TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE
October 31, 2005
Holiday Inn Bethesda
Bethesda, Maryland
SNIP...
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.
snip...
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.
snip...
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. ...
snip...
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
snip...
http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4189t1.htm
==================================================
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. ...
snip...
============================================
Greetings,
I would not agree here and would further like to state that as a 'consumer' spokesperson on this committee, Florence Kranitz does NOT speak for me. I think more of us can differentiate between mad cow and sCJD than they might think, the problem is, the officials on this very committee cannot differentiate between the UKnvCJDBSE only theory and the truth. To keep this information from the public is wrong. I AS A CONSUMER WANT TO KNOW! What gives Florence the right as a consumer to know and me or any other not to know? WE know BSE has been in the USA. WE know the June 2004 Enhanced BSE surveillance was nothing more than a surveillance system to hide any BSE and they could not even get that right after 7+ months of trying, the Honorable Phyllis Fong of the OIG proved Johanns wrong and have that negative proven postive. OF course they did manage to screw up another one without using WB and THEY did cover-up another mad cow in TEXAS, then admitted they screwed that up (FDA website). IN fact, i question the whole 500,000 plus cattle tested in the June 2004 Enhanced BSE cover-up. THE only cow we have proven was negative IHC and only proven positive with WB. NO WB were used on the 500,000 cattle in the Enhanced June 04 cover-up, except the one the Honorable Phyllis Fong made them retest, that i am aware of. IN FACT, of those same 500,000 cattle, 9,200 did not have either rapid test OR WB, only IHC, the least likely to find it. WE know Marsh et al had proven a strain of TSE was in USA cattle long ago, via TME and the feed source there i.e. 95%+ dead stock downer cattle feeder. WE now have other strains of TSE in cattle BASE that is not similar to nvCJD but very similar to sCJD. WE know in the USA, when US scrapie are fed to cattle, it does not look like the UKBSE in the infected cow. WHAT about GSS infectivity in blood? WHAT about CWD? THE myth that Scrapie does not transmit to humans is another myth. SCRAPIE in sheep will transmit freely to primate by it's non-forced ORAL consumption. FOR the ones that know this, WHY ARE WE BEING CALLED AS TOO STUPID TO HAVE THE TRUTH TOLD TO US (in a nicer way this time) $$$ maybe because some of us would question there rule making? they could not have this! many of us are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map." I remember the mothers being called to stupid once before at one of these TSE committee (see below). I may not have a PhD, but if i have been exposed to this agent (which i have in more ways othan one), i want to know about it immediately. enough secrecy already!
Subject: VACCINES and CJD -- FDA says Mothers to stupid to understand... 7/27/2000 TSE Advisory Committee
Date: Tue, 19 Sep 2000 11:12:39 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: [email protected]
######### Bovine Spongiform Encephalopathy #########
Greetings List Members,
"Ninety million Americans are either marginally or low literate, meaning
they can't understand a bus map or can't understand a bus schedule or
locate their intersection on a map." We can't communicate with the same
message to them that we might communicate to people who are making
vaccine decisions at the state or county or other levels."
But I think the Mothers are smart enough to know, that the scrapie
agent has been the model for CJD research since day one. So, I think
the Louping-ill vaccine and Scrapie episode, which killed many sheep,
from a vaccine made from scrapie-infected brain, is most important,
and I think these Mothers are smart enough to understand that...
Louping-ill vaccine blunder.....
http://www.vegsource.com/talk/madcow/messages/7634.html
Transmission of CJD from Blood and Urine Into Mice.....
http://www.vegsource.com/talk/madcow/messages/7650.html
kind regards,
Terry S. Singeltary Sr., Bacliff, Texas USA
===========================================
TSE Advisory Committee 7/27/2000
259
I feel the need to say something. It's theoretical. I agree with your
sense of how often it's going to occur totally. What could we do? What
could they do?
DR. SNIDER:
This is Dixie Snider. Yeah, we can hear from him, but you made a
criticism of my comment, and I just want -- I thought it might be useful
to have something to go along with their U.S. Today story that they were
reading. That's all. Something that's authoritative from the FDA.
CHAIRMANBROWN: I'm glad I'm the Chairman of this committee, not this
committee.
DR. RATZAN: If I could try to answer that, there is a scientific
nature to how do you look at communication. You don't overreact to
infinitesimal risks, and at the same time you don't under-react when
there is a real risk that's involved, because that does undermine the
public trust.
What I heard today were some of the steps that were being taken by some
of the manufacturers, the two that presented, that they are trying to
embody the public trust in terms of their processes. I think more of the
open nature, even meetings like this of being able to have advisory
meetings, meetings also that might have the professional associations
where you have opinion leaders who might be able to defuse the
information appropriately.
A blanket communication -- We often say Marshall McCluhan, a Canadian
scholar in media, said, if you try to reach everybody, you reach nobody.
By doing that, it's really key in thinking about communicating with the
people that need to know.
Ninety million Americans are either marginally or low literate, meaning
they can't understand a bus map or can't understand a bus schedule or
locate their intersection on a map. We can't communicate with the same
message to them that we might communicate to people who are making
vaccine decisions at the state or county or other levels.
So I'm answering in a circuitous way, because I think we've heard some
of the right steps being taken today, the open hearing, some of the
voluntary efforts that are being done in good faith by the
manufacturers, and some of the other ways that continue to monitor the
open disclosure. I think the surveillance systems that we've put in
place not only here in the United States but now abroad in looking at
BSE and looking at the CJD that we heard from CDC and others where the
numbers are.
So I would say, by all means, keep the surveillance. Keep the voluntary
efforts. Continue to focus upon the science, and communicate that
appropriately on, whether it's a quarterly basis, or use the different
channels, the Institute of Medicine channels that are out there.
I think there's a variety of different expert committees as well.
So, thank you.
CHAIRMAN BROWN: Thank you very much. Yes?
MS. FISHER: You may not want to communicate this theoretical risk to the
public, but that doesn't mean it's the right thing to do. I think that
part of what the National Childhood Injury Act of 1986 was all about,
the safety provisions, was communicating risk to parents before they get
their children vaccinated.
I think that, you know, the FDA's charge is to ensure the purity and
potency of vaccines. It seems to me that the least that we can do at
this juncture when we know something is to let the people know we know,
rather than keeping it from them.
CHAIRMAN BROWN: Hold on, Dave. Shirley?
MS. WALKER: There's an old German proverb, "Don't point the devil on
the wall; otherwise, he will jump off." I think the devil has already
jumped off.
The inserts in the packets for pharmaceuticals are great. Notification
to the doctor is great. But I represent something like 79,000 mothers
who have children in Dallas County who we actively promote to get
vaccinated.
So Monday morning when I go back to work, I'm going to have to tell
someone, a percentage of these young mothers, that, hey, your child is
at risk for whatever that minute amount is for CJD. So what do we do at
this particular point? Do we remain mute and say nothing or do we
promote and give some type of information?
So I am saying to FDA that we do need some kind of general information
that we can impart to our constituents.
CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more
comments in this discussion, and then in the event that a number of
people on the committee may have to leave, there are two or three very
specific questions that the FDA would like some discussion-on, and I
want to move to them. We've touched on some of them already, but if
there's anything more to say on this -- Yes, go ahead.
263 DR. STEPHENS: I guess I'm really concerned that this discussion is
kind of spinning out of control in terms of the risk. I must agree with
the consumer advocate who spoke a minute ago --
CHAIRMAN BROWN: Dr. Ratzan.
DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a
duty, in my view, to protect the vaccine system in this country. I think
that this discussion has gotten to the point of at least suggesting that
we believe that this is a significant problem. The data suggests that
the risk is in the billions, that there have not -- there's not been a
single case of new variant CJD in this country,
despite the use of vaccines manufactured in this way for years.
So I think the issue is we need public disclosure. That's not the
question. I think we all are in agreement on this committee, but I think
to emphasize this point where you're concerned about going back to your
group of mothers and saying there's a risk -- I think that's something
we don't want to send. That's a message we do not want to send.
CHAIRMAN BROWN: I opened this whole seminar with the notion that we're
starting from a very, very small amount of infectivity, if there is
any, and that there is a tradeoff between, as several people have said,
a theoretical risk and a real risk, which would be discrediting in some
way vaccines or causing vaccine shortages or difficulties or refusal to
get vaccines.
In other words, this is the tradeoff. Right at the outset, this was the
scene that I hoped to set. But you're right. All of our committee
discussion meetings tend to spin out of control at about this time of
the afternoon, and sometimes it's in one direction, and sometimes
it's in another direction.
