TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products

Meeting of the Transmissible Spongiform Encephalopathies Advisory Committee

Center Date Time Location

CBER August 1, 2011 9:00 a.m. - 4:30 p.m.

Hilton Washington DC/North, 620 Perry Pkwy., Gaithersburg, MD

Agenda

On August 1, 2011, in the morning, the committee will discuss donor deferral for time spent in Saudi Arabia to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue-based products.

Meeting Materials

Materials for this meeting will be available at:

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/default.htm1

Public Participation Information

Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.

Written submissions may be made to the contact person on or before July 25, 2011

Oral presentations from the public will be scheduled between approximately 2:15 p.m. and 2:45 p.m. Those individuals interested in making formal oral presentations should notify the contact person and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before July 15, 2011. Time allotted for each presentation may be limited. If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session. The contact person will notify interested persons regarding their request to speak by July 18, 2011.

Contact Information

Bryan Emery or Rosanna Harvey 1401 Rockville Pike, HFM-71, Rockville, MD 20852 301-827-1277 FAX: 301-827-0294 e-mail: Bryan.Emery@fda.hhs.gov or email: Rosanna.Harvey@fda.hhs.gov

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Greetings Doctor Emery et al @ TSEAC,


I wish to kindly submit the following Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products.

My main concern is the denial of the same risk factors from atypical CJDs here in the USA from the many overly abundant strains of TSE in animals and man.

IF the study below (see Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque "BSE-L in North America may have existed for decades", IF this comes to be true, as i have believed it to be for years and years, IT is not Saudi Arabia risk factor you should be addressing, it should be the risk factor there from here in the USA and all of North America.

AS the strains, sub-strains of TSE continue to emerge and spread, more and more humans and animals for human and animal consumption will be exposed.

WE know there is some sort of risk factor from the BAXTER study on GSS and blood. WE see now that the Nor-98 atypical scrapie, H-BSE, L-BSE, TME, GSS and some sporadic CJD, all seem to be connected in some way to each other. all of which have been documented in North America. it would be negligent in my opinion to omit this from risk factor assessments. by the time the dots are connected, it will be too late. If accumulation plays a roll, and we accumulate enough of different typical and atypical TSE, what is the threshold from exposure to sub-clinical to clinical (especially now that we know more than one type of TSE can infect a species) ? you cannot answer that. nor can anyone else. so you continue to roll the dice for everyone. we must include all human Transmissible Spongiform Encephalopathy in donor deferral, and we must take an urgent and serious look at Alzheimer's and blood donor risk factor there from, in my opinion.

I hope you can submit this to the TSEAC meeting. if not, please.........PLEASE take time to read the recent scientific studies. the tides turning, however slow it may be, and the science seems to be coming together to show what i have been saying for 14 years. however, it may take another 2 decades for officials and industry to connect the dots$ or admit$ by then it will be much too late.

(please note, the blogs i post my research of data on TSE too, please note i do NOT advertise. i make no money. i simply made a promise to my Mother. i also think science and the truth there from, should be free. i simply use these blogs as a tool to educate the public. ...tss)



please see the follow ;



Bio.108: Transmission of Prion Disease by Multiple, Clinically-Relevant Blood Components Following a Single Blood Transfusion

Sandra McCutcheon,2,† Anthony R. Alejo Blanco,2 E. Fiona Houston,1 Christopher de Wolf,2 Boon Chin Tan,2 Nora Hunter,2 Valerie Hornsey,3 Ian R. MacGregor,3 Christopher V. Prowse,3 Marc Turner3, 4 and Jean C. Manson2

1The University of Glasgow; Glasgow, UK; 2The Roslin Institute and R(D)SVS, University of Edinburgh; Edinburgh, UK; 3Scottish National Blood Transfusion Service; Edinburgh, UK; 4The University of Edinburgh; Edinburgh, UK;†Presenting author; Email: sandra.mccutcheon@roslin.ed.ac.uk

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. While the epidemic appears to be waning, there is much concern that vCJD infection may be amplified/prolonged in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported. Using the most appropriate animal model available, in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion to recipients, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components can act as potential vectors for prion transmission and highlight the importance of multiple control measures to minimize the risk of human to human transmission of vCJD by blood transfusion.


