the gym and because of the switch of power from the Federal
Government to the state government that understanding isn't there. That history
isn't there and we see our access to care being rolled back in states all over
the country.
So, I just want to make sure that if we are going to
release this kind of information it can be used as an argument but we have got
to have the Federal Government's power behind that argument.
DR. BROWN: The text says as I read it carefully,
"Provide a useful basis," and let us vote.
DR. PRIOLA: Dr.
Weiss, you had a comment you wanted to make?
DR. ASHER; Yes, I just wanted to clarify the element here
that in fact there are no recombinant von Willebrand's containing factors and
so there is a definite need for
plasma-derived materials and secondly there are current studies going on there
about potentially the advantage of using plasma-derived for immune tolerance.
It is unclear whether or not this is really preferable to recombinant but there
is some evidence that is being investigated now.
DR. PRIOLA: Let us
go ahead and vote on the issue because we are voting on is it the basis for a
reasonable risk communication.
So, Bill?
DR. FREAS: For the
record there are 17 voting members at the table. Dr. Bracey is a non-voting consultant at this meeting.
I will go around and call the roll.
Dr. Bolton?
DR. BOLTON: Yes.
DR. FREAS: Dr.
Johnson?
DR. JOHNSON: Yes.
DR. FREAS: Dr.
Telling?
DR. TELLING: Yes.
DR. FREAS: Dr.
Creekmore?
DR. CREEKMORE: Yes.
DR. FREAS: Dr.
Lillard?
DR. LILLARD: Yes.
DR. FREAS: Dr.
Sejvar?
DR. SEJVAR: Yes.
DR. FREAS: Dr.
Hogan?
DR. HOGAN: Yes.
DR. FREAS: Mr.
Bias?
MR. BIAS: Yes.
DR. FREAS: Dr.
Allen?
DR. ALLEN: Yes, with reservations noted during the
discussion.
DR. FREAS: Dr.
Priola?
DR. PRIOLA: Yes.
DR. FREAS: Mrs.
Kranitz?
MRS. KRANITZ: Yes.
DR. FREAS: Dr.
Geschwind?
DR. GESCHWIND: Yes.
DR. FREAS: Dr.
Leitman?
DR. LEITMAN: Yes, with the reservations noted during the
discussion.
DR. FREAS: Dr.
Gaylor?
DR. GAYLOR: Yes.
DR. FREAS: Dr.
Ghetti?
DR. GHETTI: Yes.
DR. FREAS: Dr.
Salman?
DR. SALMAN: Yes.
DR. FREAS: Dr.
Brown?
DR. BROWN: Yes.
DR. FREAS: The vote
is unanimous.
Agenda Item: Topic
2: Labeling Claims for Filters Intended
to Remove TSE Infectivity from Blood Components
DR. PRIOLA: Okay,
let us move on to topic 2. The Committee will have noticed there is no break
scheduled for the afternoon. So, I have asked the speakers to keep on time and
if possible we will try to take a 10-minute break or something after the first
couple of speakers if everybody is on time. We are about 20 minutes behind time
now which isn't too bad.
So, our first speaker of the afternoon session will be Dr.
Vostal.
Agenda Item:
Prospects for Reduction or Removal of TSE Agent Infectivity from Blood
Components by Filtration and Criteria for Allowing Claims: Introduction – Jaroslav Vostal, MD, PhD,
OBRR, CBER
DR. VOSTAL: Thank you for the opportunity to share with you
some of our thinking in terms of validation of labeling claims for TSE
reduction studies with blood processing filters.
Now, my talk actually starts off with several introductory
slides and since these topics have been very well covered earlier today I am
just going to go through them very briefly.
As you can see this is a brief schematic of the prion
protein. It points out that there is different conformation of the protein. One
of these is the pathologic form of the prion. It has protease resistance and
less soluble.
The main point of this would be that TSE infectivity can be
present even in the absence of PRPSC and so therefore PRPSC is only considered
as a surrogate for TSE infectivity.
Now, this is a schematic of the organs of an animal and in
terms of pathophysiology just very briefly
if there is oral inoculation the infectivity goes through the LRS system
and through the peripheral nervous system and migrates into the central nervous
system.
As was discussed by Dr. Asher earlier today these models
have demonstrated that there is infectivity in rodents during the asymptomatic
phase of the disease and so it is pretty much agreed that at least in
the rodent model there is infectivity in blood.
Those earlier experiments raised concerns that there is
transmission by blood transfusion particularly for BSE. This was confirmed by
the key experiments by Houston and Hunter where they used the sheep model and
they had an asymptomatic BSE-infected sheep.
From this animal they were able to collect a full unit of blood and
transfuse that to a healthy sheep which then went on to develop or some of these
animals went on to develop BSE.
This model is interesting in that respect that it uses a
full-size animal that is capable of donating a full unit of blood that can then
be processed by the devices that we are going to be talking about later on
today.
Moving on from the animal experiments there is now
currently epidemiological evidence for variant CJD transmission by blood
transfusion in humans. This was reported by Dr. Llewelyn and Dr. Peden. As we
already heard earlier today there is a national CJD surveillance system in the
UK that identified 48 individuals. Actually these are numbers taken from these
publications. So, those numbers are slightly different, current numbers are
slightly different. Basically there were 17 individuals identified that are
still alive who received products from 15 donors who later became diagnosed
with variant CJD. Two of these living recipients were subsequently diagnosed
with variant CJD. One died from symptoms of vCJD. One died of unrelated causes
and was later identified as having PrPres in his spleen and both of these
patients received non-leukoreduced red cells.
So, if there is infectivity in blood, TSE infectivity in
blood we are very interested in looking at devices that are capable of reducing
this and what we would like to do is to establish a system to validate the
claims for these devices.
Some of the issues to consider for validation of the
devices are the distribution of TSE infectivity in blood in humans or in the
particular animal model, whether this infectivity is cell associated, whether
it is intracellular or extracellular, whether the infectivity could be free
floating in plasma and then we have to consider the physical attributes of
infectivity in plasma, whether these are aggregates, fibrils or microvesicle.
We need to consider the interaction of the individual units
of infectivity with the devices and finally
to look into the distribution during and after processing to make sure
that the devices actually eliminate infectivity and do not only distribute it such as would happen if you
had a microvesicle formation from the infected cells.
So, the steps to validate the TSE claims of these devices
would include in vitro spiking studies and this is as was already discussed
before, these involve spiking of brain material usually homogenate into these
products and detection of infectivity either by surrogate markers for PrPres,
PrPsc or by bioassay again in an appropriate animal.
Complementary to this is a model that uses endogenous TSE
infectivity and here because the levels of infectivity are so much lower
usually the detection is done by the bioassay.
Now, when we discuss animal models there is always the
question of whether these are predictive to the human situation and some of the
things to consider in terms of deciding whether these animal models are
predictive are the comparability of the animal blood to the human blood, for
example, to look at the type, number, size of these cells and the physical
properties of the blood cells. Also, we need to look at the interaction of the
animal and human blood cells with the different materials that they are going
to be exposed to and also there are questions about the transmissibility or
infectivity of a TSE agent that can be influenced by the strain of the agent,
the dose of the agent, distribution of
infectivity in blood particular to the agent and also and sometimes we are
concerned about the distribution of normal prion, whether that can influence a
distribution of infectivity in blood cells.
Now, these are just a small table comparing the hematologic
values for various species. The species that we have listed here are human,
mouse, hamster and sheep.
You can see the human value here on the bottom line, the
red cell volume and the platelet count. For the most part the platelet counts
in these animals are equivalent and so are the white cell counts. The key
differences between the human and the animal models comes in looking at the
size of these cells. The human cells have about close to tens of liters of
volume per red cell. You can see that in the mouse it is about half and
particularly in the sheep these are very small cells and we always wonder
whether these cells, whether the size influences the way those cells are
processed by the devices and whether they can influence the way the infectivity
can be distributed after it has been processed by the devices.
It appears that the small size of these cells is
compensated by the increased number of these cells. So, the sheep and the mouse
have a significant number more red cells than you find in human blood.
This slide talks about the normal protein expression on
blood cells of different species. This is the difference. We are wondering whether the expression of
prion protein on these cells would make a difference because there is a
physical association between the pathologic conformation and the normal prion
proteins in terms of propagating the infectivity.
So we looked at distribution in human cells by flow
cytometry and for humans there is expression on platelets, erythrocytes, and
particularly on lymphocytes and monocytes.
If you look at some of these animal models that have been
used to show TSE infectivity in blood it is striking how different they are in
terms of prion protein expression, particularly for the hamster. We were not
able to detect any prion protein expression. The mouse has comparability at
least in red cells and sheep again platelets and red cells are devoid of prion
protein. So, we are not exactly sure how this can influence the distribution of
infectivity but it is something to consider when deciding the appropriateness
of the animal model for this purpose.
So, besides looking at validating the removal of TSE
infectivity these devices will also have to be evaluated for their impact on
the transfusion product quality. The evaluation of the red cells, platelets and
plasma will have to be done after they are processed through these devices and
the FDA follows a standard evaluation approach to each transfusion product
based on previous experience with the devices that process transfusion
products.
For example, we have a lot of experience with
leukoreduction filters and the next couple of slides will just share with you
the evaluation process that we go through to evaluate leukoreduction filters.
So, leukoreduction is the process of reducing the total
number of leukocytes in the transfusion component. The methods that are
employed are filtration or apheresis.
These leukoreduced products have been associated with the
reduction of febrile non-hemolytic transfusion reactions, alloimmunization and
reduction of CMV virus. Even though there is an association or beneficial
aspect of these products none of the manufacturers actually claim these beyond
meeting the criteria for leukoreduction and in the US the criteria for
leukoreduction is less than 5 times 10 to the 6th leukocytes per transfusion product and in Europe this
is reduced to less than 1 times 10 to the 6th leukocytes per transfusion
product.
So, to validate leukocyte reduction filters for efficacy we
look at the quantitation of leukocytes in a particular blood product before and
after filtration. So, there is leukocyte count and the whole blood, red cells,
platelets and plasma before and after.
We, also, look for definition of the timing of
leukoreduction from the time of collection of the product. This is because
leukocytes actually disintegrate within several days and in order to be able to
remove the whole cells it is best to filter early on in the storage period.
We, also, explore the effects of temperature on filtration efficacy whether it is done at
room temperature or cold temperature and we also look at validation of the
efficacy for a particular anticoagulant which can influence the way those cells
perform as they are being processed through the filter.
In terms of validating these products for safety we look at
biocompatibility and integrity of the materials. We look at their effect on
cellular products. In particular we have criteria for in vitro recovery which
is 85 percent. This means that we
expect to see 85 percent of the products, of the red cells that are passed
through that product to be recovered after filtration. We also have criteria
for hemolysis at the end of storage and it should be less than 1 percent and we
do in vivo recovery of radiolabeled cells in normal human volunteers and this
is done for platelets and red cells.
For plasma we look at levels and function of plasma
proteins and also complement activation.
So, this slide here summarizes our proposal for validating
a claim for reducing TSE infectivity in human blood products. We would like to
see a demonstration of a reduction of endogenous TSE infectivity by bioassay in
two animal models and we suggest that this would be a rodent model as well as a
sheep model.
We like to see a full-scale blood unit and leukoreduction
filter used. We would like to see the
TSE infectivity to come from a BSE or variant CJD strain of TSE diseases.
The reduction of PrPsc in blood products will be considered
supportive but not sufficient for a claim.
Study should be performed at two separate sites to minimize
the issues of cross contamination and differences in laboratory practice and
finally study size should be sufficient to support statistically valid
conclusion from those experiments.
So, that is my introductory talk. Here are the questions
that we are going to be asking you to comment on today. The question is are the
FDA proposed minimal criteria for validation of TSE infectivity reduction by
filtration adequate and appropriate? And we would also like you to comment on
the following points. The rationale for use of specific animal models to study
the properties of blood-borne TSE infectivity, are the experiments in rodents
sufficient or should experiments also be done in sheep?
Is it necessary that each experiment should be done in two
separate laboratory sites to ensure the reproducibility and accuracy of the
clearance and are general descriptions of informative scaled-down processes for
reducing TSE infectivity in blood?