I think the word risk has enlarged as the afternoon has progressed, and
maybe we should shrink it down a little bit and get a little better
perspective or a little different perspective. So I tend to agree with
you. Let me --
DR. BOLTON: Paul, can I get in my comment?
CHAIRMAN BROWN: I'm sorry? Go ahead.
BOLTON: I agree that it would be important to communicate known risks or
even good estimates of risk to the public, but I'm not sure what
that estimate would be at this point. I don't think that we really have
enough information to communicate to the public and have it be
meaningful and not simply scare people away.
I can't imagine the negative impact on the program in this country if
parents started thinking that, if I vaccinate my child, he or she may
come down with new variant CJD.
To me, the other way that we communicate is by action. It seems to me
that there are actions that can be taken in terms of looking at the
process of vaccine manufacture and where the real -- the greatest of the
theoretical risks are. It seems to me that the viral/bacterial master
seeds are really at the very lowest end, as are the master cell banks,
and also trying to change those creates the biggest problem.
>From that point on, from the working seeds on down through production, I
think that the manufacturers have issues that they can address in terms
of removing the use of at-risk bovine materials from that point on.
I guess my question to anybody at the FDA is: Are at-risk bovine
materials currently in use at the -- certainly from the production step
on, and even at the production of the working seeds and working
cell lines, are they in use now, and how long before they will be phased
out?
CHAIRMANBROWN: I guess what you're -- to add to that, are the sources of
anything currently coming from BSE designated countries?
DR. STEPHENS: When I say at risk, I really mean those bovine materials
are coming from Europe or at-risk countries.
CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --
DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines
there was bovine derived fermentation media where that skeletal muscle
and pancreas derived from several European countries.
I think it was Germany, Denmark, Poland, the Netherlands.
CHAIRMAN BROWN: Right. So they are currently in use in this country.
DR. EGAN: They have all agreed to -- That will be changed, but as I
mentioned, by the time -- You know, they've gotten new sources, but that
comes into new vaccines -- What?
DR. BOLTON: Is that the only material that's now sourced from at-risk
countries?
DR. EGAN: That's used in the production. I think I also mentioned hemin.
I think that was it, but I'd have to go back to it.
DR. BOLTON: So I guess my recommendation would be that the FDA work with
the manufacturers to set a definite timeline to phase out all those
materials. In terms of the master virus seeds and the bacterial stocks
and the master cell lines, I think that the risk is so small as to be
really counterproductive to try to change those, because the risk of
changing the product by changing those is much, much greater than any
risk that there would be from proceeding.
CHAIRMAN BROWN: One of the questions that the FDA specifically wanted
some judgment on was: Is it necessary to re-derive bacterial master
seeds? I mean, I'm getting the sense -- Every time I get the sense of
something, the sense changes. You know, we had a consensus about
informed consent, and now we have a consensus about not smother it, but
be awfully, awfully, awfully careful.
Now I thought we had pretty much decided that, at least for current
products, that it will not be necessary to re-derive bacterial master
seeds. That was my sense. Dr. Huang?
DR. HUANG: I completely agree. I think that the derivation of new master
seed stocks would be more dangerous than this perceived danger that we
are facing now.
CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ
from that opinion? All right. We have answered one definitive question
that the FDA wanted to asked.
They also want an answer to a question I think should be very easy to
answer. That is: Is 1980, form all that you have heard, an appropriate
cutoff date before which one need not worry about anything in terms of
sourcing of the products we are talking about?
We always worry about something, but 1980 -- is that an appropriate date
before which not to be concerned? That's a pretty focused question. Is
there anybody that feels that one should be concerned
about products produced before 1980 from anywhere? Yes?
DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect
to our blood donation pool in the United States,'we were concerned about
BSE and started with 1980.
CHAIRMAN BROWN: It has the merit of consistency as well. All right.
That's two questions.
The third question they were concerned about was: Do we think that the
small amount of fetal calf serum from the U.K. around 1985 used in the
production of master cell banks constitutes a negligible or -- well, the
phrase was "a negligible or a significant risk"? Again, a question about
fetal calf serum, sourced from the U.K. in the middle of the
1980s, use in the production of master cell banks constitutes any kind
of significant risk? Yes?
DR. CLIVER: May I start by saying negligible. We'll see if anybody
disagrees.
CHAIRMAN BROWN: Do I hear significant? Negligible?
[[[sounds like a damn auction...tss]]]
DR. BOLTON: I agree that it's negligible.
CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used
for the production -- just for this specific purpose, used in the
production of master cell banks? Well, that answers the three questions
that you most wanted some judgment on Dr. Ewenstein?
Dr. EWENSTEIN: There was also the products that are still under
investigation. I think, you know, we should address that. I think one
of the comments before was, I think, right on the point. That is that
it's different if you have a licensed drug or product that
has, therefore, documented benefit versus recruited volunteers.
I think we should think about what we should answer for number 3. I
think that it's appropriate to include again, with the correct caveat,
about theoretical and negligibly small risk in a consent form. but I
certainly wouldn't like to see all clinical trials stopped of such
vaccines.
CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We
haven't touched on that, and we might just continue that discussion a
bit. Peter?
DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him
correctly. I think that it is indeed a different situation. For one
thing, not only is the benefit of the vaccine unknown, but for
another, one actually does know the name of the patients, and
one is personal contact with those patients on a semi-regular basis.
I think that the ethical responsibility toward those people is quite
different than is owed to the population at large......
FULL TEXT AT URL BELOW PDF FORM (about 79 pages)......TSS
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3635t1c.pdf
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
1: Transfusion. 2003 Dec;43(12):1687-94. Related Articles, Links
Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy.
Cervenakova L, Yakovleva O, McKenzie C, Kolchinsky S, McShane L, Drohan WN, Brown P.
Jerome H Holland Laboratory for the Biomedical Sciences, Red Cross, Rockville, MD 20855, USA. [email protected]
BACKGROUND: The possible transmission of variant CJD (vCJD) through blood transfusion or use of plasma-derived products prompted this study comparing infectivity in murine models of vCJD and Gerstmann-Straussler-Scheinker (GSS) disease, a non-vCJD form of transmissible spongiform encephalopathy (TSE). STUDY DESIGN AND METHODS: RIII/Fa/Dk (RIII) or Swiss-Webster (Swiss) mice were inoculated intracerebrally (IC) with mouse-adapted strains of vCJD or GSS (Fukuoka-1) of similar infectivity. Groups of RIII mice were euthanized 17 weeks after inoculation (during the incubation period), and another 23 weeks after inoculation (when symptomatic). Blood was collected, separated into components, and inoculated into groups of healthy mice; brains and spleens from all mice were harvested and tested for the presence of PrPres by Western blot using 6H4 MoAb. RESULTS: Levels of 20-30 infectious doses per mL were present in buffy coat and plasma during both the incubation and symptomatic stages of disease; PLT pellet infectivity was lower (10 ID/mL) and RBCs were not infectious. The disease was transmitted more efficiently by IV than IC inoculation of plasma, but there was no difference observed with inoculation of buffy coat. The incubation period was shorter after IC inoculation of GSS- than vCJD-brain inocula. The amount of PrPres in spleens was similar for both TSE agents, but was slightly lower in brains of vCJD than GSS mice. CONCLUSION: Infectivity was detected in blood components of mice infected with a human-derived strain of vCJD during both the preclinical and clinical phases of disease in a similarly low range of concentrations as in mice infected with a human-derived nonvariant strain (GSS, Fukuoka-1). Other measures of virulence, including brain infectivity titers, incubation periods, and the accumulation of PrPres in spleens and brains, were also comparable in both experimental models.
PMID: 14641865 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=14641865&dopt=Abstract
Transfusion
Volume 43 Issue 12 Page 1687 - December 2003
doi:10.1046/j.0041-1132.2003.00586.x
Similar levels of infectivity in the blood of mice infected with
human-derived vCJD and GSS strains of transmissible spongiform
encephalopathy
Larisa Cervenakova, Oksana Yakovleva, Carroll McKenzie, Svetlana
Kolchinsky, Lisa McShane, William N. Drohan, and Paul Brown
BACKGROUND:
The possible transmission of variant CJD (vCJD) through blood
transfusion or use of plasma-derived products prompted this study
comparing infectivity in murine models of vCJD and
Gerstmann-Sträussler-Scheinker (GSS) disease, a non-vCJD form of
transmissible spongiform encephalopathy (TSE).