PPPM.18: Induction of Ab Amyloidogenesis In Vivo by Blood Transfusion

Rodrigo Morales,1,† Claudia Duran-Aniotz,1, 2 Akihiko Urayama,1 Lisbell Estrada,3 Diego Morales-Scheihing1, 2 and Claudio Soto1

1University of Texas Health Science Center at Houston; Houston, TX USA; 2Universidad de Los Andes; Santiago, Chile; 3Universidad Catolica de Chile; Santiago, Chile†Presenting author; Email: Rodrigo.MoralesLoyola@uth.tmc.edu

Alzheimer disease (AD) is the most common type of senile dementia. Disease manifestation is characterized by progressive impairment of memory and cognition which is triggered by synaptic dysfunction and neuronal loss. Compelling evidence suggests that misfolding and aggregation of Ab is a hallmark event in the disease pathogenesis. An important unanswered question related to AD involves its etiology since over 90% of the AD cases arise sporadically. Interestingly, misfolding and aggregation of proteins is the main feature of other diseases -termed Protein Misfolding Disorders (PMDs)] which include Transmissible Spongiform Encephalopathies (TSEs), among others. Convincing experimental evidences have shown that the only component of the infectious agent in TSEs is the misfolded form of the prion protein. Strikingly, the molecular mechanisms responsible for prion replication are very similar to the process of amyloid formation in all PMDs, suggesting that all these diseases have the inherent capability of being transmissible. Recent reports have shown that intra-cerebral and intra-peritoneal administration of brain homogenates containing Ab aggregates can accelerate the generation of senile plaques in mice models of AD. However, it remains to be demonstrated if this phenomenon can occur by more relevant routes of administration. The aim of this study was to assess whether AD pathogenesis can be induced intravenously, mimicking the know transmission of prion diseases through blood transfusion. For this purpose we used young tg2576 mice which were injected with blood obtained from 12 months old tg2576 mice (AD-blood) that contains a substantial quantity of cerebral Ab deposits. Mice were sacrificed at 250 days old, a time in which these animals scarcely develop Ab deposits. Interestingly, we observed that infusion of AD-blood induces substantial Ab accumulation in animals that without treatment or injected with wild type blood would barely have any detectable Ab lesion. Plaque deposition was mainly present in cortex and hippocampus, being more abundant in the former. In addition, we observed a decrease in memory in mice challenged with AD-blood. Other features such as brain inflammation and synaptic integrity were also measured. Importantly, similar results were obtained in a second and independent experiment performed in a double transgenic mouse model that develops AD plaques as early as 4 months old. Our results indicate that an AD-like pathogenesis can be induced by intravenous administration of AD-blood, presumably through induction of protein misfolding in a similar way as prion diseases. These findings may open a new avenue to understand the origin of sporadic AD and may provide new strategies for disease intervention and prevention.


http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf


Sunday, June 26, 2011

Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/risk-analysis-of-low-dose-prion.html



Saturday, June 25, 2011

Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque

"BSE-L in North America may have existed for decades"

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/transmissibility-of-bse-l-and-cattle.html



Thursday, June 23, 2011

Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/experimental-h-type-bovine-spongiform.html



Monday, June 27, 2011

Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease

http://prionopathy.blogspot.com/2011/06/comparison-of-sheep-nor98-with-human.html


IN reference to the above study, please see ;


Bio.001: Protease-Sensitive Synthetic Prions and Evidence that Tg9949 Mice Do Not Spontaneously Generate Prions

David Colby1,† and Stanley Prusiner2

1University of Delaware; Newark, DE USA; 2University of California, San Francisco; San Francisco, CA USA†Presenting author; Email: colby@udel.edu

The resistance of many forms of PrPSc to protease digestion provides a convenient assay used to identify the presence of prions in tissue samples. However, protease-sensitive prions (sPrPSc) have also been isolated, and many prion strains have been found to be composed of mixtures of sPrPSc and protease resistant prions (rPrPSc). We have generated novel synthetic prions, composed of wild-type PrP, which are serially transmissible in two lines of transgenic mice, result in neuropathology indicative of prion disease, and cause a conformational change in PrP that is not accompanied by resistance to proteinase K. Inoculation of recombinant PrP of residues 89-230, refolded into an amyloid conformation, into Tg9949 mice resulted in the generation of these protease-sensitive prions. In control experiments, Tg9949 mice, which overexpress an N-terminally truncated form of PrP, were found to be prone to late onset neurological dysfunction distinct from prion disease. Control Tg9949 mice lacked both prion neuropathology and any detectable change in the conformation of PrP. Repeated serial passage of age-matched brain material from control Tg9949 mice did not generate prions. Our results demonstrate that sPrPSc of wild-type sequence can be pathogenic and transmissible and suggest that the contribution of sPrPSc may be overlooked in many studies that rely on the measurement of rPrPSc alone.