There are several more comments that we would like your
input on, for example, levels of clearance acceptable for claims of reduced TSE
infectivity in blood components as used in clinical settings, the estimated
logs of clearance of TSE infectivity required to conclude that blood filters
have effectively removed infectivity from blood components and the methodology
appropriate to use in evaluating TSER agent clearance, bioassays for
infectivity, Western blots or other assay for prion proteins.
So, those are comments to the initial question. The
follow-up question is does the FDA's proposed labeling for a filter meet the
appropriate criteria for a claim of reduction of TSE infectivity in blood or
blood components and here we have several options. We have an option A which is
this filter or device has been shown to reduce TSE infectivity in blood from an
infected animal model. Now, A would then be coupled with labeling C which is a
disclaimer that states that due to lack of feasibility studies have not been
performed to validate this claim in the human population and the other option
for labeling would be using part B which is this filter has been shown to
reduce transmission of TSE infectivity by transfusion in an animal model and
this again would be coupled with the disclaimer C.
So, if you can help us out by commenting on some of these
issues that we presented we would be very appreciative.
Thank you.
DR. PRIOLA: Thank
you, Dr. Vostal.
The next presentation will be by Dr. Marc Turner who will
discuss evaluation of prion reduction filters.
Agenda Item:
Evaluation of Prion Reeduction Filters – Mark Turner, MB, ChB, PhD,
FCRP(Lond) University of Edinburgh
DR. TURNER: Thank you very much, Madame Chairman. I am
going to speak to you about briefly the UK evaluation process for prion
reduction filters. You would probably be aware we are really somewhat on the
front line on this issue and that we probably have put quite a lot of thought
into these issues over the past 6 to 12 months.
The first comment is that you are probably aware that there
are four UK blood services, English National Blood Service. SMBTS, and the
Irish Blood Service, the Non-irish Blood Service along with the Seven Irish Blood
Service and all accountable to different jurisdictions and so we have elected to approach this problem from
the collaborative power of a working group which really is aimed at reducing the points of contact for the
companies themselves.
So, they have one joint service rather than five different
services also reducing the amount of duplication of effort between the
services.
So, the purpose of the group is to get a primary point of contact with any
blood services or the manufacturers to foster a dialogue which I think has been
very successful with those manufacturers providing expertise and advice from
our end of the business on the clinical development requirements we require
from these systems to liaise with regarding in-house operation evaluations, to
liaise with other parts of the UK, Joint Professional Advisory Committees for
Blood Services with regard to implementation of these devices and to ensure
that the appropriate UK Department of Health decision making properties are
also kept apprised and up to date and in the UK that formally means the UK
Spongiform Encephalopathy Advisory Committee or SEAC and also the Committee on
the Microbiological Safety of Blood, Tissue and Organs.
Now, this is a, I apologize for the complexity of this
diagram but this is a diagram showing you the pathway that we have devised just to simplify it down for your
comprehension. It really breaks down into three parts. The first part on the top left here is a process of establishing the technical
specifications and that is being done through the JPAC process and there are three lines for that. One is the technical specification
around efficacy and the second is the technical specifications around quality
and third is an operation and technical specification and that work is being
doing and has been brought together and approved by the JPAC approval process.
A very important aspect of this is a risk assessment which
has been carried out on our behalf by colleagues in the Department of
Health,Economics and Operational Research, Statistics and Operational Research
and I will speak to that issue in a few minutes.
Really that is this point now in the process. On the right
hand side are what I would describe as preclinical evaluations around
independent evaluation of prion removal and also around the independent
evaluation of component quality. Those will then lead into the bottom left hand
corner which will be clinical safety evaluation studies which I will describe
to you.
The key issue from the point of view of the risk assessment
was the issue of how great a reduction in infectivity is going to be needed to
be clinically useful for us and we have made a number of assumptions around
this issue. First of all I think it is worth pointing out that the current
generation of prion reduction filters are applicable to red cell products only
and not to plasma and platelets at this stage. We assume a red cell
concentration in optimum added solution with prior leukodepletion and 10 to 30 mls of residual plasma and I will
just make an aside comment here that the two transmission events, e.g., prime
ones occurred almost certainly using an earlier generation of red cell products
and not only were they not depleted but they probably almost certainly weren't
in optimum additive solutions or they
would have been in an anticoagulant with probably about 100 to 150 mls of
residual plasma.We are making the assumption that total residual
infectivity of greater than 2 ID50s
transfusing into one infectious dose will transmit for certain and we are also making the working
assumption that prion removal is going to occur mainly from the plasma.
Now, in terms of background in risk assessment we have used
a starting proposition of 10 IDs per ml of infectivity with the assumption that
a 450 to 500 ml unit which gives you between 4-1/2 thousand and 5 thousand
infectious doses per unit. We have made a pessimistic assumption of no
differential between IV and IC and we have followed Bob Riller's work in
assuming for the purposes of this assessment that about 60 percent of
infectivity goes forward in the plasma and about 40 percent associated with the
leukocytes. So, in general terms there
are about 3000 infectious doses associated with a plasma component and about
2000 infectious doses associated with the lymphocytes.
During the component processing as you have heard the units
are subject to leukodepletion and although it is not shown but it is true it is
about 1 times 10 to the 6th residual leukocytes per unit. In point of fact in
practice we are finding that we normally get down to around 2 times 10 to the
5th residual leukocytes, so about a 4 log reduction and that is where you get
this residual leukocyte infectivity figure of 0.2 IDs and in addition to that
the residual plasma that is probably about 225 mls in a unit before component
processing and depending on processing technique that is reduced to somewhere
between 10 and 30 mls. So, traditional top-top component processing will give
you in the order of magnitude of 25 to 30 mls plasma and a more modern bottom
to top processing will leave you in the order of magnitude of 6 to 10 mls of
plasma and in some scenarios that differential is actually of some importance.
I have to say that those various assumptions that we have bought into with risk
assessment are going back to the UK SEAC probably in this month for evaluation.
So, they will be addressing some of the very similar questions that you are
addressing at this table, ladies and gentlemen and I am vaguely hopeful that
they will come up with similar kind of answers but we shall see.
In this illustration you can see that where you are only
getting say for example 1 or 2 logs of reduction of infectivity and in the
plasma you have still got enough infectious doses to infect the patient for
sure given the relatively large volume of plasma or large volume of the product
and it is really only if you start getting to around 3 logs of reduction across
the prion reduction filter itself that is in addition to any other effects of
plasma reduction or leukocyte reduction you start to make a significant impact
on the risk of infectivity. As you don't get beyond that in this model you find
that reducing the plasma infectivity even further doesn't assist you that much
because you have still got the residue of infectivity associated with the
residual leukocytes.
So, the conclusions from that assessment are that 1 to 2
logs are likely to give value as clearly highly dependent on their route of
infectivity and highly sensitive to that in the plasma. I haven't shown you
this but the estimates are that if we were to achieve 3 logs that might amount
to 75 percent reduction in the incidence of secondary transmissions in the UK
and I think important further reduction in residual plasma could augment
reduction in infectivity over the prion reduction filter and therefore the
incidence of secondary transmission and so there is an issue as to whether if
and when we implement these technologies we should really be looking also to
from top to bottom in processing with
maximal plasma reduction and in
addition any further effect on residual
leukocyte count could be of additional significant benefit. So, if your second filter serves to drive down the
residual leukocytes that might be of overall benefit as well.
So, that is obvious. The analysis has driven the prion
reduction specifications and we are looking for a 3 log reduction to be shown
and we then are sponsoring these immunoassays and bioassays. We would also like
to see data from endogenous infectivity studies up to a limit or the model and
we are asking that the model be capable of demonstrating at least 1 log
reduction by immunoblot if possible but certainly by bioassay and asking the
manufacturers to look at the issues of process, their levels including we have
processed some blood at plus 4 degree C and some at ambient temperature. We
need to know the filters work in both those environments, also, issues such as
anticoagulant and use of the head height and things like that are found to be
important for example in leukocyte reduction and we have asked the companies to
propose surrogate markers or process monitoring which is perhaps one of the
most challenging issues, but clearly it is not going to be possible on a
day-by-day basis to measure infectivity in the blood that we are prion
reducing. So, we are looking for surrogate markers. We need to be able to
demonstrate parallelism of infectivity in a surrogate marker if at all
possible.
Then where possible surrogates present themselves PrPc is
an obvious choice but the residual plasma in the red cell concentrate is
minimal and therefore the gross levels of prion protein,normal prion protein
are very small and it looks as if this might not be possible and so the
discussion we are having at the moment is
around a variety of different coagulation factors as potential surrogate
markers.
Just to comment on the component policy specification we
are advising all the various issues that of course were mentioned 5 minutes ago
as to the Payee(?) Redbook guidelines which will be very similar to the guidelines here. We are looking at volunteer
red cell survival studies. The only point I would draw out is that we have also
patterned more detail than we normally would at changes in red cell membrane
physiology and red cells do appear to
express normal prion protein albeit low levels and probably in a truncated form
and that is just a little matter of concern for those who operate by removing
prion protein itself and so we are looking at the expression of protein on the
surface of red cells before and after filtration and at the other factors which
might lead to a reduced red cell survival as well as remember that these red
cells have to be cross matched in hospital blood banks up and down the country.
So, any alteration in antigenicity would be of concern. I have to say for those that we have
evaluated so far we have not really come up with any problems using any of this preclinical evaluation and I guess our
main concern at the moment would be that this does take 14, 15 mls of blood out
of the pack in addition to the leukodepletion filter which is kind of
unavoidable and probably doesn't matter for most patients but for some patients
who are receiving large volumes of blood or frequent blood transfusions may
have a consequence of them receiving more units at the end of the day.
Now, the UK, SEAC and MSBTO and UK Blood Service chiefs
have asked us to carry out an independent evaluation study and the purpose is
really twofold. One is to provide some independent replication of some of the
key data that is being provided to use by the manufacturers and where possible
to extend that data into a more clinically relevant or clinically informative
model and certainly I think we would be keen to look at more than one model.
Data generated on a particular strain and animal species is generalizable. What
we proposed in the first instance is that we will start very close to some of
the data that has been provided by the manufacturers. We will introduce it in
3K in hamster homogenate for the exclusion homogenate for microsomal fraction
and sonicated fraction assessed by immunoblot and bioassay and in parallel with
301B BSE stedic(?) spike assessed by Western blot if possible and by bioassay
and those two studies have now gone out. Because of the size of the studies
they have to go out through a formal procurement process. So, the process is
being instigated and we expect that to be completed by the end half of the new
year. We are expecting data to be available within about 6 months of the
initiation of the study. Bioassays are going to take up to 2 years. So, we are
hoping that we will have initial data available by the third quarter perhaps of
2006. We obviously also very mindful that we would like to see endogenous
infectivity studies probably in a rodent model and in a sheep study. We haven't
planned these at the moment. We decided to focus on these initial studies in
the first instance as a kind of gatekeeper and we will be putting further
thought into these in due course. These will take an even longer period of time
to create a sheep study which takes many years and I will come back to this
theme if I may at the end. There is clearly a trade-off here certainly from our
point of view between the comprehensiveness of the evaluation and the kind of time
lines needed to implement these technologies in a timely way if they are
effective.
Finally we are running a series of clinical studies and the
primary aim here obviously is to look for the incidence of adverse events and
adverse immune responses. Study 0 has been commenced or is imminently going to
commence in Ireland where we will be putting in the very first instance a model
there that is full use of blood from the patients through the prion reduction
filter. So, 20 single units will go into patients that are being transfused and
20 double units as it were in trying to keep the patients that are receiving 3
units which may take perhaps to the end of this year, the end of 2005.
Early in 2006 we will be initiating two much larger studies
one in patients undergoing complex cardiac surgery, 300 patients in the UK all
of whom are to receive the prion
reduction filter treated with concentrates. Study 2 is a randomized blinded
study in chronic transfusion dependent patients probably MDS patients rather
than thalassemic patients because we want to note particularly these kind of
patients who could be vulnerable to allo-antibody development and we want to
look at that issue specifically and the statistical estimates are that these
two studies have around 90 percent power of picking up one additional adverse
event in these study populations.
So, that is really all I wanted to say ladies and
gentlemen. The baseline assumptions and
these proposals will go to the UK SEAC probably at the end of November for
their consideration and commentary and the only other comment I wanted to make
is that I think that clearly the
situation in the UK is an order of magnitude more grave than it is perhaps here
in the US and I think that we are going
to be faced with very difficult decisions and as to this balance between
wanting to ensure a comprehensive evaluation on the other hand and wanting to
move forward on the precautionary principle and implement these kind of
technologies as soon as is reasonably possible.