STUDY DESIGN AND METHODS:
RIII/Fa/Dk (RIII) or Swiss-Webster (Swiss) mice were inoculated
intracerebrally (IC) with mouse-adapted strains of vCJD or GSS
(Fukuoka-1) of similar infectivity. Groups of RIII mice were euthanized
17 weeks after inoculation (during the incubation period), and another
23 weeks after inoculation (when symptomatic). Blood was collected,
separated into components, and inoculated into groups of healthy mice;
brains and spleens from all mice were harvested and tested for the
presence of PrPres by Western blot using 6H4 MoAb.
RESULTS:
Levels of 20-30 infectious doses per mL were present in buffy coat and
plasma during both the incubation and symptomatic stages of disease; PLT
pellet infectivity was lower (10 ID/mL) and RBCs were not infectious.
The disease was transmitted more efficiently by IV than IC inoculation
of plasma, but there was no difference observed with inoculation of
buffy coat. The incubation period was shorter after IC inoculation of
GSS- than vCJD-brain inocula. The amount of PrPres in spleens was
similar for both TSE agents, but was slightly lower in brains of vCJD
than GSS mice.
CONCLUSION:
Infectivity was detected in blood components of mice infected with a
human-derived strain of vCJD during both the preclinical and clinical
phases of disease in a similarly low range of concentrations as in mice
infected with a human-derived nonvariant strain (GSS, Fukuoka-1). Other
measures of virulence, including brain infectivity titers, incubation
periods, and the accumulation of PrPres in spleens and brains, were also
comparable in both experimental models.
http://www.blackwellsynergy.com/openurlgenre=article&sid=nlm
ubmed&issn=00411132&date=2003&volume=43&issue=12&spage=1687
1: Brain. 1990 Dec;113 ( Pt 6):1891-909. Related Articles, Links
Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Straussler-Scheinker diseases.
Baker HF, Duchen LW, Jacobs JM, Ridley RM.
Division of Psychiatry, MRC Clinical Research Centre, Harrow, Middlesex, UK.
A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Straussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.
Publication Types:
Case Reports
PMID: 2276050 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=2276050&dopt=Abstract
Infectivity in the blood of mice with a BSE-derived agent
D. M. Taylor, K. Fernie, H. E. Reichl, R. A. Somerville
Sir,
The occurrence of variant Creutzfeldt-Jakob disease (vCJD) was first reported in 1996, and there is now convincing evidence that is caused by the bovine spongiform encephalopathy (BSE) agent. So far, 61 cases have been detected in the UK but it is unknown how many more will occur. PrPres, a disease-specific form of normal PrP protein, has been consistently detected in lymphoid tissues from cases of vCJD but not classical sporadic CJD.1 The healthcare industry has therefore been obliged to consider the possibility that the vCJD agent may be present in the blood of apparently healthy individuals incubating the disease. To minimize the risk of iatrogenic transmission, blood for transfusion in the UK is now leuco-depleted, and plasma-derived products are only manufactured from imported plasma.
Although there have been several reports of infectivity being detected in the blood of individuals with sporadic CJD, none of these stand up to rigorous scrutiny2. We can now report that the plasma of mice challenged with the 301V strain of mouse-passaged strain of BSE agent contains low levels of infectivity during the clinical stages of disease. The blood from 55 VM mice infected with the 301V mouse-passaged strain of BSE agent was collected aseptically by heart-puncture when they developed clinical neurological disease. The individual samples where pooled after their collection into citrate dextrose anticoagulant (10% v/v), and the plasma was drawn off after sedimentation. The plasma was injected intracerebrally into 48 VM mice (20µL per mouse) that were observed for up to 300 days for the development of clinical neurological disease. When such symptoms appeared, the affected mice were killed and their brains where examined histopathologically to confirm the presence of the spongiform encephalopathy that is pathognomonic for 301V in VM mice. Of the 48 mice injected, four became infected with 301V. The average incubation period was 208 days (SE+16.60) which is at the end of the dose-response curve for 301V in VM mice, and means that the plasma contained around five intracerebral ID50/mL.
In two studies where small amounts of scrapie infectivity were detected in mouse blood by bioassay, it was suggested that this might have originated from heart-muscle during the collection of blood by heart-puncture. This was speculative, however, and seems unlikely in view of the failure to detect scrapie infectivity in mouse blood by bioassay in the most extensive study of this type that has been carried out. Also, infectivity has not been detectable in heart-muscle of the nine sheep with natural scrapie3, or the four humans with sporadic CJD4 that have been investigated to date.
The data presented here relating to 301V should not be interpreted as a definitive representation of the situation in humans with vCJD. They do, however, add to the increasing evidence that low levels of infectivity can be detected in the blood of individuals with CJD-like diseases if the sensitivity of the assay systems is adequate. Somewhat similar levels of infectivity have been detected in the plasma of mice showing clinical signs after challenge with a mouse-passaged strain of Gerstmann-Straussler-Scheinker syndrome agent, although it was much more difficult to detect infectivity during the pre-clinical stage of disease.5 It is unknown at present whether infectivity can be recovered from the blood of 301V-infected mice during the pre-clinical phase of disease, and this may be an important question if (as seems likely) the pathogenesis 301V in mice and that of vCJD in humans are similar.
D. M. Taylor, Neuropathogenesis Unit
K. Fernie, Institute for Animal Health
H. E. Reichl, West Mains Road
R. A. Somerville, Edinburgh EH9 3JF, UK
And Haemosan GmbH
Kahngasse 20, A - 8045 Graz, Austria
References
Hill AF, Butterworth RJ, Joiner S et al. Investigation of variant Creutzfeldt-Jakob disease and other human Prion disease with tonsil biopsy samples. Lancet 1999; 353: 183-189
Brown P. Can Creutzfeldt-Jakob disease be transmitted by transfusion? Curr Opin Haematol 1995; 2: 472-477
Hadlow WJ, Kennedy RC, Race RE. Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 1982; 146 : 657-664.
Asher DM, Gibbs CJ, Gajdusek DC. Subacute spongiform encephalopathies: slow infections of the nervous system. Microbiol Newsletter 1985, 7: 129-133.
Brown P, Cervenakova L, McShane LM et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39: 1169-1178.
http://tse-ip.org/article-infectivity-blood-mice.html
Transmission of prion diseases by blood transfusion
http://www.socgenmicrobiol.org.uk/JGVDirect/18580/18580ft.pdf
Sir, -- Professor Manuelidis and his colleagues (Oct 19, p896) report transmission to animals of Creutzfeldt-Jakob disease (CJD) from the buffy coat from two patients. We also transmitted the disease from whole blood samples of a patient (and of mice) infected with CJD.1 Brain, Cornea, and urine from this patient were also infectious, and the clinicopathological findings2 are summarised as follows.
A 70-year-old man was noted to have a slowing of speech and writing and some disorientation, all of which progressed rapidly. Decorticate rigidity, forced grasping, positive snout reflex, and myoclonus appeared within 2 months. Electroencephalogram revealed typical periodic synchronous discharge, and he died of pneumonia and upper gastrointestinal haemorrhage, about 3 months after onset of the symptoms. The Brain weighed 1290g and showed severe histological changes diagnostic of CJD, including spongiform change, loss of nerve cells, and diffuse proliferation of astrocytes. There were no inflammatory cells, microglia, neurofibrillary tangles, and amyloid plaques, although virus-like particles were detected by electron microscopy.
Results of innoculation in Mice
Inocula NO* Incubation period (days)+ Brain 7/10 (4) 789 (+ or - 112) Cornea 1/6 (0) 1037 Blood 2/13 (0) 1080 (+ or - 69) Urine 5/10 (1) 880 (+ or - 55) CSF 0/10
* Number of mice with CJD change/number examined histologically. Number with amyloid plaques shown in parentheses.