http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf


Monday, May 23, 2011

Atypical Prion Diseases in Humans and Animals 2011

Top Curr Chem (2011)

DOI: 10.1007/128_2011_161

# Springer-Verlag Berlin Heidelberg 2011

Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar

Abstract

Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.

M.A. Tranulis (*)

Norwegian School of Veterinary Science, Oslo, Norway

e-mail: Michael.Tranulis@nvh.no

S.L. Benestad

Norwegian Veterinary Institute, Oslo, Norway

T. Baron

Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France

H. Kretzschmar

Ludwig-Maximilians University of Munich, Munich, Germany

Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type

http://resources.metapress.com/pdf-preview.axd?code=f433r34h34ugg617&size=largest


snip...

SEE FULL TEXT AND MUCH MORE HERE;

Monday, May 23, 2011

Atypical Prion Diseases in Humans and Animals 2011

http://bse-atypical.blogspot.com/2011/05/atypical-prion-diseases-in-humans-and.html


Monday, June 27, 2011

Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates

http://chronic-wasting-disease.blogspot.com/2011/06/zoonotic-potential-of-cwd-experimental.html



Tuesday, June 14, 2011

Clinical research in CJD at a U.S. clinical prion research center: CJD Quinacrine Study results and improved diagnosis of prion disease

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/clinical-research-in-cjd-at-us-clinical.html


Sunday, May 01, 2011

STUDY OF ATYPICAL BSE 2010 Annual Report May 2011

http://bse-atypical.blogspot.com/2011/05/study-of-atypical-bse-2010-annual.html


Friday, June 03, 2011

Estimation of variant Creutzfeldt-Jakob disease infectivity titers in human blood

http://vcjdtransfusion.blogspot.com/2011/06/estimation-of-variant-creutzfeldt-jakob.html


Saturday, May 14, 2011

USA Blood products, collected from a donor who was at risk for vCJD, were distributed Nationally and Internationally MAY 11, 2011

http://vcjdtransfusion.blogspot.com/2011/05/usa-blood-products-collected-from-donor.html


Sunday, May 1, 2011

W.H.O. T.S.E. PRION Blood products and related biologicals May 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/05/who-tse-prion-blood-products-and.html


Saturday, April 30, 2011

Blood product, collected from a donor who was at risk for variant Creutzfeldt-Jakob disease (vCJD), was distributed APRIL 27, 2011

http://vcjdtransfusion.blogspot.com/2011/04/blood-product-collected-from-donor-who.html


Sunday, March 6, 2011

U.K. and U.S.A. vCJD, CJD, TSE screen (a) the blood supply and (b) blood donors Commons Hansard Written Answers and FDA March 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/uk-and-usa-vcjd-cjd-tse-screen-the.html


Saturday, March 5, 2011

MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/mad-cow-atypical-cjd-prion-tse-cases.html


Tuesday, April 26, 2011

sporadic CJD RISING Text and figures of the latest annual report of the NCJDRSU covering the period 1990-2009 (published 11th March 2011)

http://creutzfeldt-jakob-disease.blogspot.com/2011/04/sporadic-cjd-rising-text-and-figures-of.html


Tuesday, March 29, 2011

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY EXPOSURE SPREADING VIA HOSPITALS AND SURGICAL PROCEDURES AROUND THE GLOBE

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/transmissible-spongiform-encephalopathy.html


FC5.1.1

Transmission Results in Squirrel Monkeys Inoculated with Human sCJD, vCJD, and GSS Blood Specimens: the Baxter Study

Brown, P1; Gibson, S2; Williams, L3; Ironside, J4; Will, R4; Kreil, T5; Abee, C3 1Fondation Alliance BioSecure, France; 2University of South Alabama, USA; 3University of Texas MD Anderson Cancer Center, USA; 4Western General Hospital, UK; 5Baxter BioSience, Austria

Background: Rodent and sheep models of Transmissible Spongiform Encephalopathy (TSE) have documented blood infectivity in both the pre-clinical and clinical phases of disease. Results in a (presumably more appropriate) non-human primate model have not been reported.