Thank you very much.
DR. PRIOLA: Okay,
thank you, Dr. Turner. I am going to put a question to the Committee. We have
another hour's worth of talks on removal of prions using various filters. We
can take a 10-minute break or we can plow through. If we take a 10-minute break
we are going to be later. We are about one-half hour behind.
So, do the Committee members want to break or do you want
to plow through?
We will take a short break for 10 minutes to sort of
re-energize people and then we will come back at ten to four.
(Brief recess.)
DR. PRIOLA: Take
your seats so we can get going. Our next speaker will be Dr. Sam Coker from
Pall Corporation.
Agenda Item:
Performance of Pall Corporation Leukoreduction Filters on TSE
Infectivity of Blood Components:
Experimental Studies and European Experience – Dr. Sam Coker, Pall
Corporation
DR. COKER: Thank you very much. What I am going to share
with you today are some of the results of the validation work that we have done
on this particular filter which is currently being licensed for use in Europe.
Some of the topics that I will be going over today include
how we validated the particular product. I will talk a little bit about the
process that we use and then I will give you some of the results that we
obtained using this particular Western blot.
I will go to part three very quickly just to give you a
brief update in terms of the ongoing validation work that we are currently
doing.
In part 4 of my discussion I will also give you some of the
work that is also ongoing at Pall to identify a particular surrogate that can
be used as a QC for looking at the efficient removal of infectivity using this
particular product and I will give you a brief rundown of some of the red cell
quality that we have already done and finally I will just give you an
understanding of some of the work that we are currently doing in Europe.
Some of the tests that we had done to validate this
particular product including Western blot which is mainly an exogenous spiking study to kind of give us an idea of
how efficiently this particular product is working and then we also did a
bioassay to give us a much more realistic indication of the log removal and
finally which we think is also the most
important aspect of this is to demonstrate the removal of the infectivity from
blood that had been infected endogenously using hamster model. So, these are
the three main approaches that we use to validate this particular product.
The type of materials that we used in the validation
included brain homogenates in this particular case using the hamster model. We
also have data using mouse adapted variant CJD which is the closest we can get
to variant CJD itself and we also did additional work with sporadic CJD but the
main validation data that we used for CE map of this particular product was
based on the hamster model.
The Western blot assay that we used is based on the
publication from Wadsworth and his group in Edinburgh and we also validated
assay using an outside contractor BioReliance which is an FDA licensed contract
lab. I will skip some of this but these
are just the dilutions that we used to validate the Western blot assay. So, you
have an indication of how to measure the infectivity level or the level of the
residual amount of PrPres that is present in the blood.
So, the spiking study we did especially we used brain
homogenates from hamster. We homogenized it. We added it to the red cells and
we simply just filtered. We measured the level of infectivity before and after
filtration using the Western blot and we evaluated several different processing
conditions, the effects of different anticoagulant filtration heights, effects
of leukocytes, the effects of different filter lots.
This is mainly to kind of study the filter that we
developed. This is just an example of what a typical Western blot looks like.
This is before filtration. This is the proteinase K resistant form which is believed
to be the infectious form of the prion. This is before filtration and this is
what we obtain after filtration and looking at this over a whole lot of
processing conditions, anticoagulants, we saw no significant difference
especially between the CPD and the SAGM. However, there is a slight increase or
improvement in removal efficiency using CPDA-1 but a critical aspect of this is
that the filter is effective in removing infectivity using different
anticoagulants.
We also looked at the leukocyte reduced and non-leukocyte
reduced blood that had been spiked with infectious prions.
Again, we didn't see any significant difference between
that. We looked at different filter lots and again t he level of removal is
consistent which again indicates that
the manufacturing process that is being used to produce the filter is very
consistent and we looked at the effect of filtration heights. We identified
that the lower the filtrational height the more effective the removal process.
So, that allows that to kind of identify the particulate filtrational height
that would be used by this particular product.
We, also, identified filtrational temperature as well as
the contribution to improve it in prion removal. Just to summarize this initial
aspect of this particular filter it has already been CE Mark in Europe. So, it
is available in Europe for use and the CE Mark is based on the hamster model.
We have about 2.9 plus or minus .7 logs and we have demonstrated that this
filter is effective across all processing conditions and most importantly we
saw no significant difference between different lots of filters which indicates
consistency in the production of this particular filter.
So, what I am going to share with you now are some of the
additional tests that we did to kind of confirm that the filter is able to
remove not only the hamster prion but also prions from sporadic CJD and most
importantly from mouse adapted variant CJD which I think is very critical and
relevant to discussion here.
Again, when you think of the same experiments again, but
here using brain homogenates with red cell measured in levels before and after
using the Western blot assay and typically for most of the sporadic CJD you can
see very clearly the three bands or the three different forms of the PrPres,the
diglycosylate and monoglycosylate and this is very important because this shows
that the sporadic CJD the amount of these different bands can be used as a way
of identifying different strains of sporadic CJD.
Over here in type 4 which is believed to be very typical of
variant CJD the main impact of this particular one is to demonstrate the
effectiveness of the filter in removing different strains of prion.
So, we collected brain homogenates from different groups of
patients that have various forms of neurological disease. Some of them have
sporadic CJD and some of them have Alzheimer's disease and this was done in a
double-blind study with the New York Medical School and the results show very
clearly that the fourth filtration will identify those three bands that are
present and identify what particular group has type 1 or type 2. The fourth
filtration will identify the presence of those bands after filtration, The
filter completely removed the level of infectivity that is present.
The next part of the study was to now go forward and repeat
this same experiment using mouse adapted form of infectious prion.
Again, this is before filtration using mouse adapted prion
and after filtration again there is removal below the limit of detection of the
current assay that we have.
This is just to summarize what we have done to date with
this particular product. This is the result that we used for the CEMAC(?) using
the scrapie infected hamster and you can see the fourth filtration. So, we are
removing about 2.87 plus or minus .7 logs and this is using mouse-adapted
variant CJD and there is about 2.2 plus or minus .32 logs and again we will find significant removal with sporadic
CJD.
The next aspect of our work is to now demonstrate that the
endogenous infectivity can be moved on to similarly. We can see additional
confirmation of the exogenous work using a bioassay to determine the log
reduction.
We, also, have an experiment going on using endogenous
infectivity study and essentially this is just
a simple endpoint titration assay to kind of give us an indication of
whatever we had with the Western blot correlates with the bioassay. These
experiments are currently ongoing and the results should be available early
next year and this is the endogenous infectivity again. This we believe is
probably one of the most critical aspects of the validation program because as
we have discussed earlier today the use of the brain homogenates has its
limitations and the best way to avoid the controversy regarding brain
homogeneity is to actually use endogenously infected blood samples. So, we have
blood collected from about 100 to 200 hamsters and these are then processed as
you normally process with the red cell and plasma and the red cell that is
endogenously infected is then filtered with the filter. The filtered blood is
transfused or intracerebrally injected into about 400 hamsters. Two hundred of
them receive the pre-filtration sample and these particular experiments are
finally ongoing and by the middle of next year to early part of next year we
should be able to get some indication as to what the results are.
So, in summary some of the validation work that we used to
study to see clearly were based on the Western blot. We are currently doing the
endogenous infectivity study to obtain the actual log reduction that will
complement what we have with Western blot.
We, also, have the endogenous infectivity study that is
also currently ongoing. So, we will be able to get an indication of how
effective the filter is in preventing the transmission of prion disease.
The next part of my talk actually relates to what Marc
Turner mentioned earlier about identifying a particular surrogate that can be
used to monitor the effectiveness of removal of infectious prions from blood.
We have done quite a lot of work in looking at several
different plasma proteins that are present and we have currently identified a
couple of proteins instead of the PrPc because of this limitation that we can
use to monitor how effective the filter is in removing prions from blood. So,
this can be easily incorporated into any blood bank and we feel that this
should be a very good way of performing a QC.
The next aspect from my work, I mean this we have already
gone through is to give an indication of the red cell quality. We talked about
how we validated the product. We have also talked about the effectiveness of
the filter being able to remove different strains. The next aspect is to see
what is the quality of the red cell after going through the filter.
We did a whole series of studies including hemolysis study
looking at the membrane integrity and the neurologic properties in the survivor
and by all accounts of what we have done to date this is just an indication of
the results. We didn't see any particular change at all and when we look at the
hemolysis at the end of a 42-day study especially for sagendazen(?) it is still
well below the Council of Europe guidelines as well as the standard from the
FDA.
In addition to looking at the quality we also look at the
safety of the product itself and all of this is really according to the
regulations from the FDA that had been established for leukocyte reduction
filters and so today all of this has been passed and we have not seen any
particular concern.
So, in summary the red cell quality is very well maintained
and we did not see any concerns about the safety of the product or of any of
the parameters that we measured to kind of look at the safety.
Overall the filter that I have just described to you has
been able to demonstrate that we can remove at least a significant level of
infectious prions from blood using brain homogenate. We have demonstrated it can remove different strains of prions,
sporadic as well as mouse adapted and overall the cell quality was very well
maintained throughout the whole process and most importantly we have also
identified a series of proteins or a couple of proteins that can be used as you
see of the prion removal efficiency of the filter.
The European experience is that currently we have a series
of studies that are currently going on in Europe just to try to validate some
of the work that we have done. So, we expect some of these results to come back
sometime in 2006.
Thank you very much.
DR. PRIOLA: Thank
you, Dr. Coker.
Our next speaker will be Dr. Bob Rohwer who will talk about
selection and performance of resin-bound ligands for removal of TSE
infectivity.
Agenda Item:
Selection and Performance of Resin-Bound Ligands for Removal of TSE
Infectivity From Plasma – Robert Rohwer, PhD, PRDT (with Prometic and ARC)
DR. ROHWER: Thank
you very much. I am wearing a little different hat than I usually do here
because I am representing Pathogen Removal and Diagnostic Technologies who is
the company which I helped found and which is developing this removal
technology.
I am going to concentrate mostly on the infectivity studies
because that has been my contribution to this effort and I will summarize the
work of the other partners in this.
As we heard earlier in the day we do have now a
confirmation that there is a transfusion risk associated with variant CJD. I
won't go over this anymore and Dave Asher very nicely summarized this data for
me earlier, that at least in the hamster model that we have characterized in
our laboratory we get a median value of about 10 infectious doses per ml in
blood and that doesn't seem like very much of a risk unless you consider it in
terms of a unit. For example, at the same time in this disease when we have 10
infectious doses per ml in blood we have got
10 billion infectious doses in the brain per gram of brain in the
hamster model.
So, it really is a very, very small effect compared to what
is going on in this animal at that stage of the disease.
On the other hand if we consider the way in which we
actually use blood it is not on a per ml basis but a per unit basis. In a 500
ml unit we might have as much as 3-1/2 logs of infectivity.
The other important piece of data is our studies on the
appearance of infectivity in blood. Dave Asher showed this earlier and the main
point here is that we first saw the infectivity in this part of the infection
but because we took points along the way if we extrapolate this back to here it
is about one-third of the way through the infection that we first start seeing
infectivity.
This would be nothing on the basis of infectious doses per
ml, but if we put it in terms of infectious doses per unit even at these very
early times we have significant amounts of infectivity probably plenty to cause
an infection if a whole unit was given.
How do we deal with this? This is the usual triad of, triad
because usually these are lumped, of approaches to controlling TSE pathogens
and these particular diseases this
group up here are all problematical in various ways and therefore we decided to
or I have had been advocating this approach to controlling the risk from these
particular pathogens for some time and there are some other real advantages to
this in my opinion.
First, it removes infectivity that can't be detected with
diagnostics. Every diagnostic has a limit of detection and a perfectly working
which we may never get to, but in theory at least a removal device would be
able to remove infectivity that could not be detected, i.e., infectivity that
was below the window period limit of detection for any pathogen, not just these
pathogens.
In the case of TSE diseases this would be even clinical
disease for blood because we still don't have a convincing assay for detection
of the infectivity in blood or the POP signal in blood from the infection, but
it also applies to preclinical disease from brain or other tissues where if you
go back early enough in the infection you still may have a risk for example for
tissue donation or something like that and still be up against this same limit
of detection.
The other advantage of this method is a very big advantage.