+ means + or - SD
Samples were taken aseptically at necropsy. 10% crude homogenates of brain and cornea in saline, whole blood (after crushing a clot), and untreated CSF and urine were innoculated intracerebrally into CF1 strain mice (20 ul per animal). Some mice showed emaciation, bradykinesia, rigidity of the body and tail, and sometimes tremor after long incubation periods. Tissues obtained after the animal died (or was killed) were studied histologically (table). Animals infected by various inocula showed common pathological changes, consisting of severe spongiform changes, glial proliferation, and a moderate loss of nerve cells. A few mice inoculated with brain tissue or urine had the same amyloid plaques found in patients and animals with CJD.3
In our long-term experiments, inoculating materials taken from twenty patients with CJD or Gerstmann-Straussler-Scheinker's disease (GSS) into rodents, positive results were obtained in seventeen cases, including this patient. Brain tissue transmitted the disease most frequently within the shortes incubation period, except for one case where the lymph node was the most infectious. Transmission through the cornea has been noted in man4 and in guineapigs.5 Whole blood samples taken from three patients were inoculated and a positive transmission occured only in the case recorded here. Mouse-to-mouse transmission through blood inoculation was successful after a mean incubation period of 365 days.1 Transmission through urine was positive in this patient only, and negative in one other patient and in many infected animals. Transmission through the CSF from eight patients was negative, yet transmission via the CSF of infected rats was positive.1
As viraemia has been proved in guineapigs,6 mice,1,7 and lately in patients with CJD, blood for transfusion or blood products for medical use must be tested for unconventional pathogens. For this purpose, we inoculated blood products inot rodents.8 The CJD pathogen was not found in the products examined. However, this approach takes too long to be of practical value. More efficient methods must be developed to detect pathogens and to eliminate them from blood. One proposal9 is to apply membrane filtration to the pruification protocol of human growth hormone suspected of being contaminated with CJD. Similar methods are needed for blood contamination.
Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka812, Japan
JUN TATEISHI
1. Tateishi J, Sato Y, Kaga M. Don H, Ohta M. Experimental transmission of (bum??cannot read) subacute spongiform encephalopathy to small rodents I: Clinical and histological observations. Acta Neuropathol (Berl) 1980; 51: 127.
2. Shibayama Y, Sakaguchi Y, Nakata K, et al, Creutzfeldt-Jakob disease with demonstration of virus-like particles. Acta pathol Jpn 1982;32: 695.
3. Tateishi J, Nagara H, Hikita K, Sato Y. Amyloid plaques in the brains of mice with Creutzfeldt-Jakob disease. A?? Neurol 1984; 15: 278.
4. Duffy P, Wolf J, Colings G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974; 290?: 692.
5. Manuelidis EE, Angelo JN, Gorgacz EJ, Kim JH, Manuelidis L. Experimental Creutzfeldt-Jakob disease transmitted via the eye with infected cornea. N Engl J Med 1977; 296: 1334.
6. Manuelidis EE, Gorgacz EJ, Manuelidis L. Viremia in experimental Creutzfeldt-Jakob disease. Science 1978: 209?: 1069.
7. Kuroda Y, Gibbs CJ Jr, Amyx HL, Gajdusek DC. Creutzfeldt-Jakob disease in mice. Persistent viremiam and preferential replication of virus in low-density lymphocytes. Infect Immun 1983; 41: 154.
8. Tateishi J, Tsuji S. Unconventional pathogens causing spongiform encephalopathis absent in blood products. J Med Virol 1985; 15: 11.
9. Tateishi J, Kitamoto T, Hiratani H. Creutzfeldt-Jakob disease pathogen in growth hormone preparations is eliminatable. Lancet (in press).
=================================
-----Original Message-----
From: Terry S. Singeltary Sr. [mailto:[email protected]]
Sent: Tuesday, February 18, 2003 12:45 PM
To: Freas, William
Cc: Langford, Sheila
Subject: Re: re-vCJD/blood and meeting of Feb. 20, 2003
Greetings FDA,
http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.pdf
PDF]Freas, William TSS SUBMISSION
File Format: PDF/Adobe Acrobat -
Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary
Sr. [[email protected]] Monday, January 08,200l 3:03 PM freas ...
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
Asante/Collinge et al, that BSE transmission to the 129-methionine
genotype can lead to an alternate phenotype that is indistinguishable
from type 2 PrPSc, the commonest _sporadic_ CJD;
http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm
Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)
https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument
Docket No. 03-080-1 -- USDA ISSUES PROPOSED RULE TO ALLOW LIVE ANIMAL
IMPORTS FROM CANADA
https://web01.aphis.usda.gov/BSEcom.nsf/0/b78ba677e2b0c12185256dd300649f9d?OpenDocument&AutoFramed
Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION]
http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt
Docket Management Docket: 02N-0273 - Substances Prohibited From Use in
Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed
Comment Number: EC -10
Accepted - Volume 2
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html
PART 2
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html
Docket Management Docket: 96N-0417 - Current Good Manufacturing Practice
in Manufacturing, Packing, or Holding Dietary Ingredients a
Comment Number: EC -2
Accepted - Volume 7
http://www.fda.gov/ohrms/dockets/dailys/03/Mar03/031403/96N-0417-EC-2.htm
[PDF] Appendices to PL107-9 Inter-agency Working Group Final Report 1-1
File Format: PDF/Adobe Acrobat - View as HTML
Agent, Weapons of Mass Destruction Operations Unit Federal Bureau of
those who provided comments in response to Docket No. ...
Meager 8/18/01 Terry S. Singeltary Sr ...
http://www.aphis.usda.gov/lpa/pubs/pubs/PL107-9_Appen.pdf
Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION
TO DOCKET 2003N-0312]
http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt
# Docket No: 02-088-1 RE-Agricultural Bioterrorism Protection Act of
2002; [TSS SUBMISSION ON POTENTIAL FOR BSE/TSE & FMD 'SUITCASE BOMBS'] -
TSS 1/27/03 (0)
Docket Management
Docket: 02N-0276 - Bioterrorism Preparedness; Registration of Food Facilities, Section 305
Comment Number: EC-254 [TSS SUBMISSION]
http://www.fda.gov/ohrms/dockets/dockets/02n0276/02N-0276-EC-254.htm
Dockets Entered On October 2, 2003 Table of Contents, Docket #,
Title, 1978N-0301,
OTC External Analgesic Drug Products, ... EMC 7, Terry S. Singeltary Sr.
Vol #: 1, ...
http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm
Daily Dockets Entered on 02/05/03
DOCKETS ENTERED on 2/5/03. ... EMC 4 Terry S. Singeltary Sr. Vol#: 2.
... Vol#: 1.
03N-0009 Federal Preemption of State & Local Medical Device Requireme. ...
http://www.fda.gov/ohrms/dockets/dailys/03/Feb03/020503/020503.htm
Docket Management
Docket: 02N-0370 - Neurological Devices; Classification of Human Dura Mater
Comment Number: EC -1
Accepted - Volume 1
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be11.html
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfe.html
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfc.html
Daily Dockets - 04/10/03
... 00D-1662 Use of Xenotransplantation Products in Humans.
EMC 98 Terry S. Singeltary Sr. Vol#: 3. 01F ...
http://www.fda.gov/ohrms/dockets/dailys/03/Apr03/041003/041003.htm - 05-20-2003
- Cached
2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 1
Terry S. Singeltary Sr.
Vol #:
1
http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm
2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7
Terry S. Singeltary Sr.
Vol #:
1
2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7
Terry S. Singeltary Sr.
Vol #:
1
http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm
01N-0423 Substances Prohibited from use in animal food/Feed Ruminant
APE 5 National Renderers Association, Inc. Vol#: 2
APE 6 Animal Protein Producers Industry Vol#: 2
APE 7 Darling International Inc. Vol#: 2
EMC 1 Terry S. Singeltary Sr. Vol#: 3
http://www.fda.gov/ohrms/dockets/dailys/01/Oct01/101501/101501.htm
[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle
03-025IFA
03-025IFA-2
Terry S. Singeltary
Page 1 of 17
From: Terry S. Singeltary Sr. [[email protected]]
Sent: Thursday, September 08, 2005 6:17 PM
To: [email protected].
Subject: [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements
for the Disposition of Non-Ambulatory Disabled Cattle
Greetings FSIS,
I would kindly like to submit the following to [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and
Requirements for the Disposition of Non-Ambulatory Disabled Cattle
THE BSE/TSE SUB CLINICAL Non-Ambulatory Disabled Cattle
Broken bones and such may be the first signs of a sub clinical BSE/TSE Non-Ambulatory Disabled Cattle ;
snip...FULL TEXT ;
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
Importation of Whole Cuts of Boneless Beef from Japan [Docket No. 05-004-1] RIN 0579-AB93 TSS SUBMISSION
http://docket.epa.gov/edkfed/do/EDKStaffItemDetailView?objectId=090007d480993808
http://docket.epa.gov/edkfed/do/EDKStaffAttachDownloadPDF?objectId=090007d480993808
http://docket.epa.gov/edkfed/do/EDKStaffCollectionDetailView?objectId=0b0007d48096b40d
TSS
ADVISORY COMMITTEE
October 31, 2005
Holiday Inn Bethesda
Bethesda, Maryland
SNIP...