Objective: To determine if blood components (red cells, white cells, platelets, and plasma) from various forms of human TSE are infectious.

Methods: Blood components were inoculated intra-cerebrally (0.1 ml) and intravenously (0.5 ml) into squirrel monkeys from 2 patients with sporadic Creutzfeldt- Jakob disease (sCJD) and 3 patients with variant Creutzfeldt-Jakob disease (vCJD). Additional monkeys were inoculated with buffy coat or plasma samples from chimpanzees infected with either sCJD or Gerstmann-Sträussler-Scheinker disease (GSS). Animals were monitored for a period of 5 years, and all dying or sacrificed animals had post-mortem neuropathological examinations and Western blots to determine the presence or absence of the misfolded prion protein (PrPTSE).

Results: No transmissions occurred in any of the animals inoculated with blood components from patients with sporadic or variant CJD. All donor chimpanzees (sCJD and GSS) became symptomatic within 6 weeks of their pre-clinical phase plasmapheresis, several months earlier than the expected onset of illness. One monkey inoculated with purified leukocytes from a pre-clinical GSS chimpanzee developed disease after 36 months.

Conclusion: No infectivity was found in small volumes of blood components from 4 patients with sporadic CJD and 3 patients with variant CJD. ***However, a single transmission from a chimpanzee-passaged strain of GSS shows that infectivity may be present in leukocytes, and the shock of general anaesthesia and plasmspheresis appears to have triggered the onset of illness in pre-clinical donor chimpanzees.



Saturday, September 5, 2009

TSEAC MEETING FEBRUARY 12, 2004 THE BAXTER STUDY GSS

snip...

But the first thing is our own study, and as I mentioned, it's a Baxter primate study, and those are the major participants. And the goal was twofold, and here is the first one: to see whether CJD, either sporadic or familial -- actually it turns out to be the familial CJD is incorrect. It really should be the Fukuoka strain of Gerstmann-Straussler-Scheinker disease. So it's really GSS instead of familial CJD -- when passaged through chimps into squirrel monkeys using purified blood components, very pure blood components.

So this addresses the question that was raised just recently about whether or not red cell infectivity that's been found in rodents is really in the red cells or is it contaminated.

We prepared these samples with exquisite care, and they are ultra-ultra-ultra purified. There's virtually no contamination of any of the components that we looked at ? platelets, red cells, plasma, white cells -- with any other component.

These are a sort of new set of slides, and what I've tried to do is make them less complicated and more clear, but I'm afraid I haven't included the build. So you'll just have to try and follow what I explain with this little red pointer.

There were three initial patients. Two of them had sporadic CJD. One of them had Gerstmann-Straussler-Scheinker syndrome. Brain tissue from each individual patient was inoculated intracerebrally into a pair of chimpanzees. All right?

From those chimps, either plasma or ultra purified -- in fact, everything is ultra-purified. I'll just talk about purified plasma, purified white cells -- were inoculated intracerebrally and intravenously to get the maximum amount of infective load into a pair of squirrel monkeys.

The same thing was done for each of these three sets. This monkey died from non-CJD causes at 34 months post inoculation.

Let me go back for a second. I didn't point out the fact that these were not sacrificed at this point. These chimpanzees were apheresed at 27 weeks when they were still asymptomatic. In this instance, we apheresed them terminally when they were symptomatic.

And before I forget, I want to mention just a little sidelight of this. Chimpanzees in our experience -- and I think we may be the only people that have ever inoculated chimpanzees, and that's no longer a possibility, so this was 20, 30 years ago -- the shortest incubation period of any chimpanzee that we have ever seen with direct intracerebral inoculation is 13 months.

So we chose 27 weeks, which is about seven months, and incidentally typically the incubation period is more like 16 or 18 months. The shortest was 13 months. We chose the 27th week, which is about six and a half months, thinking that this would be about halfway through the incubation period, which we wanted to check for the presence or absence of infectivity.