There is no reason necessarily to need to discriminate between the abnormal
from the normal form of PrP.
In the case of blood we can remove both and there is
actually even some advantage to doing so because there is measurable PrPc in
blood and so far there has been no demonstration of PrPres in blood or we don't
have methods sensitive enough to detect it.
So, we can use the removal of PrPc as a assay for the
removal of both as long as we have a device that will use both and in fact we
selected on purpose for resins that do both and because it can actually access
this area of the infection that is
below the limit of detection of diagnostics it may be more comprehensive than a
diagnostic and in the end it could even be less costly to deploy than
diagnostics.
PRDT, Pathogen Removal and Diagnostics Technologies was a
company that was put together by Dave Hammond and Rubin Carbonell, a couple of
combinatorial chemists. Dave Hammond has, also, had a lot of experience in the
plasma industry. Rubin is an engineer at North Carolina State and myself
providing the prion expertise and we interested the Red Cross Informetic(?) in
investing in this and it has become a joint venture of these two corporations
and we now have Macropharma(?) as a major blood bank manufacturer in Europe as
the partner for marketing and production of devices.
The way these things came into being is we screened several
libraries of various compounds. They represented over 64 million combinations
in total. We looked at 8 million beads in the course of doing this, doing a selection assay based on protein methods,
a blotting method and the Western blot. Once we picked out the first 200
candidates we decoded the beads and then made larger quantities of these
materials so we could go through a secondary characterization based on protein
and then out of that we got another group from which we selected seven for
infectivity characterization, first by spiked TSE experiments and then an
endogenous experiment and I am going to spend the rest of the talk talking
about these experiments here.
These are the kinds of things you get out of these
screenings. What you are looking at here is the binding in duplicate. These are
duplicate samples which is why you see pairs here without protein PHK and with
protein PHK in plasma as a couple of resins.
So, this particular resin binds well in buffer and in plasma. Here is
one that binds well in buffer but not in plasma. Obviously we are interested in
this type of resin for further development. That doesn't mean that this
particular compound, this particular resin wouldn't be useful but it won't be
useful for this particular application and we have in our pocket about 200 of
these.
The infectivity experiments, this has been discussed before
but I want to go over it once more just to emphasize the difference of what we
can get out of the various modalities.
If we spike brain-derived infectivity into red blood cells
we have the advantage of high titer, high levels of removal that can be
demonstrated but will have uncertain relevance because we don't know how well
this spike regardless of how we may manipulate it before spiking represents the
infectivity in blood.
This is a somewhat earlier readout. It is a fairly crude
measurement and it is less costly. If
we do an endogenous experiment relevance is not an issue. It is relevant. It is
blood-borne infectivity but the titer is very low about 10 infectious doses per
ml in whole blood and even lower for our red blood cells where the plasma
concentration is lower and the white
blood cells have been removed and the most we can hope to demonstrate
inoculating 5 mls of this product into hamsters, into 100 hamsters is about
1-1/2 logs of removal.
It is a long experiment. We have to take the animals to the end of their life essentially but
the measurement is very precise by the limiting dilution method which Dave
Asher referred to earlier and I really don't have time to explain right here
and it is quite a bit more costly for
those reasons.
Typically in this type of experiment to measure the
infectivity in these models we do endpoint dilution titration. We do serial
10-fold dilutions, inoculate into groups of animals. They get sick and at some
point you run out of infectivity and you can calculate a titer from that.
There is also a dose-response associated with this. These
animals come down quicker than these and the dose response as Dave showed
earlier disappears in this group right
here. We are going to make one set of measurements using the dose response in
this part of the curve and the endogenous measurements using the infection at
the limiting dilution using the Poisson distribution of infectivity into
animals at the end.
Now, the dose-response measurements I have always had a
problem with this. I have always resisted it but we had a lot of samples we
wanted to screen this way and as a consequence we needed something that we
could afford to do basically and the
main problem I have had with it, one of the
problems I have had with it is that the endpoint is hard to define
because there is a progression of symptoms especially in the hamster model but
saying exactly when one stage of the disease ends and another starts there is a
lot of interobserver variation in that.
We developed this method of just weighing the animals. They
gain weight throughout their life and as they get sick their weight falls and
taking this cutoff at 80 percent of maximum weight as an endpoint.
So, from this we get an empirical determination. It is
observer independent. We developed our dose-response curves from duplicate
measurements, two completely independent measurements. They are indicated here.
Each animal is indicated by a circle here and the means by these triangles and they are displaced around these
values. So, you can see the data actually and it is actually much more tightly
clustered than I ever would have thought.
Here we are getting at limiting dilution where some of the
animals do not get sick and so how does this assay work? We took a large pool
of human red blood cell concentrate and then divided it into one unit
quantities after spiking it and mixing it. So, all of these challenges were
identical and then passed it through
our device. This was a prototype device at this time in the development and
then collected the unit here, looked at the PrP scrapie signal that is retained
on the device here and measured the incubation time of the infectivity that
remains in this bag in a test group here.
So here is a case where we removed the infectivity. We can
see it here. There is not enough infectivity left. There is not enough PrPres
signal left in this bag to measure it by Western blot. So we have to go through
the infectivity measurement. Here is our standard curve again. Here is our test
group. Here are the incubation times for the test group. They are at this
concentration but they are displaced off the curve to this level.
We carry this down to where it belongs on the dose-response
curve and we see that we have got 4.33 log of dilution between here and here
and we presume that we have removed around 4 logs of infectivity.
We did that for a number of samples. These are all
different resins here. These are controls here. They are all at 10 to the minus
3. They all belong on this line but I displaced then so you can see them. This
is the data I just showed you. Here is the next best one and here is the worse
one right here.
So, the clustered in this fashion. Here is the data
summarized in a bar graph, log removal on this side and log reduction on this
side. These are our controls again and these are all probably pretty much
equivalent within the error associated with this type of measurement.
Just to remind you we challenge with a million infectious
doses per ml. The actual blood will contain about 10 infectious doses per ml,
but if you will remember we did get infections and that worked out to about 20
infectious doses per ml. Not all of the infectivity was removed by this filter
and this infectivity right here when passed through subsequent resins of the
same type was not removable. This is
in some form that is not recognized by the resin.
So, what we have is we have a spike at this level, a
residua at this level and in blood if the proportion is the same we will start
with 10 infectious per ml with a residual way out here at .0002 infectious
doses per ml. This would not be significant and we would still have quite a
significant margin of safety.
Nevertheless we can't be sure of this. We don't know that
this distribution is the same because of this question that has been discussed
throughout the day. We don't know what the form actually is in blood. Therefore
it behooves us to measure this to the best that we can that we can actually
remove the endogenous infectivity from blood. What if it is all in this form,
for example?
There is a form that would not be removed by our device and
that is cell associated infectivity. Everything that we will have to do looking
at endogenous infectivity will have to be done with leukoreduced blood because
we don't claim that the resin would remove cell-associated infectivity and we
know that there is a significant amount of cell-associated infectivity from
this leukoreduction experiment that we did a couple of years ago in our
laboratory where we took a unit of whole blood prepared from hamsters, that was
500 mls of blood, passed it through a
leukoreduction filter and titered the infectivity before and after
leukoreduction and got this type of data. This is the leukoreduced whole blood.
These are the incubation times down here. These are the animals that did not
come down and there is about 40 percent removal here of the starting infectivity by leukoreduction.
This, also, gave us a way to do the experiment because we
had this as a precedent and we knew what to expect in terms of the amount of
infectivity we could in the leukoreduced blood in order to challenge the device
with endogenous infectivity. So, we
expected about six infectious doses per ml in whole blood. We knew that if we
had made red blood cell concentrate from this and ended up with 20 or 30 mls of
plasma our expectation was that we would be down to less than a single
infectious dose per ml in that material and this would not be, we didn't
consider this to be even though this is the target of the device and the target
we were going for we didn't think we could do a meaningful experiment with this
material.
So, we actually have done this with whole blood even though
we consider it to be a, leukofiltered whole blood even though we consider it to
be a worst case. It gives sufficient
titer from measurable effect and we have the preceding experiment to inform us.
We are currently at about 420 days, well, at 420 days when
I made this slide which was about 30 days ago and this is where we are in this
experiment. What I have plotted here is this is incubation time on this axis
and the number of animals on this axis. This is all of the limiting dilution
titrations we have done to date in our laboratory that are summarized in that
first slide that I showed you showing you 10 infectious doses per ml where this
is a distribution of about 500 animals from blood infections that have come
down over the course of those experiments and this is the distribution of those
infections and the point I want to make here and this is, if we add these all
up and say, "What proportion of the infections have occurred by 215 days
for example?" it is about 50 percent of them, and that is indicated on
this red curve here. This is the cumulative number of infections that have
occurred at any given time. You can see that they go all the way out to 550
days. So, you can get infections out at this level but at 420 days when I
summarized the data that I am going to show
you next we are about two-thirds of the way through the infection but we
are about 94 percent, we have seen 94 percent of the infections we are going to
see. That is the main point. We are very close to seeing everything we are
going to see in this experiment. So, here is the data. In this case we took our non-leukoreduced
whole blood before leukoreduction and put it into 50 animals instead of 100 and
so you need to multiply these numbers by two to get a direct comparison with
these values over here.
Each dot here is an animal. Each S means an animal that has
come down with scrapie. Here we are in
the challenge. This is the titer in the leukoreduced blood. One of our
disappointments is we are seeing a lot less infectivity in the leukoreduced
blood than we saw in our first experiment, the experiment that was published in
the Lancet last year.
Here is the final flow through the device and thank God we
haven't seen any infections yet though every time I get this update on this
data I get a little heart flutter because we are getting so close to the end of
this.
We are 94 percent complete. This is the data in terms of
infected over total number of animals inoculated and this is what if we project
what it should look like at 100 percent completion we will get another
infection here, another infection here, another infection here and hopefully we
will see no more infections here.
This titer is coming out to exactly what we always get,
about 10 infectious doses per ml or what we usually get but on the other hand
we are seeing a lot less infectivity in the challenge. We were expecting about 6.2 infectious
doses. Here we are only seeing 2.6, about half that and what has happened here
is that the leukoreduction was much more efficient this time than it was the
first time around where you lose 75 percent of the infectivity in the
leukoreduction instead of 40 percent.
Nevertheless if this relationship remains because we have
inoculated 5 mls of this we will have 13 infectious doses in that 5 mls of
blood and we will be able to demonstrate a log. We have already demonstrated a
log of removal.
Now, just two more comments on what is going on in this
leukoreduction. We have done another experiment during the last year and that
is we have spent a lot of time over the last 8 years or so trying to figure out
what white blood cell type actually harbors the infectivity and every time we
purify the white cells we seem to lose the infectivity. So, we just did a
simple experiment. We collected the white blood cells from a buffy coat and
measured the infectivity before and after a simple centrifugal wash in PBS and
that centrifugal wash removed 80 percent of the infectivity.
So, in a typical leukoreduction we have been thinking about
this in terms of 50 percent of the infectivity in plasma, 50 percent in the
white blood cell fraction because we have shown in other experiments that it is
not in the red blood cells intrinsically associated with red blood cells or
platelets at least in this model and 80
percent of this plus this leads us to believe that we really should be thinking
about the infectivity as plasma associated and it is not that tightly
associated white blood cells at that and as a consequence there may be some
variability here in the leukofiltration results just based on things like flow
rate or pretty mild parameters that we don't have a understanding of yet.
So, that is just summarizing that in words. So, where are
we now with this? We have this resin which we have now characterized in an
endogenous experiment. It has a very high affinity for the prion protein, 10 to
the minus 9 KD. This is mysterious to me and I think it is indicating that
there is some cooperativity in this binding. It removes PrP from rodent brain
and human brain. We have looked at scrapie, sporadic CJD, familial CJD and variant
CJD using the WHO standards and it binds to all of these. It works in red blood
cell concentrates, whole blood and plasma. The plasma work has only been done
in vitro so far. We get 4 logs of removal of brain derived infectivity greater
than 1 log from endogenous infectivity to date and the human compatibility
studies have all been done by the Red Cross and of course they have done them
very well and so far we have seen no impact on red blood cells, plasma proteins
or platelet activation.
By this I mean plasma proteins that are important for
therapeutic development. We have a partnership now with Macropharma and they will manufacture and supply this and it
is in the latter stages of development.