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.
snip...
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.
snip...
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. ...
snip...
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
snip...
http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4189t1.htm
==================================================
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. ...
snip...
============================================
Greetings,
I would not agree here and would further like to state that as a 'consumer' spokesperson on this committee, Florence Kranitz does NOT speak for me. I think more of us can differentiate between mad cow and sCJD than they might think, the problem is, the officials on this very committee cannot differentiate between the UKnvCJDBSE only theory and the truth. To keep this information from the public is wrong. I AS A CONSUMER WANT TO KNOW! What gives Florence the right as a consumer to know and me or any other not to know? WE know BSE has been in the USA. WE know the June 2004 Enhanced BSE surveillance was nothing more than a surveillance system to hide any BSE and they could not even get that right after 7+ months of trying, the Honorable Phyllis Fong of the OIG proved Johanns wrong and have that negative proven postive. OF course they did manage to screw up another one without using WB and THEY did cover-up another mad cow in TEXAS, then admitted they screwed that up (FDA website). IN fact, i question the whole 500,000 plus cattle tested in the June 2004 Enhanced BSE cover-up. THE only cow we have proven was negative IHC and only proven positive with WB. NO WB were used on the 500,000 cattle in the Enhanced June 04 cover-up, except the one the Honorable Phyllis Fong made them retest, that i am aware of. IN FACT, of those same 500,000 cattle, 9,200 did not have either rapid test OR WB, only IHC, the least likely to find it. WE know Marsh et al had proven a strain of TSE was in USA cattle long ago, via TME and the feed source there i.e. 95%+ dead stock downer cattle feeder. WE now have other strains of TSE in cattle BASE that is not similar to nvCJD but very similar to sCJD. WE know in the USA, when US scrapie are fed to cattle, it does not look like the UKBSE in the infected cow. WHAT about GSS infectivity in blood? WHAT about CWD? THE myth that Scrapie does not transmit to humans is another myth. SCRAPIE in sheep will transmit freely to primate by it's non-forced ORAL consumption. FOR the ones that know this, WHY ARE WE BEING CALLED AS TOO STUPID TO HAVE THE TRUTH TOLD TO US (in a nicer way this time) $$$ maybe because some of us would question there rule making? they could not have this! many of us are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map." I remember the mothers being called to stupid once before at one of these TSE committee (see below). I may not have a PhD, but if i have been exposed to this agent (which i have in more ways othan one), i want to know about it immediately. enough secrecy already!
Subject: VACCINES and CJD -- FDA says Mothers to stupid to understand... 7/27/2000 TSE Advisory Committee
Date: Tue, 19 Sep 2000 11:12:39 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: [email protected]
######### Bovine Spongiform Encephalopathy #########
Greetings List Members,
"Ninety million Americans are either marginally or low literate, meaning
they can't understand a bus map or can't understand a bus schedule or
locate their intersection on a map." We can't communicate with the same
message to them that we might communicate to people who are making
vaccine decisions at the state or county or other levels."
But I think the Mothers are smart enough to know, that the scrapie
agent has been the model for CJD research since day one. So, I think
the Louping-ill vaccine and Scrapie episode, which killed many sheep,
from a vaccine made from scrapie-infected brain, is most important,
and I think these Mothers are smart enough to understand that...
Louping-ill vaccine blunder.....
http://www.vegsource.com/talk/madcow/messages/7634.html
Transmission of CJD from Blood and Urine Into Mice.....
http://www.vegsource.com/talk/madcow/messages/7650.html
kind regards,
Terry S. Singeltary Sr., Bacliff, Texas USA
===========================================
TSE Advisory Committee 7/27/2000
259
I feel the need to say something. It's theoretical. I agree with your
sense of how often it's going to occur totally. What could we do? What
could they do?
DR. SNIDER:
This is Dixie Snider. Yeah, we can hear from him, but you made a
criticism of my comment, and I just want -- I thought it might be useful
to have something to go along with their U.S. Today story that they were
reading. That's all. Something that's authoritative from the FDA.
CHAIRMANBROWN: I'm glad I'm the Chairman of this committee, not this
committee.
DR. RATZAN: If I could try to answer that, there is a scientific
nature to how do you look at communication. You don't overreact to
infinitesimal risks, and at the same time you don't under-react when
there is a real risk that's involved, because that does undermine the
public trust.
What I heard today were some of the steps that were being taken by some
of the manufacturers, the two that presented, that they are trying to
embody the public trust in terms of their processes. I think more of the
open nature, even meetings like this of being able to have advisory
meetings, meetings also that might have the professional associations
where you have opinion leaders who might be able to defuse the
information appropriately.
A blanket communication -- We often say Marshall McCluhan, a Canadian
scholar in media, said, if you try to reach everybody, you reach nobody.
By doing that, it's really key in thinking about communicating with the
people that need to know.
Ninety million Americans are either marginally or low literate, meaning
they can't understand a bus map or can't understand a bus schedule or
locate their intersection on a map. We can't communicate with the same
message to them that we might communicate to people who are making
vaccine decisions at the state or county or other levels.
So I'm answering in a circuitous way, because I think we've heard some
of the right steps being taken today, the open hearing, some of the
voluntary efforts that are being done in good faith by the
manufacturers, and some of the other ways that continue to monitor the
open disclosure. I think the surveillance systems that we've put in
place not only here in the United States but now abroad in looking at
BSE and looking at the CJD that we heard from CDC and others where the
numbers are.
So I would say, by all means, keep the surveillance. Keep the voluntary
efforts. Continue to focus upon the science, and communicate that
appropriately on, whether it's a quarterly basis, or use the different
channels, the Institute of Medicine channels that are out there.
I think there's a variety of different expert committees as well.
So, thank you.
CHAIRMAN BROWN: Thank you very much. Yes?
MS. FISHER: You may not want to communicate this theoretical risk to the
public, but that doesn't mean it's the right thing to do. I think that
part of what the National Childhood Injury Act of 1986 was all about,
the safety provisions, was communicating risk to parents before they get
their children vaccinated.
I think that, you know, the FDA's charge is to ensure the purity and
potency of vaccines. It seems to me that the least that we can do at
this juncture when we know something is to let the people know we know,
rather than keeping it from them.
CHAIRMAN BROWN: Hold on, Dave. Shirley?
MS. WALKER: There's an old German proverb, "Don't point the devil on
the wall; otherwise, he will jump off." I think the devil has already
jumped off.
The inserts in the packets for pharmaceuticals are great. Notification
to the doctor is great. But I represent something like 79,000 mothers
who have children in Dallas County who we actively promote to get
vaccinated.
So Monday morning when I go back to work, I'm going to have to tell
someone, a percentage of these young mothers, that, hey, your child is
at risk for whatever that minute amount is for CJD. So what do we do at
this particular point? Do we remain mute and say nothing or do we
promote and give some type of information?
So I am saying to FDA that we do need some kind of general information
that we can impart to our constituents.
CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more
comments in this discussion, and then in the event that a number of
people on the committee may have to leave, there are two or three very
specific questions that the FDA would like some discussion-on, and I
want to move to them. We've touched on some of them already, but if
there's anything more to say on this -- Yes, go ahead.
263 DR. STEPHENS: I guess I'm really concerned that this discussion is
kind of spinning out of control in terms of the risk. I must agree with
the consumer advocate who spoke a minute ago --
CHAIRMAN BROWN: Dr. Ratzan.
DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a
duty, in my view, to protect the vaccine system in this country. I think
that this discussion has gotten to the point of at least suggesting that
we believe that this is a significant problem. The data suggests that
the risk is in the billions, that there have not -- there's not been a
single case of new variant CJD in this country,
despite the use of vaccines manufactured in this way for years.
So I think the issue is we need public disclosure. That's not the
question. I think we all are in agreement on this committee, but I think
to emphasize this point where you're concerned about going back to your
group of mothers and saying there's a risk -- I think that's something
we don't want to send. That's a message we do not want to send.
CHAIRMAN BROWN: I opened this whole seminar with the notion that we're
starting from a very, very small amount of infectivity, if there is
any, and that there is a tradeoff between, as several people have said,
a theoretical risk and a real risk, which would be discrediting in some
way vaccines or causing vaccine shortages or difficulties or refusal to
get vaccines.
In other words, this is the tradeoff. Right at the outset, this was the
scene that I hoped to set. But you're right. All of our committee
discussion meetings tend to spin out of control at about this time of
the afternoon, and sometimes it's in one direction, and sometimes
it's in another direction.