But within four weeks after the apheresis, which was conducted under general anesthesia for three or four hours apiece, every single one of the six chimpanzees became symptomatic. That is another experiment that I would love to conclude, perhaps because this is simply not heard of, and it very much smells like we triggered clinical illness. We didn't trigger the disease, but it certainly looks like we triggered symptomatic disease at a point that was much earlier than one would have possibly expected.

Maybe it will never be done because it would probably open the floodgates of litigation. There's no end of little things that you can find out from CJD patients after the fact. For example, the neighbor's dog comes over, barks at a patient, makes him fall down, and three weeks later he gets CJD. So you have a lawsuit against the neighbor.

I mean, this is not an unheard of matter, but I do think that physical stress in the form of anesthesia and four hours of whatever goes on with anesthesia, low blood pressure, sometimes a little hypoxemia looks like it's a bad thing.

So here we have the 31st week. All of the chimps are symptomatic, and here what we did was in order to make the most use of the fewest monkeys, which is always a problem in primate research, we took these same three patients and these six chimps. Only now we pooled these components; that is to say, we pooled the plasma from all six chimps. We pooled ultra-purified white cells from all six chimps because here we wanted to see whether or not we could distinguish a difference between intracerebral route of infection and intravenous route of infection.

With respect to platelets and red blood cells, we did not follow that. We inoculated both intracerebral and intravenously, as we had done earlier because nobody has any information on whether or not platelets and red cells are infectious, and so we wanted again to get the maximum.

This is an IV versus IC goal. This one, again, is just getting the maximum load in to see whether there is, in fact, any infectivity in pure platelets, in pure red cells.

And of all of the above, the only transmission of disease related to the inoculation was in a squirrel monkey that received pure leukocytes from the presymptomatic apheresis. So that goes some way to address the question as to whether or not it's a matter of contamination. To date the red cells have not been -- the monkeys that receive red cells have not been observed for more than a year because that was a later experiment.

So we still can't say about red cells, but we're about four and a half years down the road now, and we have a single transmission from purified leukocytes, nothing from plasma and nothing from platelets.

That was the first part of the experiment. The second part was undertaken with the cooperation of Bob Will and others supplying material to us. These were a couple of human, sporadic cases of CJD and three variant cases of CJD from which we obtained buffy coat and plasma separated in a normal way. That is, these are not purified components.

The two cases of sporadic CJD, the plasma was pooled from both patients. The buffy coat was pooled from both patients, and then inoculated intracerebrally and intravenously into three squirrel monkeys each. This is a non-CJD death five years after inoculation. The other animals are still alive.

For variant CJD we decided not to pool. It was more important to eliminate the possibility that there was just a little bit of infectivity in one patient that would have been diluted to extinction, if you like, by mixing them if it were to so occur with two patients, for example, who did not have infectivity. So each one of these was done individually, but the principle was the same: plasma and buffy coat for each patient was inoculated into either two or three squirrel monkeys. This is, again, a non-CJD related death.

In addition to that, we inoculated rain as a positive control from the two sporadic disease cases of human -- from the two human sporadic cases at ten to the minus one and ten to the minus three dilutions. We have done this many, many times in the past with other sporadic patients. So we knew what to expect, and we got exactly what we did expect, namely, after an incubation period not quite two years, all four monkeys developed disease at this dilution and at the minus three dilution, not a whole lot of difference between the two.

Now, these are the crucial monkeys because each one of these monkeys every three to four months was bled and the blood transfused into a new healthy monkey, but the same monkey all the time. So this monkey, for example, would have received in the course of 21 months about six different transfusions of blood from this monkey into this monkey, similarly with this pair, this pair, and this pair. So you can call these buddies. This is sort of the term that was used. These monkeys are still alive.

In the same way, the three human variant CJD specimens, brain, were inoculated into four monkeys, and again, each one of these monkeys has been repeatedly bled at three to four month intervals and that blood transfused into a squirrel monkey, the same one each time. Ideally we would love to have taken bleeding at three months and inoculated a monkey and then let him go, watch him, and then done the same thing at six months. It would have increased the number of monkeys eightfold and just unacceptably expensive. So we did the best we could.

That, again, is a non-CJD death, as is this.