I wanted to acknowledge Louisa Grigoria in my laboratory
and her staff who have spearheaded this effort on its day-to-day basis and I
will conclude there.
DR. PRIOLA: Thank
you, Dr. Rohwer. We will move on to our final presentation and that is Dr.
Ralph Zahn from Alicon.
Agenda Item:
Other Industry/Academic Filter Chromatography Develper – Dr. Ralph Zahn,
CEO, Alicon AG
DR. ZAHN: Good afternoon and thank you very much to the
Committee for inviting me here to talk which is a big honor for a small Swiss
company actually. So, when we started with our company at the beginning of last
year we decided to work on BSE diagnostics and also on biochemicals which are somehow related to BSE but then we
found that our technologies can actually also be applied for other diagnostics
like scrapie or CJD and it also works with prion filtration and most probably
also for Alzheimer's diagnostics and so we currently have 35 products to supply
which are 33 different recombinant prion proteins and two monoclonal antibodies
and so two of these prion proteins are probably important for diagnostics and also for prion
filtration, PrP pure and also PrP beta.
So, why are they important? I think they are important for
TSE diagnostics and prion filtration because they can be used for research and
development. They can be used as
positive and negative controls and they can also be used for checking
the quality control for assays and filters and so Alicon PrP pure corresponds
to the natural prion protein found in healthy humans and animals or in other words
PrPc and this is available for different species including bovine, deer,
hamster, human, mouse and sheep.
So, we not only have different species available but all
the different lengths of different
constructs in particular for the human protein. We have seven different
constructs. Also for sheep we have three different polymorphisms and then on
the other hand we have PrP beta which corresponds to the natural form of the
prion protein found in infected humans and animals or in other words the PrPsc and
again we have different species available for this protein.
So, PrP beta is produced starting from PrP pure, the same
principle in a three-step procedure which should somehow mimic the production
of PrPsc in nature. So, we start with PrP pure and then in the first step we
have a conversion from PrP pure to PrP beta star where PrP beta star is the
better suited protein. It is oligomeric and it is completely water soluble, and in the second step we have a
conformational transition in 2 PrP beta fibrils. So, we think that these three
forms of recombinant prion proteins resemble very much the three forms in vivo,
so, PrPc, oligomeric PrPsc and also PrPsc fibrils and I also should mention
that this procedure has been worked out at the ETH in Zurich in the lab of
Professor Retrich and the main work was done by Atoss and Vias and this is some
of the biophysical data just to show the conformational transition from PrP
pure into PrP beta. You see PrP pure before conversion there is an alpha
helical secondary structure and after conversion there was a better secondary
structure as indicated by the single minimolar to 15 approximately and this
also works for a different construct as is shown here. Then this is the PrP
beta fibril which is typically formed off of filaments which are elegantly
wound as shown here and where the single protofilaments(?) show this beta
substructure and exactly the same morphology has been described for PrPsc, for
natural PrPsc and similar to PrPsc the PrP beta also binds Congo red and shows
this typical Congo red bifringence(?) and it is also, PrP beta is also more
proteinase K resistant compared to the normal prion protein PrP pure. There is
at least a factor of 10 difference and there is also an accumulation of this
typical 16 kieregard(?) fragment which has been ultimately described for PrPsc
and PrP beta binds also to PrPsc conformation specific antibody which is the 15
P3 antibody from another Swiss company. So, this binds PrP beta not PrP pure.
Now, we also have done the biosafety checks because we
wanted to know whether this protein, PrP beta is also infectious. So, this was
actually what we wanted to show at the beginning but we are trying this since a
very long time but we never could really show infectivity. So, we did infectivity
checks in TG20 mice but also in wild-type mice. We inoculated about 18
micrograms of mouse PrP beta into these mice. We, also did a serial
transmission experiment but we never got clinical signs or pathological signs or proteinase K
resistance in the brain homogenate.
Of course, this also has some advantages because if you
want to work under less stringent biosafety conditions then the PrP beta has
some advantages over natural PrPsc.
So, the main project we are working on or we have worked on
is the matrix which has a very high affinity to all kind of prion proteins and
so why is this so? Because this matrix does not have only one binding site for
PrP but it has three different binding sites indicated here by different
colors, so making this contact between PrP and the matrix very efficient and
does really very tight binding and another interesting feature of this matrix is that the specificity for
the PrPsc conformation can be
modulated. In the absence of aligning with X, so zero concentration the matrix
binds to PrP pure. So, corresponding to PrPc and to PrP beta corresponding to
PrPsc and it also binds to dimeric forms of those proteins and there is only a
very low amount of unspecific binding of these averages here in 1000-fold
excess over the prion proteins, but if you increase the concentration of this
ligand X let us say for example to four then there is only PrPsc bound but not
PrPc anymore. So, the specificity of this matrix can be modulated.
So, the applications of this matrix technology, the name of
this we call Octapetform(?) for more for historical reasons so that there are
two main applications. One is PrP enrichments which can be used for prion
detection and the other application is PrP removal which is of course necessary
for prion filtration.
So, I would like to show you some examples for PrP
enrichment. So, this is an enrichment experiment where we started with 4 mls of
plasma and we did an 800-fold enrichment of PrPc in a lot of healthy cows which
are not infected with BSE and as you can see here we have a nice signal of PrPc
which is 800-fold more sensitive compared to the normal Western blot assay and
so we mostly observed the diglycosylated form of PrPc in the one blood in this
case in plasma and if we add some proteinase K then of course the protein is
degraded.
A similar picture we see also in interface cells or in
white blood cells. Again we have a strong signal here after enrichment
corresponding to diglycosylated PrPc. This is our standard protein and this is
a dimer of the standard and again if you add proteinase K then we get an
intermediate fragment first and then at 5 micrograms per ml the PrPc is
completely degraded and the same also works for platelets, again this strong
signal here for the platelets and this also works for PrPsc from scrapie brain
homogenate which was added to bovine plasma in this case here. So, we started
with 1.5 mls of plasma. So, we have a 300-fold enrichment and we can show how
we can measure very low amounts of proteins for example here 800, 200 and 40
picograms of PrPsc using this enrichment procedure.
Now, so to summarize using this technology we are able to
at least 5000-fold increase the signal for example in Western blot assays using
this matrix and I am sure we can go even to a higher concentration if we would
try. We didn't try so far and in terms of protein concentration we even have a
more than 50,000-fold enrichment process going on here.
Now, so we have applied this technology for a BSE live test
for cattle and so I would like to show you just one result here. So, on the
left side you see a cow which has been experimentally infected with BSE prions
about two twenty months ago and this blood was sent us from Germany and on the
right hand side you see a control. There is no proteinase K resistant protein
seen and this pattern of four bands we observed for, as well as we observed
experimentally infected cows as well as natural BSE cows.
This is also an important figure which shows different
variants of our matrix which has been used for treatment with BSE infected cows
again but which will also spike with PrPsc and as you can see here only one
matrix bound to this typical four band pattern which indicates endogenous PrP
from an infected cow but the other matrices only recognize PRSE after spiking.
So, this means that this is quite important in my opinion because this shows if
you have a matrix which binds to PrPsc from brain homogenate this doesn't mean
that it also hinds at the same time endogenous PrP.
Now, I am now changing to prion filtration. As we heard
this morning there are some important applications like plasma fractionation,
plasma banks and also for pharmaceutical
industry. This is an example where we have completely removed PrPc from
bovine plasma of a healthy cow. So, we did this experiment similarly like
before. So, we started with 20 mls of plasma, treated this plasma with our
matrix and then we diluted the bound protein and loaded this on a Western blot
here for two different cows, A and B. You can see one cow has a little bit more
PrPc than the other cow and this is the recombinant protein again and this is
done after recombinant protein and if you do this experiment a second time then
after the second time there is no PrP left anymore in the plasma. So, this
means that we have completely removed the PrPc from the plasma using our
matrix and with a detection limit of
less than 1 picogram per 20 mls which is about 50 femtograms per ml which corresponds to approximately 0.5
infectious units per ml of blood plasma.
Now, this is a similar experiment with human plasma which was spiked with PrPsc. Again, after the first treatment we
see a lot of PrPc and PrPsc before and after proteinase K digest on the Western
blot and after the second treatment we only see recombinant prion protein which
we used as a marker to show that the matrix works actually but after proteinase
K there is no protein left anymore. So, again we have completely removed PrPsc
in this case at the concentration of lower than 1 picogram per 20 mls and of
course we wanted to know whether our matrix has some effect on blood
coagulation. So, we did some different, we did various tests on the different
variants of matrices and the results are summarized here. So, there is some
effect for some matrices for example here in this global factor but there is a
small difference compared to the control. There is also some effect of matrix
on the two. There is a slight increase in Factor 7 and there is also a small
decrease of von Willebrand's factor of measures 1 and 3 but all the other
parameters for example, fibrinogen Factor 5, Factor 8, Factor 9, the fibrin
dimers, the three inhibitors of the protein concentration are not changed at
all and most importantly there is one matrix where we didn't observe any change
in these parameters. So, this matrix is probably quite useful for that
transfusion.
So, to summarize the advantage of our technology in our
opinion at a really high affinity matrix first and second we can completely
remove all prion proteins including PrPc and PrPsc and also endogenous PrPsc as
we have seen from this in cows and this matrix also has a high compatibility to
blood plasma.
These are the people who did the work finally and thank you
very much.
Agenda Item:
Open Public Hearing
DR. PRIOLA: Thank
you, Dr. Zahn.
Okay, I think we will move on to the open public hearing
portion of the afternoon.
DR. FREAS: Dr.
Priola, at this time we have not received any request to speak in the open
public hearing in the afternoon. Is there anyone in the audience at this time
who would like to address the Committee on this topic?
I see none. So, we will move on.
Agenda Item:
Committee Discussion and Recommendations
DR. PRIOLA: Okay,
so I think we should address the two questions that the FDA has posed to us
based upon topic 2.
So, the first question is are the FDA's proposed minimal
criteria for validation of TSE infectivity reduction by filtration adequate and
appropriate and I think if you will put the slide up there this is a voting
question but before we vote they would like us to go through and comment on
some of the points behind this question.
So, if you look in the handout from Dr. Vostal on the last
page you will see those comments, the points they would like us to comment on.
The first is the rationale for the use of specific animal
models to study the properties of blood-borne TSE infectivity. Specifically are
experiments in rodents sufficient or should experiments also be done in sheep
or any other sort of TSE model?
So, I would like to open that for comments from the
Committee.
One model, two models?
DR. TELLING: I had a comment talking about using sheep but
another large animal model that springs to mind is infected cervines because
obviously there are large amounts of blood available from such models, and it
would appear that the lymphoreticular distribution of infectivity to the extent
it has been looked at may mimic variant CJD.
DR. BROWN: Just as
a practical matter I don't think the FDA can require companies to use small
ruminants if they are going to require bioassays. I think bioassays and small
ruminants or large ruminants or any ruminants simply won't get done in time to
be of any use. We won't have a problem anymore when the titers are finally in.
If they were to use Western blot as a marker for
infectivity then I think it is possible to require larger animals. My
inclination would be to go with two
strains in an appropriate rodent model and I think one of those strains would
have to be 301V mouse adapted variant and the other model could be sort of
anything you want, 263K in a hamster but I think maybe two species, two models,
that is a strain in a mouse and a strain in a hamster and the mouse strain
clearly should be 301V as the closest thing that is in a rodent to variant CJD.
DR. PRIOLA: One of
the speakers brought up earlier that
the size of the blood cells for example differs in blood from different
species. What about trying to address that sort of issue? That might be one of
the things the FDA is thinking of with using different animal models and using
rodents, either mice or hamsters wouldn't necessarily address that unless you
just want to stick with Western blot for ruminant models.
David?
DR. BOLTON: What if the infected blood came from naturally infected
larger ruminants but the bioassays were done in transgenic mice? Then you have
a chance of getting the data back in some sort of reasonable time but you are
actually studying the natural product which is closer to what you are looking
for.
DR. BRACEY: Are
transgenic mice of this sort readily available? I am not a transgenic person.
If they are not that kind of throws a wrench into practicality, but if they are
--
DR. BOLTON: I don't have them either but I understand that
they are in development. Glenn, ovinized transgenic mice, are they --
DR. TELLING: Yes, the ovinized mice have certainly been
published on by the French group in particular. As to whether or not they are
available, you know, there are cervinized mice.