I think the word risk has enlarged as the afternoon has progressed, and
maybe we should shrink it down a little bit and get a little better
perspective or a little different perspective. So I tend to agree with
you. Let me --
DR. BOLTON: Paul, can I get in my comment?
CHAIRMAN BROWN: I'm sorry? Go ahead.
BOLTON: I agree that it would be important to communicate known risks or
even good estimates of risk to the public, but I'm not sure what
that estimate would be at this point. I don't think that we really have
enough information to communicate to the public and have it be
meaningful and not simply scare people away.
I can't imagine the negative impact on the program in this country if
parents started thinking that, if I vaccinate my child, he or she may
come down with new variant CJD.
To me, the other way that we communicate is by action. It seems to me
that there are actions that can be taken in terms of looking at the
process of vaccine manufacture and where the real -- the greatest of the
theoretical risks are. It seems to me that the viral/bacterial master
seeds are really at the very lowest end, as are the master cell banks,
and also trying to change those creates the biggest problem.
>From that point on, from the working seeds on down through production, I
think that the manufacturers have issues that they can address in terms
of removing the use of at-risk bovine materials from that point on.
I guess my question to anybody at the FDA is: Are at-risk bovine
materials currently in use at the -- certainly from the production step
on, and even at the production of the working seeds and working
cell lines, are they in use now, and how long before they will be phased
out?
CHAIRMANBROWN: I guess what you're -- to add to that, are the sources of
anything currently coming from BSE designated countries?
DR. STEPHENS: When I say at risk, I really mean those bovine materials
are coming from Europe or at-risk countries.
CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --
DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines
there was bovine derived fermentation media where that skeletal muscle
and pancreas derived from several European countries.
I think it was Germany, Denmark, Poland, the Netherlands.
CHAIRMAN BROWN: Right. So they are currently in use in this country.
DR. EGAN: They have all agreed to -- That will be changed, but as I
mentioned, by the time -- You know, they've gotten new sources, but that
comes into new vaccines -- What?
DR. BOLTON: Is that the only material that's now sourced from at-risk
countries?
DR. EGAN: That's used in the production. I think I also mentioned hemin.
I think that was it, but I'd have to go back to it.
DR. BOLTON: So I guess my recommendation would be that the FDA work with
the manufacturers to set a definite timeline to phase out all those
materials. In terms of the master virus seeds and the bacterial stocks
and the master cell lines, I think that the risk is so small as to be
really counterproductive to try to change those, because the risk of
changing the product by changing those is much, much greater than any
risk that there would be from proceeding.
CHAIRMAN BROWN: One of the questions that the FDA specifically wanted
some judgment on was: Is it necessary to re-derive bacterial master
seeds? I mean, I'm getting the sense -- Every time I get the sense of
something, the sense changes. You know, we had a consensus about
informed consent, and now we have a consensus about not smother it, but
be awfully, awfully, awfully careful.
Now I thought we had pretty much decided that, at least for current
products, that it will not be necessary to re-derive bacterial master
seeds. That was my sense. Dr. Huang?
DR. HUANG: I completely agree. I think that the derivation of new master
seed stocks would be more dangerous than this perceived danger that we
are facing now.
CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ
from that opinion? All right. We have answered one definitive question
that the FDA wanted to asked.
They also want an answer to a question I think should be very easy to
answer. That is: Is 1980, form all that you have heard, an appropriate
cutoff date before which one need not worry about anything in terms of
sourcing of the products we are talking about?
We always worry about something, but 1980 -- is that an appropriate date
before which not to be concerned? That's a pretty focused question. Is
there anybody that feels that one should be concerned
about products produced before 1980 from anywhere? Yes?
DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect
to our blood donation pool in the United States,'we were concerned about
BSE and started with 1980.
CHAIRMAN BROWN: It has the merit of consistency as well. All right.
That's two questions.
The third question they were concerned about was: Do we think that the
small amount of fetal calf serum from the U.K. around 1985 used in the
production of master cell banks constitutes a negligible or -- well, the
phrase was "a negligible or a significant risk"? Again, a question about
fetal calf serum, sourced from the U.K. in the middle of the
1980s, use in the production of master cell banks constitutes any kind
of significant risk? Yes?
DR. CLIVER: May I start by saying negligible. We'll see if anybody
disagrees.
CHAIRMAN BROWN: Do I hear significant? Negligible?
[[[sounds like a damn auction...tss]]]
DR. BOLTON: I agree that it's negligible.
CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used
for the production -- just for this specific purpose, used in the
production of master cell banks? Well, that answers the three questions
that you most wanted some judgment on Dr. Ewenstein?
Dr. EWENSTEIN: There was also the products that are still under
investigation. I think, you know, we should address that. I think one
of the comments before was, I think, right on the point. That is that
it's different if you have a licensed drug or product that
has, therefore, documented benefit versus recruited volunteers.
I think we should think about what we should answer for number 3. I
think that it's appropriate to include again, with the correct caveat,
about theoretical and negligibly small risk in a consent form. but I
certainly wouldn't like to see all clinical trials stopped of such
vaccines.
CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We
haven't touched on that, and we might just continue that discussion a
bit. Peter?
DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him
correctly. I think that it is indeed a different situation. For one
thing, not only is the benefit of the vaccine unknown, but for
another, one actually does know the name of the patients, and
one is personal contact with those patients on a semi-regular basis.
I think that the ethical responsibility toward those people is quite
different than is owed to the population at large......
FULL TEXT AT URL BELOW PDF FORM (about 79 pages)......TSS
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3635t1c.pdf
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
1: Transfusion. 2003 Dec;43(12):1687-94. Related Articles, Links
Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy.
Cervenakova L, Yakovleva O, McKenzie C, Kolchinsky S, McShane L, Drohan WN, Brown P.
Jerome H Holland Laboratory for the Biomedical Sciences, Red Cross, Rockville, MD 20855, USA. [email protected]
BACKGROUND: The possible transmission of variant CJD (vCJD) through blood transfusion or use of plasma-derived products prompted this study comparing infectivity in murine models of vCJD and Gerstmann-Straussler-Scheinker (GSS) disease, a non-vCJD form of transmissible spongiform encephalopathy (TSE). STUDY DESIGN AND METHODS: RIII/Fa/Dk (RIII) or Swiss-Webster (Swiss) mice were inoculated intracerebrally (IC) with mouse-adapted strains of vCJD or GSS (Fukuoka-1) of similar infectivity. Groups of RIII mice were euthanized 17 weeks after inoculation (during the incubation period), and another 23 weeks after inoculation (when symptomatic). Blood was collected, separated into components, and inoculated into groups of healthy mice; brains and spleens from all mice were harvested and tested for the presence of PrPres by Western blot using 6H4 MoAb. RESULTS: Levels of 20-30 infectious doses per mL were present in buffy coat and plasma during both the incubation and symptomatic stages of disease; PLT pellet infectivity was lower (10 ID/mL) and RBCs were not infectious. The disease was transmitted more efficiently by IV than IC inoculation of plasma, but there was no difference observed with inoculation of buffy coat. The incubation period was shorter after IC inoculation of GSS- than vCJD-brain inocula. The amount of PrPres in spleens was similar for both TSE agents, but was slightly lower in brains of vCJD than GSS mice. CONCLUSION: Infectivity was detected in blood components of mice infected with a human-derived strain of vCJD during both the preclinical and clinical phases of disease in a similarly low range of concentrations as in mice infected with a human-derived nonvariant strain (GSS, Fukuoka-1). Other measures of virulence, including brain infectivity titers, incubation periods, and the accumulation of PrPres in spleens and brains, were also comparable in both experimental models.
PMID: 14641865 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=14641865&dopt=Abstract
Transfusion
Volume 43 Issue 12 Page 1687 - December 2003
doi:10.1046/j.0041-1132.2003.00586.x
Similar levels of infectivity in the blood of mice infected with
human-derived vCJD and GSS strains of transmissible spongiform
encephalopathy
Larisa Cervenakova, Oksana Yakovleva, Carroll McKenzie, Svetlana
Kolchinsky, Lisa McShane, William N. Drohan, and Paul Brown
BACKGROUND:
The possible transmission of variant CJD (vCJD) through blood
transfusion or use of plasma-derived products prompted this study
comparing infectivity in murine models of vCJD and
Gerstmann-Sträussler-Scheinker (GSS) disease, a non-vCJD form of
transmissible spongiform encephalopathy (TSE).