This was of interest mainly to show that the titer of infectivity in brain from variant CJD is just about the same as it from sporadic. We didn't do a minus five and a minus seven in sporadic because we have an enormous experience already with sporadic disease in squirrel monkeys, and we know that this is exactly what happens. It disappears at about ten to the minus five. So the brain titer in monkeys receiving human vCJD is identical to the brain titer in monkeys that have been inoculated with sporadic CJD.

That's the experiment. All of the monkeys in aqua are still alive. They are approaching a five-year observation period, and I think the termination of this experiment will now need to be discussed very seriously in view of a probable six-year incubation period in the U.K. case. The original plan was to terminate the experiment after five years of observation with the understanding that ideally you would keep these animals for their entire life span, which is what we used to do when had unlimited space, money, and facilities. We can't do that anymore.

It's not cheap, but I think in view of the U.K. case, it will be very important to think very seriously about allowing at least these buddies and the buddies from the sporadic CJD to go on for several more years because although you might think that the U.K. case has made experimental work redundant, in point of fact, anything that bears on the risk of this disease in humans is worthwhile knowing, and one of the things we don't know is frequency of infection. We don't know whether this case in the U.K. is going to be unique and never happen again or whether all 13 or 14 patients have received blood components are ultimately going to die. Let's hope not.

The French primate study is primarily directed now by Corinne Lasmezas. As you know, the late Dominique Dromont was the original, originally initiated this work, and they have very active primate laboratory in France, and I'm only going to show two very simple slides to summarize what they did.

The first one is simply to show you the basis of their statement that the IV route of infection looks to be pretty efficient because we all know that the intracerebral route of infection is the most efficient, and if you look at this where they inoculated the same infective load either intracerebrally or intravenously, the incubation periods were not substantially different, which suggests but doesn't prove, but doesn't prove that the route of infection is pretty efficient.

Lower doses of brain material given IV did extend the incubation period and presumably it's because of the usual dose response phenomenon that you see in any infectious disease.

With a whopping dose of brain orally, the incubation period was even lower. Again, just one more example of inefficiency of the route of infection and the necessity to use more infective material to get transmissions.

And they also have blood inoculated IV which is on test, and the final slide or at least the penultimate slide shows you what they have on test and the time of observation, that taken human vCJD and like us inoculated buffy coat, they've also inoculated whole blood which we did not do.

So to a great extent their studies are complementary to ours and makes it all worthwhile.

We have about -- oh, I don't know -- a one to two-year lead time on the French, but they're still getting into pretty good observation periods. Here's three-plus years.

They have variant CJD adapted to the macaque. That is to say this one was passaged in macaque monkeys, the cynomolgus, and they did the same thing. Again, we're talking about a study here in which like ours there are no transmissions. I mean, we have that one transmission from leukocytes, and that's it.

Here is a BSE adapted to the macaque. Whole blood, and then they chose to inoculate leukodepleted whole blood, in both instances IV. Here they are out to five years without a transmission.

And then finally oral dosing of the macaque, which had been infected with -- which was infected with BSE, but a macaque passaged BSE, whole blood buffy coat and plasma, all by the IC route, and they're out to three years.

So with the single exception of the leukocyte transmission from our chimp that was inoculated with a sporadic case of CJD or -- excuse me -- with a GSS, Gerstmann-Straussler, in neither our study nor the French study, which are not yet completed have we yet seen a transmission.

And I will just close with a little cartoon that appeared in the Washington Post that I modified slightly lest you get too wound up with these questions of the risk from blood. This should be a "corrective."

(Laughter.)

DR. BROWN: Thanks.

Questions?

CHAIRPERSON PRIOLA: Yes. Any questions for Dr. Brown? Dr. Linden.

DR. LINDEN: I just want to make sure I understand your study design correctly. When you mention the monkeys that have the IV and IC inoculations, the individual monkeys had both or --

DR. BROWN: Yes, yes, yes. That's exactly right.

DR. LINDEN: So an individual monkey had both of those as opposed to some monkeys had one and some had the other?

DR. BROWN: Correct, correct. Where IC and IV are put down together was IC plus IV into a given monkey.

DR. LINDEN: Into a given monkey. Okay.

And the IC inoculations, where were those given?

DR. BROWN: Right parietal cortex, Southern Alabama.

(Laughter.)

DR. BROWN: Oh, it can't be that clear. Yeah, here, Pierluigi.

CHAIRPERSON PRIOLA: Dr. Epstein.