DR.BOLTON: We
produce cervinized mice as you guys have produced them and the group at Case
Western has and Stan's group has and we are certainly committed to making all
of our transgenic mouse models available and those include not only cervinized
but also ovinized and bovinized. So, yes, as far as we are concerned they are
available.
DR.ALLEN: I am certainly not expert in this area but I will
make the general comment that we have heard an update today and certainly been
given enough background information to suggest that there is a lot of variation
here both in terms of the host animals as well as the prions themselves and I
would suggest as the former speakers have said that looking at multiple models
makes a lot of sense and not going with just a single model.
In addition assuming that this is to be used on human blood
and plasma certainly one wants to make certain that there is no damage to any
of the cellular components or to the end product from the use of the
filtration.
So, one looks at it, needs to look at it from both the
safety as well as the efficacy points.
DR. PRIOLA: So,
from a practical point of view where would this blood come from if it were, I
mean would manufacturers be required to have scrapie-positive sheep and CWD
positive deer and elk or are there other sources for that available?
DR. BOLTON: They can just go to Colorado and Wyoming, can't
they?
DR. PRIOLA: It is
possible I guess. That is a practical point but if that blood were available
then it would provide a basis for that sort of test. It would also sort of
negate the second comment there, is it necessary that each experiment should be
done at two separate laboratory sites and that has to do with the contamination
issue from people not being careful enough when injecting their animals and if
you had common source blood and the same sort of transgenic model systems it
would be easier for independent labs to do that.
Comments on any of those first two points? I think it is a really good idea, actually
taking blood and using the transgenic mice to test.
DR. ROHWER; I could
say a lot about this but I will try to
keep my remarks fairly brief. Obviously
the best of all possible worlds would be to use human blood inoculated into a
transgenic animal that was sensitive enough to assay it and I think that has
always been the dream behind the transgenic work was to make that possible but
as far as I know it is not possible or not possible yet and certainly there
have been a lot of people trying.
The next best thing would be to have a large animal model
like the sheep assayable in a transgenic and I think there are a number of us
who are trying to do this and we have
been talking to each other and hopefully that will come to fruition but we have
no idea whether it works now. You know
we know you can infect transgenics with brain-derived sheep infectivity but
whether that will work for blood and at
what efficiency who knows, and the final thing I want to say is just you should
consider the following aspects. There is a reason that we use the hamster and
we stumbled on it but it turned out to be a pretty ideal model. It produces
enough blood that we can actually obtain the blood in quantity. Using 120
hamsters we can make a unit of blood and that is a doable thing. It takes a
morning, etc., and we can quantitate it because the animal is small enough we
can put it into a large number of animals to do that.
Doing the same types of experiments in mice and we have
done this a couple of times now in the 301V mouse it takes eight times as many animals to get the same volume
of blood and it takes twice as many animals to do the titration because you can
only put half as much inoculum in the brain of a mouse compared to a
hamster. So, the cost and logistics go
way up, plus it takes a lot longer for the infections to develop in mice.
So, they are also much more sensitive to blood. Blood is
toxic when it is inoculated IC. The hamster can tolerate it if you do it
right. In the mouse it is much harder
to do and so there are lots of things working against the mouse and for that
reason we have recently passaged through OMV into the hamster just so we will
have access to it but of course by putting it in the hamster that doesn't give
us access to transgenics because so far no one has made a transgenic hamster
though we have been watching that very carefully and then the other thing I
think you should consider is in the sheep model besides these, there are some
serious differences in the behavior of sheep blood and plasma compared to
humans and hamsters. Actually we find the hamster to be a better model for
human blood than sheep even though we use the sheep a lot.
Nevertheless it is going to be hard to quantitate it unless
we have a transgenic and if try to do the Fiona Houston type of experiment back
into sheep when would we ever know whether the experiment is over? What we are
looking for is a negative and a negative result. We don't want the animals to
get infected. Well, do you wait until
they die? Is that 10, 12, 15 years, something like that? They have a fairly
long life span in captivity anyway and so anyway these are some other things
that I think have to go into the planning of this and I think it would be
important for what I would like to see the FDA do which is voice their concerns
in a more general way and give people
as much flexibility as possible in
meeting the requirements that you want to see them meet so that as animal models develop they may converge on this
need or not but basically what we want to do is the best possible experiments
we can whatever they happen to be at a given time.
In terms of two sites I think you are going to have trouble
doing that with sheep. There aren't that many places you can do this. We have a
sheep flock that we couldn't use for this particular application because they
are all infected.
DR. BROWN: That recapitulates the notion that several of us
have already expressed which is the need for two strains, two hosts. Yes, give
people enough flexibility to make their own decisions. As information comes in
one host strain combination may turn out to be the ideal. Mice I think are
certainly as Bob said in some ways, many ways less practical than hamsters. On
the other hand you can get around most of that by doing a spiking experiment
with 301V in the mouse and do an endogenous infectivity experiment in the
hamster and you don't have to wait 2 years when you use high input infectivity
in the mouse and you don't have to collect a unit of blood to necessarily do
the spiking experiment.
So, that would be a sort of reversal that might be
practical.
DR. EPSTEIN: I just wanted to ask the question how
important is it to do an actual transfusion experiment because the advantage of
the large animal model is you can actually transfuse an intact unit into a
whole animal with volume relationships comparable to human transfusion and I
know you certainly can study infectivity with IC inoculations in readout
animals but I think part of the idea
which embedded suggesting a model in sheep
is the actual transfusion experiment
and also you know looking forward to question 2 we are sort of suggesting that
one might stratify efficacy labeling according to whether an actual transfusion
experiment had or had not been done. So, you know the idea of waiting forever
for the result you might be able to approve products with more limited labels
pending a more definitive experiment.
So, I would like to hear opinion from the Committee
specifically on the question of whether an experiment needs to be done with
actual transfusion in a large animal model in order to mimic human transfusion.
DR. BROWN: The goal
is to detect infectivity in blood before and after a process and so you want to
use the technique which is optimum for detecting infectivity. If that turns out
to be a transfusion then yes you would want to use a transfusion experiment but
I think there probably are more optimal ways, more sensitive, right,
sensitivity and one is the transgenic mouse and it may well be that
intracerebral inoculation of smaller volumes in the proper host strain model
will be more sensitive than transfusion
where you know the transfusion is a very sensible method to detect infectivity
in sheep. It is if I am not mistaken, Bob, much less sensitive in hamsters,
that is when you inoculate it in blood intracerebrally you got a far greater
number of takes than when you transfused blood even in larger volume.
So, in that sense transfusion would be less sensitive than intracerebral even if
the volume was smaller.
DR.ROHWER: That is true except that we don't know what the
actual titer was in the sheep blood. That same effect may be present there. It
is just that by giving 500 mls instead of 2 mls you overwhelm it and you don't see it. So, I don't think that
question can be resolved by that comparison.
DR. BROWN: At least
not yet. We just don't know yet, but
the point, the principle is what you want is the most sensitive method using
more than a single strain.
DR. PRIOLA: Any
other comments from the Committee on the comment?
So, if we go on to B is it necessary that each experiment
should be done at two separate laboratory sites I think we sort of addressed
that to ensure reproducibility and accuracy
of clearance. Any comments on that?
I know that this is always an issue in any scrapie lab where you are looking at low levels of
infectivity. Is it a practical issue in this instance?
DR. BROWN: The difficulty is actually in the wrong
direction that is to say if you do get cross contamination you are out of the
business. So, it behooves anybody who
does such an experiment in a single laboratory to be extremely careful and so
there is an enormous motivation to avoid cross contamination if you do it in a
single place.
DR. PRIOLA: And
with appropriate and rigorous controls that is completely doable. I am not so
concerned about the two laboratory sites anyway as long as the experiments are
appropriately controlled.
DR. GESCHWIND: Particularly with that issue of large
animals making it really just impractical.
DR.VOSTAL; I would just like to point out the fact that
when we evaluate things like leukoreduction filters we always ask for two
laboratories to minimize laboratory differences and practices and such.
DR. PRIOLA: It is a
bit more difficult situation in the TSE field because of the specialized nature
of the infectivity and there are very few labs that can do it. So, it might not
be as practical to do that but I see
your point.
Any other comments?
Now, C, is general description of informative scaled down
processes for reducing TSE infectivity in blood and I have got to admit I am
not exactly sure what that means.
DR. VOSTAL; I think we are trying to ask whether scaled
down experiments are acceptable or whether it would be better to do a
full-scale transfusion like in the sheep.
DR. PRIOLA: Anybody
want to hazard a comment?
Dr. Bolton?
DR.BOLTON: Paul actually beat me to it. I guess at some point if you were trying to
certify a particular filter you are going to have to have that particular
device and geometry to run the full unit of blood through it or some
configuration. I don't know how you would do 500 microliters of infected mouse
blood through this thing and get any kind of meaningful answer but as Paul said
there is a lot of experiments that you can do sort of in the preliminary stage
to get a foundation to say that yes, we should go on, but I think eventually
you would have to run the particular geometry that is going to be approved.
DR. ALLEN: I think that there are two components to that.
As Dr. Bolton said you are going to want to make sure that the process runs on
a whole unit of blood.
On the other hand how you analyze it doesn't mean that you
have to then infuse that whole unit of blood in a large animal and follow it
for X amount of time. If you have got another more sensitive or equally
sensitive method of detection and a residual infectivity that should be
perfectly adequate. You do it to assess the process itself in full volume.
DR.BOLTON: And the demonstration of the filter, the product
coming through the filter still has all the appropriate biological
specifications, wouldn't even need to be done on an infected unit. At least in
my opinion you could run a parallel unit on normal uninfected blood that we
would then define the parameters in terms of its blood qualities and separately
test in infected units for the removal of infectivity. Does that make sense?
DR. PRIOLA: Any
other comments?
Let us move on to D which is what are the levels of
clearance acceptable for claims of reduced TSE infectivity in blood components
as used in clinical settings. So, this harks back a bit to what we talked about
this morning. I think Dr. Rohwer showed with his filter he can remove so far at
least as far as he can tell all the massive infectivity he has in his blood
model using an endogenous sample as well as a good chunk of something in a
spiked sample but what would be the clearance that would be acceptable?
DR. BOLTON: Paul, I thought you would jump in here with the
two species, two strains. I am reading your mind but I think you would say
that it depends on the, if you are
doing a spiking study you are going to get one potential level of clearance. If
you are doing an endogenous study you are not going to be able to achieve that
clearance. So, Bob, you have got what 1 log. You could demonstrate 1 log
endogenous. You can't do more than that at least right now.
DR.ROHWER: It is a
matter of how many animals you inoculate but there is a point of diminishing return because the
returns go down as a factor of two actually, but to inoculate a whole unit
would need 10,000 hamsters and I don't think anyone is prepared to do an
experiment like that. So, we do 5 mls.
It is something we can do and occasionally we have gone to 10 mls but
generally you can get an idea of what
you are going to get from that kind of data.
For example, you don't get another log for that. You get another
fraction of a log.
DR. BROWN; The
other interesting thing from one of the presentations is it is conceivable that
a methodology such as we saw from Alicon could concentrate infectivity in assay
experiments so that you could in fact by inoculating, by using a concentrating
device you could get the equivalent of a whole unit of blood in a couple of
milliliters. That is something that might be considered.
DR. PRIOLA: Yes,
especially in combination with the two-mouse model or two-rodent model.
DR. ROHWER: All
these devices by definition are concentrating infectivity in the device and in
our particular case we haven't been able to figure out how to get this stuff
back off without killing it because it sticks so tight, but we are still
working on that and if we can figure that out that is definitely a way you
could go.
DR. ALLEN: As I read the question it is what are the levels
of clearance that should be acceptable for clearance of induced TSE infectivity
in blood components as used in clinical settings. Obviously in clinical
settings you are not going to have anything above endogenous infectivity. So,
you know if using spiked samples you
can show a level of clearance is well above what would normally be found in
endogenous infectivity and in the endogenous experiments that are done you
don't get any evidence of transmissibility it would seem to me that you have
satisfied the claim and I understand that this is all hypothetical. It is a
statistical process. Nonetheless given what we know now I will be reluctant to
accept any evidence that suggested that there could be a breakthrough with or
likely be a breakthrough with endogenous level of infectivity. I would like to
see it well below that.