STUDY DESIGN AND METHODS:
RIII/Fa/Dk (RIII) or Swiss-Webster (Swiss) mice were inoculated
intracerebrally (IC) with mouse-adapted strains of vCJD or GSS
(Fukuoka-1) of similar infectivity. Groups of RIII mice were euthanized
17 weeks after inoculation (during the incubation period), and another
23 weeks after inoculation (when symptomatic). Blood was collected,
separated into components, and inoculated into groups of healthy mice;
brains and spleens from all mice were harvested and tested for the
presence of PrPres by Western blot using 6H4 MoAb.
RESULTS:
Levels of 20-30 infectious doses per mL were present in buffy coat and
plasma during both the incubation and symptomatic stages of disease; PLT
pellet infectivity was lower (10 ID/mL) and RBCs were not infectious.
The disease was transmitted more efficiently by IV than IC inoculation
of plasma, but there was no difference observed with inoculation of
buffy coat. The incubation period was shorter after IC inoculation of
GSS- than vCJD-brain inocula. The amount of PrPres in spleens was
similar for both TSE agents, but was slightly lower in brains of vCJD
than GSS mice.
CONCLUSION:
Infectivity was detected in blood components of mice infected with a
human-derived strain of vCJD during both the preclinical and clinical
phases of disease in a similarly low range of concentrations as in mice
infected with a human-derived nonvariant strain (GSS, Fukuoka-1). Other
measures of virulence, including brain infectivity titers, incubation
periods, and the accumulation of PrPres in spleens and brains, were also
comparable in both experimental models.
http://www.blackwellsynergy.com/openurlgenre=article&sid=nlm
ubmed&issn=00411132&date=2003&volume=43&issue=12&spage=1687 1: Brain. 1990 Dec;113 ( Pt 6):1891-909. Related Articles, Links
Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Straussler-Scheinker diseases.
Baker HF, Duchen LW, Jacobs JM, Ridley RM.
Division of Psychiatry, MRC Clinical Research Centre, Harrow, Middlesex, UK.
A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Straussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.
Publication Types:
Case Reports
PMID: 2276050 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=2276050&dopt=Abstract
Infectivity in the blood of mice with a BSE-derived agent
D. M. Taylor, K. Fernie, H. E. Reichl, R. A. Somerville
Sir,
The occurrence of variant Creutzfeldt-Jakob disease (vCJD) was first reported in 1996, and there is now convincing evidence that is caused by the bovine spongiform encephalopathy (BSE) agent. So far, 61 cases have been detected in the UK but it is unknown how many more will occur. PrPres, a disease-specific form of normal PrP protein, has been consistently detected in lymphoid tissues from cases of vCJD but not classical sporadic CJD.1 The healthcare industry has therefore been obliged to consider the possibility that the vCJD agent may be present in the blood of apparently healthy individuals incubating the disease. To minimize the risk of iatrogenic transmission, blood for transfusion in the UK is now leuco-depleted, and plasma-derived products are only manufactured from imported plasma.
Although there have been several reports of infectivity being detected in the blood of individuals with sporadic CJD, none of these stand up to rigorous scrutiny2. We can now report that the plasma of mice challenged with the 301V strain of mouse-passaged strain of BSE agent contains low levels of infectivity during the clinical stages of disease. The blood from 55 VM mice infected with the 301V mouse-passaged strain of BSE agent was collected aseptically by heart-puncture when they developed clinical neurological disease. The individual samples where pooled after their collection into citrate dextrose anticoagulant (10% v/v), and the plasma was drawn off after sedimentation. The plasma was injected intracerebrally into 48 VM mice (20µL per mouse) that were observed for up to 300 days for the development of clinical neurological disease. When such symptoms appeared, the affected mice were killed and their brains where examined histopathologically to confirm the presence of the spongiform encephalopathy that is pathognomonic for 301V in VM mice. Of the 48 mice injected, four became infected with 301V. The average incubation period was 208 days (SE+16.60) which is at the end of the dose-response curve for 301V in VM mice, and means that the plasma contained around five intracerebral ID50/mL.
In two studies where small amounts of scrapie infectivity were detected in mouse blood by bioassay, it was suggested that this might have originated from heart-muscle during the collection of blood by heart-puncture. This was speculative, however, and seems unlikely in view of the failure to detect scrapie infectivity in mouse blood by bioassay in the most extensive study of this type that has been carried out. Also, infectivity has not been detectable in heart-muscle of the nine sheep with natural scrapie3, or the four humans with sporadic CJD4 that have been investigated to date.
The data presented here relating to 301V should not be interpreted as a definitive representation of the situation in humans with vCJD. They do, however, add to the increasing evidence that low levels of infectivity can be detected in the blood of individuals with CJD-like diseases if the sensitivity of the assay systems is adequate. Somewhat similar levels of infectivity have been detected in the plasma of mice showing clinical signs after challenge with a mouse-passaged strain of Gerstmann-Straussler-Scheinker syndrome agent, although it was much more difficult to detect infectivity during the pre-clinical stage of disease.5 It is unknown at present whether infectivity can be recovered from the blood of 301V-infected mice during the pre-clinical phase of disease, and this may be an important question if (as seems likely) the pathogenesis 301V in mice and that of vCJD in humans are similar.
D. M. Taylor, Neuropathogenesis Unit
K. Fernie, Institute for Animal Health
H. E. Reichl, West Mains Road
R. A. Somerville, Edinburgh EH9 3JF, UK
And Haemosan GmbH
Kahngasse 20, A - 8045 Graz, Austria
References
Hill AF, Butterworth RJ, Joiner S et al. Investigation of variant Creutzfeldt-Jakob disease and other human Prion disease with tonsil biopsy samples. Lancet 1999; 353: 183-189
Brown P. Can Creutzfeldt-Jakob disease be transmitted by transfusion? Curr Opin Haematol 1995; 2: 472-477
Hadlow WJ, Kennedy RC, Race RE. Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 1982; 146 : 657-664.
Asher DM, Gibbs CJ, Gajdusek DC. Subacute spongiform encephalopathies: slow infections of the nervous system. Microbiol Newsletter 1985, 7: 129-133.
Brown P, Cervenakova L, McShane LM et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39: 1169-1178.
http://tse-ip.org/article-infectivity-blood-mice.html
Transmission of prion diseases by blood transfusion
http://www.socgenmicrobiol.org.uk/JGVDirect/18580/18580ft.pdf
Sir, -- Professor Manuelidis and his colleagues (Oct 19, p896) report transmission to animals of Creutzfeldt-Jakob disease (CJD) from the buffy coat from two patients. We also transmitted the disease from whole blood samples of a patient (and of mice) infected with CJD.1 Brain, Cornea, and urine from this patient were also infectious, and the clinicopathological findings2 are summarised as follows.
A 70-year-old man was noted to have a slowing of speech and writing and some disorientation, all of which progressed rapidly. Decorticate rigidity, forced grasping, positive snout reflex, and myoclonus appeared within 2 months. Electroencephalogram revealed typical periodic synchronous discharge, and he died of pneumonia and upper gastrointestinal haemorrhage, about 3 months after onset of the symptoms. The Brain weighed 1290g and showed severe histological changes diagnostic of CJD, including spongiform change, loss of nerve cells, and diffuse proliferation of astrocytes. There were no inflammatory cells, microglia, neurofibrillary tangles, and amyloid plaques, although virus-like particles were detected by electron microscopy.
Results of innoculation in Mice
Inocula NO* Incubation period (days)+ Brain 7/10 (4) 789 (+ or - 112) Cornea 1/6 (0) 1037 Blood 2/13 (0) 1080 (+ or - 69) Urine 5/10 (1) 880 (+ or - 55) CSF 0/10
* Number of mice with CJD change/number examined histologically. Number with amyloid plaques shown in parentheses.