DR. BROWN: Pierluigi always damns me with feint praise. He always says that's a very interesting study, but. I'm waiting for that, Pierluigi.

I think Jay Epstein --

DR. GAMBETTI: I will say that there's an interesting study and will say, but I just --

(Laughter.)

DR. GAMBETTI: -- I just point of review. You talk about a point of information. You say that -- you mention GSS, I guess, and the what, Fukuowa (phonetic) --

DR. BROWN: Yes, Fukuoka 1.

DR. GAMBETTI: Fukuowa, and is that from the 102, if I remember correctly, of the --

DR. BROWN: Yes, that is correct.

DR. GAMBETTI: Because that is the only one that also --

DR. BROWN: No, it's not 102. It's 101. It's the standard. It's a classical GSS. Oh, excuse me. You're right. One, oh, two is classical GSS. It's been so long since I've done genetics. You're right.

DR. GAMBETTI: Because that is the only one I know, I think, that I can remember that has both the seven kv fragment that is characteristic of GSS, but also the PrPsc 2730. So in a sense, it can be stretching a little bit compared to the sporadic CJD.

DR. BROWN: Yeah, I think that's right. That's why I want to be sure that I made you aware on the very first slide that that was not accurate, that it truly was GSS.

There's a GSS strain that has been adapted to mice, and it's a hot strain, and therefore, it may not be translatable to sporadic disease, correct. All we can say for sure is that it is a human TSE, and it is not variant. I think that's about it.

DR. GAMBETTI: I agree, but this is also not perhaps the best --

DR. BROWN: No, it is not the best. We understand --

DR. GAMBETTI: -- of GSS either.

DR. BROWN: Yeah. If we had to do it over again, we'd look around for a -- well, I don't know. We'd probably do it the same way because we have two sporadics already on test they haven't transmitted, and so you can take your pick of what you want to pay attention to.

Jay?

DR. EPSTEIN: Yes, Paul. Could you just comment? If I understood you correctly, when you did the pooled apheresis plasma from the six chimps when they were symptomatic at 31 weeks, you also put leukocytes into squirrel monkeys in that case separately IV and IC, but in that instance you have not seen an infection come down in squirrel monkey, and the question is whether it's puzzling that you got transmission from the 27-week asymptomatic sampling, whereas you did not see transmission from the 31-week sampling in symptomatic animals.

DR. BROWN: Yes, I think there are two or three possible explanations, and I don't know if any of them are important. The pre-symptomatic animal was almost symptomatic as it turned out so that we were pretty close to the period at which symptoms would being, and whether you can, you know, make much money on saying one was incubation period and the other was symptomatic in this particular case because both bleedings were so close together. That's one possibility.

The other possibility is we're dealing with a very irregular phenomenon and you're not surprised at all by surprises, so to speak so that a single animal, you could see it almost anywhere.

The third is that we, in fact, did just what I suggested we didn't want to do for the preclinical, namely, by pooling we got under the threshold. See?

You can again take that for what it's worth. It is a possible explanation, and again, until we know what the levels of infectivity are and whether by pooling we get under the threshold of transmission, we simply cannot make pronouncements.

CHAIRPERSON PRIOLA: Dr. DeArmond.

DR. DeARMOND: Yeah, it was very interesting data, but the --

(Laughter.)

DR. BROWN: I just love it. Go ahead.

DR. DeARMOND: Two comments. The first one was that the GSS cases, as I remember from reading your publications -- I think Gibbs was involved with them -- when you transmitted the GSS into animals, into monkeys, perhaps I think it was chimps, the transmission was more typical of CJD rather than GSS. There were no amyloid plaques. It was vacuolar degeneration so that you may be transmitting a peculiar form, as I criticized once in Bali and then you jumped all over me about.

DR. BROWN: I may do it again.

DR. DeARMOND: Calling me a bigot and some other few things like that.

(Laughter.)

DR. BROWN: Surely not. I wouldn't have said that.

DR. DeARMOND: So there could be something strange about that particular --

DR. BROWN: Yeah. I think you and Pierluigi are on the same page here. This may be an unusual strain from a number of points of view.

DR. DeARMOND: The other question though has to do with species barrier because the data you're showing is kind of very reassuring to us that it's hard to transmit from blood, but the data from the sheep and from the hamsters and some of the work, I think, that has been done by others, that it's easy in some other animals to transmit, hamster to hamster, mouse to mouse.