DR. TELLING: So, the answer is a log?
DR. PRIOLA: You
mean for the endogenous.
Paul?
DR. BROWN: I don't think anybody would be happy with that
and I think your question, well, I said, anybody would be happy; you know, you
are looking for 5 and historically 6 logs of with HIV and a few other
things. Certainly you have to sterilize
endogenous infectivity whatever it is, if it is a log, 1 log, 1-1/2, 2 logs. We
can't have a single particle left. There can be no transmission. Any
transmission from an experiment on endogenous infectivity is a failure. That is
one criterion. I think you can set your own criteria for spiking. We learned
from Marc that according to his model it only requires about 3 logs. I think
that is more than you need but that is what he got. So, he is the expert.
DR. PRIOLA: Also,
this morning we came up with an upper limit of 2 logs. So, from a limit of 2 up
to 100. So, perhaps for a validation study 2 logs would be the upper limit in
this case as well because that should clear everything in the blood based upon
what work has been presented.
DR. BROWN: And that would be my feeling but I know that
that makes other people uncomfortable because they like more margin for error and
there is always this issue of transferring the exquisite care that goes into
the laboratory experiments to the manufacturing scene and so it is not possible just to say, "Okay, in
the laboratory here we get 2 logs and say that that is good enough for the manufacturer," So, partly for that reason I think that
people want a margin of error. So, I
think 3 logs in the spiking experiment might be appropriate.
DR. ALLEN: Yes, one would like to see a reasonable
significant margin of error. I think it is easier to get rid of that first 99
percent than it is to get rid of that last 1 percent or the last 1/10 percent or 1/100 percent. So, to get to the
point that you have sterilized, you know one of my mentors when I was much
younger always, "Sterility is actually a theoretical concept. You can
never guarantee it," and you try to set up a process that goes well beyond
whatever would be detectable in a clinical situation and I think that is what
we would like to do here.
DR.BROWN: And the other thing that I would emphasize is
that almost simply as important and
possibly more important than defining a minimum with a margin of error is
requiring absolute guaranteed reproducibility in test after test after test and
only in that way can you get a feel for whether or not your margin of error is
satisfactory.
DR. LEITMAN: So, this whole process tends to put a lot of
responsibility on the manufacturer. For leukoreduction filters the blood center
validates and does quality control very easily because the readout is so
simple. It is a flow white cell count or something like that but the blood center here, that is where
this will be used and the surface service won't have the tools to do the
correct readout. So, they can't validate their process really. So, I had a little
difficulty with that because everything you perform as a manufacturing step we
can do a quality control on but not this.
DR. PRIOLA: Perhaps
that is another reason for having it done at two independent laboratories, the
manufacturer and somebody else to basically back the manufacturer up or not by
doing the same studies. Would that be better? You would never be able to do it
at the local level. There is no way unless someone comes up with a surrogate
easily detectable marker and even then it might be questionable.
Dr. Weinstein? Oh,
I am sorry, Dr. Vostal?
DR.VOSTAL: I just want to ask when you do an endogenous
infectivity experiment do you do a leukoreduction on that product first and
then process your product through your device or does leukoreduction become
part of that, the accounting of the
infectivity from start to finish?
DR. COKER: From
what we are doing at Pall there was no leukoreduction prior to doing the
filtration. So, the whole blood is actually not leukoreduced at all.
DR. ROHWER: In terms of PRDT device it is not a
leukofilter. It is a light and it binds PrP specifically and it will only
remove from plasma. There is no claim
that it would remove cell-associated infectivity. So, this device would be
docked below the leukofilter in a collection scheme and will be an add on and
in terms of evaluating what these things do it is important I think to get an
idea of whether it removes from plasma, whether these devices remove from
plasma or not because basically I think
that is the residual risk we are trying to get rid of. We already know the
leukofilter will remove white blood cells and we can get rid of that risk with
the leukofilter and so in terms of figuring out what these things actually do
and whether they actually work I think it is important to test it against the
residual plasma component.
DR. PRIOLA: So, D
and E sort of go together in a way. It is all about levels of clearance, the
first in blood components in clinical settings and the second to conclude that
blood filters have effects with related infectivity from those blood
components. So, does the Committee have kind of a consensus as to what that
range of clearance is then? Are we talking as we did earlier this morning about
spike being a really good way to show high clearance and then doing it with
endogenous infectivity as well?
DR. BROWN: Yes, I think there is a consensus. I think
everybody agrees that sterility of an endogenous infectious sample is mandatory
and I don't know we might leave it up to the FDA folks in attendance to make
their own decision about what kind of level of concentration of infectivity
represents something that they are comfortable with. We certainly had a lot of discussion about it this morning and
whether it is 3 logs or 2 logs or 4 logs maybe it is best that they decide. I
doubt that we are going to be able to make the decision here.
DR. PRIOLA: I think
that is exactly right. We are not going to come up with a bottom line here for
this.
So, I think the final point that they would like us to comment
on is the methodology appropriate to use in evaluating TSE agent clearance and
we heard this afternoon that they start with Western blot and then move to
bioassay and I know my opinion is always the bioassay has to be in there before
anything is approved because that is the most sensitive technique so far.
Dr. Brown?
DR.BROWN: In terms
of reproducibility you can design a spiking experiment and do 100 spiking
experiments and use a Western blot. That is okay. You can't do 100 bioassays.
That is unreasonable but you could do one or two bioassays to complement and
you could use Westerns for reproducibility and the bioassay as the most
appropriate test for what you are looking for which is transmissibility.
DR. PRIOLA: As long
as your Western blots are reproducible, right.
Dr. Telling?
DR. TELLING: Along those lines we heard about almost 3 log
reductions based on Western blot and what is the dynamic range of that assay?
DR. COKER: It is between
about 1 log and 3 logs. So, 3 logs is about the maximum.
DR. TELLING: So, how do you know that you are going to get
3 log reduction if you are at the limit of your --
DR.COKER: I don't
understand. Do you mean for the endogenous?
DR. TELLING: Three logs is your limit. You are saying that
that is what you are achieving. How do you know that you are not --
DR. BROWN: The best Westerns that I know of were done by
Bayer and on a good day they could detect close to 2 logs of infectivity. So
the 3 log minimum threshold is sort of your everyday best. So, you certainly
have to if you want to demonstrate 3 log reduction of infectivity using a Western blot as a marker you have to start
with 6 logs and then if you get nothing in the filtrate you know you have got
at least 3 logs. You might have more but you know you have got that.
DR.ROHWER: Considering this is another complication and
that is that doing a Western blot out of plasma is almost the most difficult
challenge you can present a Western blot with, so you have to do some sort of
preprocessing in order to get a signal in the first place.
DR. PRIOLA: Yes, maybe the Western blot would only really
work well with the spiking experiments.
DR. GESCHWIND: I just had maybe a point of clarification.
Are we leaving open the option of tests other than a Western blot just checking
that there are tests that are currently out there and tests that have just been
presented in Dusseldorf that are certainly more sensitive than the standard
Western blot; so, I want to make sure that we are not restricting it to the
Western blot.
DR. PRIOLA: You
mean like CDI or PMCA or something?
Yes, I am sure we are not
restricting it.
Dr. Creekmore?
DR. CREEKMORE: It actually says, "Or other assay for
serum proteins."
DR. GESCHWIND: And
we are also in the bioassay. Is there
another question about biomarkers or is that a separate question?
DR. PRIOLA: I don't
think that, but go ahead and comment on the biomarkers.
DR. GESCHWIND: Just
from the clinical side and seeing the biomarkers that have been touted for the diagnosis I am very worried about the
use of biomarkers when we actually have
the actual protein itself or the
disease, the bioassay. So, I just would say that I am against the idea right
now of biomarkers particularly because of the difficulty with reproducibility
between lab to lab. I think we should really go down that path with great
caution.
DR. PRIOLA: I think
it was Dr. Turner who presented some data that they might have a couple of
proteins in plasma, but I agree that really has to be validated and
studied very hard.
Dr. Allen, did you have anything you wanted to say?
Bob?
DR. ROHWER: Marc,
please correct me but my understanding is that the idea of using the biomarker is simply to get a way of routinely
testing whether the thing is working at all, you know, are there holes in it,
that kind of thing and if you have a biomarker protein that you know also binds
to the device you can at least assay for whether it is being removed. If it is
easier to assay for it then the PrP protein and the idea is to do that on a
routine basis to make sure that the device is working.
DR. PRIOLA: Just
for reproducibility, yes, although I still think it would be nice to someday
have another biomarker for TOC here but I would like a lot of things.
Any other comments from the Committee?
Should we vote on this issue? Are the FDA's proposed
minimal criteria -- we are not voting?
DR. FREAS: We are
not voting on this issue.
DR. PRIOLA: We are
not voting on this issue. So, we have had a discussion. Would the FDA like us
to have any other thing they would like to mention or point out or have us
discuss?
DR. EPSTEIN: I guess we would like a vote overall whether
we have the right set of criteria.
DR. PRIOLA: Okay,
so we will vote on do they have the right set of criteria given what has been
discussed this morning and this
afternoon. Are the FDA's proposed
minimal criteria for validation of TSE infectivity reduction by filtration
adequate and appropriate?
Do we have a slide of that?
So, again, these are the minimal criteria.
I don't know if they have to delete the sheep but I think
the point is just to have two animal models, or one that might be applicable to
transfusion experiments and that would be sheep if they can do it.
DR. BROWN: Susan,
yes, I think rodent and sheep should probably be excluded.
DR. PRIOLA: Just
two animal models in general.
DR. BROWN: Two animal models and I would in that first one demonstrate elimination not reduction.
We were just talking about that. If you can only reduce a log and one-half you
are not in business, okay? So, it is the elimination of endogenous TSE
infectivity and then reduction of spiked infectivity.
DR. CREEKMORE: I agree with that and then also in our
discussion about the two separate sites how does the Committee feel about that?
It seemed like if there were adequate controls that the two separate sites
weren't that critical.
DR. PRIOLA: That is
what I would think. I mean I agree with that but apparently with other
infectious organisms the FDA requires that. So, it might be nice and then Dr.
Leitman brought up that it would be another way to validate the manufacturer's
claims to have it done independently but I agree. I don't think it is
essential, but Glenn, did you have a comment?
DR. TELLING: Basically only to underscore your earlier
comments that if these are adequately controlled and from reputable
laboratories then I wouldn't have any problems from one location.
DR. BOLTON; I recall going through this once before some
years ago but it seems to me that we are in fact rewriting the criteria that we
are asked to give. The question was whether or not we thought that they were
appropriate and adequate and it seems to me that we have decided that they are
not appropriate and adequate and we are not rewriting them. Which would you prefer? Do you want us to rewrite them or do you want us to just
tell you what we thought about the original ones?
DR. VOSTAL: I think we already know what you thought about
the original ones. I think any comments are very helpful and if you care to
rewrite them for us that would be helpful in itself.
DR. BROWN: We are
not doing a whole lot of rewriting. We changed a word and eliminated a
parenthesis. That is not bad and if you want to eliminate necessity to perform
the study at two different sites it seems to me there is a kind of a sense
around the table that that would be okay as well but since we are talking about
minimums it could also be left in.
DR. VOSTAL: The concern we have is that if we get data from
a manufacturer who has had 5 years of perfecting their procedure we are always
wondering whether that will work in somebody else's hands and I think that is
what Dr. Leitman was trying to point out.
DR. PRIOLA: And
that is a very valid point because we have had that experience in the research
field where you can't replicate what somebody does.
Yes, Dr. Turner?
DR. TURNER: That is exactly the concern we had in the UK
which is exactly the reason we are
going down the road of commissioning our own independent validation
studies.
DR. ALLEN: The third bullet point that requires TSE
infectivity from BSE or vCJD, I assume that would be spiked experiment?
DR. PRIOLA: That
would presumably be along the lines of what Dr. Brown said which is 301V. It is
the rodent version of BSE, yes, and that could be spiking.
DR. BROWN: And the study performed at two separate sites,
what you might want to do is just add since apparently the real reason is
indicate that this is a test which is doable in more than one place which is
neither an issue of cross contamination or maybe even differences but we might
want to reword differences in laboratory practice and just indicate reproducibility
in different labs.
DR. COKER: I just
have one comment on that. If the manufacturer decides to use to do the tests
well then will they be required to use another contract lab because most of the
manufacturers or some of them do not do the studies in house? They actually contract it out. So, if you are
requesting two sites that means they will have to have two contractors doing
the tests.