+ means + or - SD
Samples were taken aseptically at necropsy. 10% crude homogenates of brain and cornea in saline, whole blood (after crushing a clot), and untreated CSF and urine were innoculated intracerebrally into CF1 strain mice (20 ul per animal). Some mice showed emaciation, bradykinesia, rigidity of the body and tail, and sometimes tremor after long incubation periods. Tissues obtained after the animal died (or was killed) were studied histologically (table). Animals infected by various inocula showed common pathological changes, consisting of severe spongiform changes, glial proliferation, and a moderate loss of nerve cells. A few mice inoculated with brain tissue or urine had the same amyloid plaques found in patients and animals with CJD.3
In our long-term experiments, inoculating materials taken from twenty patients with CJD or Gerstmann-Straussler-Scheinker's disease (GSS) into rodents, positive results were obtained in seventeen cases, including this patient. Brain tissue transmitted the disease most frequently within the shortes incubation period, except for one case where the lymph node was the most infectious. Transmission through the cornea has been noted in man4 and in guineapigs.5 Whole blood samples taken from three patients were inoculated and a positive transmission occured only in the case recorded here. Mouse-to-mouse transmission through blood inoculation was successful after a mean incubation period of 365 days.1 Transmission through urine was positive in this patient only, and negative in one other patient and in many infected animals. Transmission through the CSF from eight patients was negative, yet transmission via the CSF of infected rats was positive.1
As viraemia has been proved in guineapigs,6 mice,1,7 and lately in patients with CJD, blood for transfusion or blood products for medical use must be tested for unconventional pathogens. For this purpose, we inoculated blood products inot rodents.8 The CJD pathogen was not found in the products examined. However, this approach takes too long to be of practical value. More efficient methods must be developed to detect pathogens and to eliminate them from blood. One proposal9 is to apply membrane filtration to the pruification protocol of human growth hormone suspected of being contaminated with CJD. Similar methods are needed for blood contamination.
Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka812, Japan
JUN TATEISHI
1. Tateishi J, Sato Y, Kaga M. Don H, Ohta M. Experimental transmission of (bum??cannot read) subacute spongiform encephalopathy to small rodents I: Clinical and histological observations. Acta Neuropathol (Berl) 1980; 51: 127.
2. Shibayama Y, Sakaguchi Y, Nakata K, et al, Creutzfeldt-Jakob disease with demonstration of virus-like particles. Acta pathol Jpn 1982;32: 695.
3. Tateishi J, Nagara H, Hikita K, Sato Y. Amyloid plaques in the brains of mice with Creutzfeldt-Jakob disease. A?? Neurol 1984; 15: 278.
4. Duffy P, Wolf J, Colings G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974; 290?: 692.
5. Manuelidis EE, Angelo JN, Gorgacz EJ, Kim JH, Manuelidis L. Experimental Creutzfeldt-Jakob disease transmitted via the eye with infected cornea. N Engl J Med 1977; 296: 1334.
6. Manuelidis EE, Gorgacz EJ, Manuelidis L. Viremia in experimental Creutzfeldt-Jakob disease. Science 1978: 209?: 1069.
7. Kuroda Y, Gibbs CJ Jr, Amyx HL, Gajdusek DC. Creutzfeldt-Jakob disease in mice. Persistent viremiam and preferential replication of virus in low-density lymphocytes. Infect Immun 1983; 41: 154.
8. Tateishi J, Tsuji S. Unconventional pathogens causing spongiform encephalopathis absent in blood products. J Med Virol 1985; 15: 11.
9. Tateishi J, Kitamoto T, Hiratani H. Creutzfeldt-Jakob disease pathogen in growth hormone preparations is eliminatable. Lancet (in press).
=================================
-----Original Message-----
From: Terry S. Singeltary Sr. [mailto:[email protected]]
Sent: Tuesday, February 18, 2003 12:45 PM
To: Freas, William
Cc: Langford, Sheila
Subject: Re: re-vCJD/blood and meeting of Feb. 20, 2003
Greetings FDA,
http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.pdf
PDF]Freas, William TSS SUBMISSION
File Format: PDF/Adobe Acrobat -
Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary
Sr. [[email protected]] Monday, January 08,200l 3:03 PM freas ...
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
Asante/Collinge et al, that BSE transmission to the 129-methionine
genotype can lead to an alternate phenotype that is indistinguishable
from type 2 PrPSc, the commonest _sporadic_ CJD;
http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm
Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)
https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument
Docket No. 03-080-1 -- USDA ISSUES PROPOSED RULE TO ALLOW LIVE ANIMAL
IMPORTS FROM CANADA
https://web01.aphis.usda.gov/BSEcom.nsf/0/b78ba677e2b0c12185256dd300649f9d?OpenDocument&AutoFramed
Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION]
http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt
Docket Management Docket: 02N-0273 - Substances Prohibited From Use in
Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed
Comment Number: EC -10
Accepted - Volume 2
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html
PART 2
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html
Docket Management Docket: 96N-0417 - Current Good Manufacturing Practice
in Manufacturing, Packing, or Holding Dietary Ingredients a
Comment Number: EC -2
Accepted - Volume 7
http://www.fda.gov/ohrms/dockets/dailys/03/Mar03/031403/96N-0417-EC-2.htm
[PDF] Appendices to PL107-9 Inter-agency Working Group Final Report 1-1
File Format: PDF/Adobe Acrobat - View as HTML
Agent, Weapons of Mass Destruction Operations Unit Federal Bureau of
those who provided comments in response to Docket No. ...
Meager 8/18/01 Terry S. Singeltary Sr ...
http://www.aphis.usda.gov/lpa/pubs/pubs/PL107-9_Appen.pdf
Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION
TO DOCKET 2003N-0312]
http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt
# Docket No: 02-088-1 RE-Agricultural Bioterrorism Protection Act of
2002; [TSS SUBMISSION ON POTENTIAL FOR BSE/TSE & FMD 'SUITCASE BOMBS'] -
TSS 1/27/03 (0)
Docket Management
Docket: 02N-0276 - Bioterrorism Preparedness; Registration of Food Facilities, Section 305
Comment Number: EC-254 [TSS SUBMISSION]
http://www.fda.gov/ohrms/dockets/dockets/02n0276/02N-0276-EC-254.htm
Dockets Entered On October 2, 2003 Table of Contents, Docket #,
Title, 1978N-0301,
OTC External Analgesic Drug Products, ... EMC 7, Terry S. Singeltary Sr.
Vol #: 1, ...
http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm
Daily Dockets Entered on 02/05/03
DOCKETS ENTERED on 2/5/03. ... EMC 4 Terry S. Singeltary Sr. Vol#: 2.
... Vol#: 1.
03N-0009 Federal Preemption of State & Local Medical Device Requireme. ...
http://www.fda.gov/ohrms/dockets/dailys/03/Feb03/020503/020503.htm
Docket Management
Docket: 02N-0370 - Neurological Devices; Classification of Human Dura Mater
Comment Number: EC -1
Accepted - Volume 1
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be11.html
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfe.html
http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfc.html
Daily Dockets - 04/10/03
... 00D-1662 Use of Xenotransplantation Products in Humans.
EMC 98 Terry S. Singeltary Sr. Vol#: 3. 01F ...
http://www.fda.gov/ohrms/dockets/dailys/03/Apr03/041003/041003.htm - 05-20-2003
- Cached
2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 1
Terry S. Singeltary Sr.
Vol #:
1
http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm
2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7
Terry S. Singeltary Sr.
Vol #:
1
2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
EMC 7
Terry S. Singeltary Sr.
Vol #:
1
http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm
01N-0423 Substances Prohibited from use in animal food/Feed Ruminant
APE 5 National Renderers Association, Inc. Vol#: 2
APE 6 Animal Protein Producers Industry Vol#: 2
APE 7 Darling International Inc. Vol#: 2
EMC 1 Terry S. Singeltary Sr. Vol#: 3
http://www.fda.gov/ohrms/dockets/dailys/01/Oct01/101501/101501.htm
[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle
03-025IFA
03-025IFA-2
Terry S. Singeltary
Page 1 of 17
From: Terry S. Singeltary Sr. [[email protected]]
Sent: Thursday, September 08, 2005 6:17 PM
To: [email protected].
Subject: [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements
for the Disposition of Non-Ambulatory Disabled Cattle
Greetings FSIS,
I would kindly like to submit the following to [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and
Requirements for the Disposition of Non-Ambulatory Disabled Cattle
THE BSE/TSE SUB CLINICAL Non-Ambulatory Disabled Cattle
Broken bones and such may be the first signs of a sub clinical BSE/TSE Non-Ambulatory Disabled Cattle ;
snip...FULL TEXT ;
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
Importation of Whole Cuts of Boneless Beef from Japan [Docket No. 05-004-1] RIN 0579-AB93 TSS SUBMISSION
http://docket.epa.gov/edkfed/do/EDKStaffItemDetailView?objectId=090007d480993808
http://docket.epa.gov/edkfed/do/EDKStaffAttachDownloadPDF?objectId=090007d480993808
http://docket.epa.gov/edkfed/do/EDKStaffCollectionDetailView?objectId=0b0007d48096b40d
TSS