DR. PRIOLA: So,with
the modifications that have been made to these bullet points does the Committee
feel comfortable on voting?
DR. GESCHWIND: There is only one thing. The infusion aspect
doesn't seem to be put in there that there has to be a model.
DR. PRIOLA: You
mean the transfusion?
DR. GESCHWIND: The transfusion or is that No. 2 where there
has to be a model in which you are infusing a unit.
DR. PRIOLA: I think
that is why sheep was originally up there.
DR. GESCHWIND: Right, but I thought we had taken that out.
DR. PRIOLA: Okay,
rodent, sheep or other model.
DR. BRACEY: I
thought we changed it to say that the key point was demonstrating lack of
infectivity.
DR. PRIOLA: Yes,
elimination.
DR. BRACEY:
Elimination of infectivity so that we weren't really, we were requiring
the process of an entire unit but not infusion of an entire unit.
DR. PRIOLA: Any
other comments?
Shall we vote?
Oh, sorry, Bob.
DR. ROHWER: I have a question for Paul. Paul, I am not
clear on what you mean by demonstrating that there is sterility in a unit
because right now we don't have, endogenous sterility in a unit because right
now we don't have as far as I know the capability of doing that unless we do a
transfusion in sheep in which case we could but it would take years to know
whether the sheep is actually transmitted or not especially if we are looking
at very low individual titers and so, I see a practical issue here that needs
to be considered.
DR. BROWN: You used a full unit in the hamster.
DR. ROHWER: Yes, but we only measured 5 mls of blood for
that unit.
DR. BROWN: But that represented a unit for a hamster, more
than a unit.
DR. ROHWER: Oh, that is more than a unit for a
hamster. Is that what you mean? That is
what I want to get at. Is that what you mean?
DR. BROWN: Yes,
right.
DR. PRIOLA: Dr.
Epstein?
DR.EPSTEIN: This is the very issue I was trying to raise before in other words if a
whole unit in a human might contain 5000 infectious units and if the processed
leukoreduced unit still might contain 2 or 3 thousand infectious units and then
you only do an assay on a few milliliters then you do not have the ability to
assure that you have sterilized the unit. If the residual infectivity were for
argument's sake 20 or 30 infectious units then at any feasible volume studied
in a rodent model you could not exclude a residual infectivity of a whole unit
and in fact that is --
DR. BROWN: Of a whole human unit, but that is what we are
saying.
DR. EPSTEIN: But how else will you model filtration of a
volume which may contain endogenous infectivity of 5000 or 3000 IU? This is precisely the dilemma and that is
why we have stratified two potential labels. One potential label says that the
filter has been shown to reduce the infectivity. The other label essentially
says that it has been shown to remove the infectivity of the transfused unit
and we understand fully that you can't get to that second endpoint without
either waiting a long time or some advancement in the experimental models but
we are not really comforted that showing logs reduction in a scaled down model
shows that you have eliminated endogenous infectivity and that is precisely the
point.
DR. BROWN: I couldn't agree more with you, Jay but we can't
figure out how to do the experiment or we would do it.
DR. BOLTON: You
know how to do it, 10,000 hamsters.
DR. ROHWER: I agree
that I do know how to do the experiment but I despair of talking anybody into
doing it.
DR. EPSTEIN: But
the endpoint may be that we get to labeling A and not labeling B because the
end point isn't that we can't review claims for filters. The issue then becomes
what exactly is the claim that has been supported by that experiment.
DR. BOLTON: You could achieve the first bench mark by a
spiking and clearance study or the hamster endogenous study maybe, but the
second bench mark you would have to meet by say for example doing a sheep
transfusion study or
a 10,000 hamster study or
something that would end up being equivalent to examining an entire unit of
blood.
DR. TELLING: But even in the sheep transfusion study a
negative result wouldn't necessarily give you the confidence that there was no
infectivity in that blood.
DR.BOLTON: There would have to be more than one sheep. What
would be the statistical number? I don't know that anybody is going to do that
study to get that second label.
DR. PRIOLA: Because
you have to determine the level of sensitivity in sheep.
DR. BROWN: Of course, you could also use a filter with a
T-median level column, I mean do a real scale down which is actually a serious
problem in terms of people being comfortable with X degree of scale down or Y
degree of scale down as opposed to the real thing and you can never do the real
thing. You can't do an experiment on 10,000 pints of plasma. So, it is a
question of degree and I have to say
that personally I am comfortable in seeing a reduction of a concentration of
whatever is in endogenous infected blood whether it be 10 or 30 or 50
infectious doses per ml eliminated in a reasonable number of mls to say that I
have sterilized, I mean just as a
practical matter as we have just been talking about.
DR. PRIOLA: Any
other comments?
Okay, let us move to the vote, keeping in mind what has
just been said and we have proposed slight modifications to those bullet
points.
Let us vote yes or no to are the FDA's proposed minimum
criteria for validation of TSE infectivity reduction by filtration adequate and
appropriate.
MR. BIAS: I think we can just state what has been modified.
DR. PRIOLA: Okay,
good point. So, the modifications as I remember them were to demonstrate
elimination and to take out rodent and sheep. Do we still agree for that first
bullet point? Do we still agree with that?
MR. BIAS: Are there two animal models that are okay if we
are taking out rodent and sheep?
DR. PRIOLA: I think
we just leave it to the FDA. I mean we can leave that open. You don't have to
constrain the animal models. I think that was the idea.
DR. BOLTON: I think Paul's suggestion was two different
species, two different strains.
DR. PRIOLA: Yes,
but that is getting, I mean stili that is two animal models or more than one
animal model. So, I don't think we have to get that specific.
DR.BOLTON: Would you accept mouse scrapie and hamster
scrapie? I am trying to figure out are
you going to select --
MR. BIAS: I am sure they will but are we sure they are
going to select an animal model that
applies?
DR. BROWN: I think it is probably important to specify two
strains, two hosts rather than two animals because you could. You know, you
could study two different strains of scrapie and you could study two different
strains of scrapie in mice and that wouldn't be adequate in my opinion.
DR. PRIOLA: So, two
strains, two hosts in those parentheses instead of sheep and rodents, two
strains, two hosts.
Okay, was there another? Now, I can't remember if there was
another modification. The two
sites? Do we still want the two
separate sites? Oh, to minimize issues of cross contamination and
reproducibility, so to take out differences in laboratory practice.
DR. BROWN: You could even depending on how the Committee
felt include the word "preferably" after the word "study."
DR. PRIOLA:
Preferably performed to give them some leeway.
DR. TELLING: So, a
clarification, implicit in what one of those combinations of animal, host and
strain will be is bullet point No. 3, question mark. So, one of them should be BSE or vCJD.
DR. PRIOLA: Right.
DR. BROWN; The other point here is that I see nothing on
this slide about a spike experiment.
DR. PRIOLA: There
is a recommendation, that is right, for the first one. So, you had recommended
demonstrate elimination of endogenous infectivity and reduction of spiked
infectivity going back to the two approaches by 3 logs.
DR. TELLING: Again, that is implicit in bullet point No. 4
because the only way you would be able to detect the scrapie is by spiking,
right?
DR. PRIOLA: Right.
Lynn, did you have something you wanted to add?
DR. CREEKMORE: Just that with the point that Glenn was
making about the TSE infectivity from BSE or vCJD strain it doesn't say
endogenous versus spiked. So, it doesn't connect back to that demonstrate
reduction of endogenous because they could choose to do a spiked experiment for
that.
DR. BROWN: Susan, I
think you have to have a bullet in here. Either put it in as a first
sentence on bullet point 4 or add
another bullet but you have to mention explicitly a spike experiment. You can't
just leave it implicit in the PrP bullet.
DR. PRIOLA: We can
add it to the first one, reduction in spiked infectivity and that will take
care of that.
So, it is starting to get a little bit confusing. So, I
just want to make sure. You know, I don't want to get stuck on this for the
next 20 minutes. So, the modification of the first one is elimination of endogenous TSE
infectivity or reduction of spiked
infectivity, and, excuse me, and reduction of spiked infectivity by 3 logs in
animal models, two strains, two hosts. We can't give this detail. The 301B is
implied. It is definitely implied in TSE infectivity from BSE or vCJD strain, I
am sure. So, I think that is okay. Then the other change was bullet point 5 and
that is cross contamination and reproducibility. Is that correct?
Okay, so, let us go ahead and vote on this issue.
DR. FREAS: We will
go around the table.
Dr. Bolton?
DR. BOLTON: Yes.
DR. FREAS: Dr.
Johnson?
DR. JOHNSON: Yes.
DR. FREAS: Dr.
Telling?
DR.TELLING: Yes.
DR. FREAS: Dr.
Creekmore?
DR. CREEKMORE: Yes, amended.
DR. FREAS: Dr.
Hogan?
DR.HOGAN: Yes, as amended.
DR. FREAS: Mr.
Bias?
MR. BIAS: Yes, as amended.
DR. FREAS: Dr.
Allen?
DR. ALLEN: Yes.
DR. FREAS:
Dr.Priola?
DR. PRIOLA: Yes.
DR. FREAS: Dr.
Geschwind?
DR. GESCHWIND: Yes.
DR. FREAS: Dr.
Brown?
DR. BROWN: Yes,with the modifications.
DR. FREAS: That is
unanimous, yes, with modifications.
DR. PRIOLA: All
right, the final thing that we have been asked to address is -- is this a
voting question as well? I am sorry I
don't know. Is question 2 on top of 2 a voting question? It seems like it
is. It is, okay.
So, does the FDA's proposed labeling for a filter meet the
appropriate criteria for a claim of reduction of TSE infectivity in blood or
blood components and we have already
gone through all this I think with the first question.
So, this filter has been shown to reduce TSE infectivity in
blood from an infected animal model plus C, right?
DR. FREAS: Right,
that is the disclaimer that goes along with it.
DR. PRIOLA: And
that disclaimer goes with both or if you get a transfusion model the label
would be B.
DR. JOHNSON: Shouldn't it say it has been shown to
eliminate? We already said that in the
other.
DR.BOLTON: No, because the spiking experiment won't necessarily --
DR.JOHNSON; Or reduce by 3 logs.
DR. BOLTON: That is going to be too confusing.
DR. PRIOLA: I think
maybe David is right that since we have reduced for the spiked reduced would be
better there. Does anybody have any
major objections to the way these labels
are phrased?
DR. BOLTON: No major objections. I just would point out
that phrases like infected animal model I am not sure what that means tot he
general public. So, some thought maybe could be given to what phrases of those
type mean the most to people.
DR.JOHNSON: The general public won't be buying filters.
DR. PRIOLA: Let us
go ahead and I don't sense any major problems with this. So, let us go ahead
and vote on this final question.
DR. FREAS:
Dr.Bolton?
DR. BOLTON: Yes.
DR. FREAS: Dr.
Johnson?
DR.JOHNSON: Yes.
DR. FREAS: Dr.
Telling?
DR. TELLING: Yes.
DR. FREAS: Dr.
Creekmore?
DR. CREEKMORE: Yes.
DR. FREAS: Mr.
Bias?
DR. BIAS: Yes.
DR. FREAS: Dr.
Allen?
DR. ALLEN: Yes.
DR. FREAS: Dr.
Priola?
DR. PRIOLA: Yes.
DR. FREAS: Dr.
Geschwind?
DR.GESCHWIND: Yes.
DR. FREAS:
Dr.Brown?
DR. BROWN: Yes.
DR. FREAS: Again, a
unanimous yes with nine people voting,
I believe.
DR. PRIOLA: Okay,
that I think, thank you all very much for your patience. I know it has been a
very intense day and this meeting is adjourned.
DR. BROWN: Sue, congratulations. In 5 years as Chairman I
never had a clean slate of unanimous votes at a single meeting.
DR. PRIOLA: That is
because of the participants.
DR. FREAS: I do
have one more announcement regarding Dr. Alan Jenny. I received this message.
The services will be held Tuesday, November 1, at 1:30 p.m., at the Starkwellin
Funeral Home, 609 7th Street, Boone, Iowa, and memorial contributions will be
accepted in Dr. Jenny's name for the local Ike's(?) Club for Conservation, and
if you need more information, please see me.
(Thereupon, at 5:50 p.m., the meeting was adjourned.)