Could you comment on the --

DR. BROWN: That's exactly why we went to primates. That's exactly it, because a primate is closer to a human than a mouse is, and that's just common sense.

And so to try and get a little closer to the human situation and not totally depend on rodents for transferrable data, that is why you would use a primate. Otherwise you wouldn't use them. They're too expensive and they cause grief to animal care study people and protocol makers and the whole thing.

Primate studies are a real pain.

DR. DeARMOND: But right now it's inconclusive and you need more time on it.

DR. BROWN: I believe that's true. I think if we cut it off at six years you could still say it was inconclusive, and cutting it off at all will be to some degree inconclusive, and that's just the way it is.

DR. DeARMOND: So what has to be done? Who do you have to convince, or who do we all have to convince to keep that going?

DR. BROWN: Thomas?

Without trying to be flip at all, the people that would be the first people to try to convince would be the funders of the original study. If that fails, and it might for purely practical reasons of finance, then we will have to look elsewhere because I really don't want to see those animals sacrificed, not those eight buddies. Those are crucial animals, and they don't cost a whole lot to maintain. You can maintain eight -- well, they cost a lot from my point of view, but 15 to $20,000 a year would keep them going year after year.

CHAIRPERSON PRIOLA: Dr. Johnson.

DR. JOHNSON: Yeah, Paul, I'm intrigued as you are by the shortening of the incubation period. Have you in all of the other years of handling these animals when they were transfused, when they were flown out to Louisiana at night -- a lot of the stressful things have happened to some of these chimps. Have you ever noticed that before or is this a new observation?

DR. BROWN: Brand new.

MR. JOHNSON: Brand new. Okay.

CHAIRPERSON PRIOLA: Bob, did you want to say something? Dr. Rohwer.

DR. ROHWER: The Frederick fire, wasn't that correlated with a lot of --

DR. BROWN: Not that I k now of, but you may --

DR. ROHWER: Well, that occurred shortly after I came to NIH, and what I remember is that there were a whole bunch of conversions that occurred within the few months following the fire. That was fire that occurred adjacent to the NINDS facility, but in order to protect it, they moved the monkeys out onto the tarmac because they weren't sure it wouldn't burn as well.

DR. BROWN: Well, if you're right, then it's not brand new, but I mean, I'm not sure how we'll ever know because if I call Carlton and ask him, I'm not sure but what I would trust the answer that he gives me, short of records.

You know, Carlot is a very enthusiastic person, and he might say, "Oh, yeah, my God, the whole floor died within three days," but I would want to verify that.

On the other hand, it may be verifiable. There possibly are records that are still extant.

DR. ROHWER: Actually I thought I heard the story from you.

(Laughter.)

DR. BROWN: You didn't because it's brand new for me. I mean, either that or I'm on the way

(Laughter.)

CHAIRPERSON PRIOLA: Dr. Bracey.

DR. BRACEY: I was wondering if some of the variability in terms of the intravenous infection route may be related to intraspecies barriers, that is, the genetic differences, the way the cells, the white leukocytes are processed, whether or not microchimerism is established, et cetera.

DR. BROWN: I don't think that processing is at fault, but the question, the point that you raise is a very good one, and needless to say, we have material with which we can analyze genetically all of the animals, and should it turn out that we get, for example, -- I don't know -- a transmission in one variant monkey and no transmissions in another and a transmission in three sporadic monkeys, we will at that point genetically analyze every single animal that has been used in this study, but we wanted to wait until we could see what would be most useful to analyze.

but the material is there, and if need be, we'll do it.

CHAIRPERSON PRIOLA: Okay. Thank you very much, Dr. Brown.

I think we'll move on to the open public hearing section of the morning.

snip...

http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4019t1.DOC



snip...

see full text ;

http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html


Friday, June 03, 2011

Estimation of variant Creutzfeldt-Jakob disease infectivity titers in human blood

http://vcjdtransfusion.blogspot.com/2011/06/estimation-of-variant-creutzfeldt-jakob.html


Wednesday, March 2, 2011

Transmissible Spongiform Encephalopathies Advisory Committee Meeting Transcript Posted: 3/2/2011 Posted: 3/2/2011

October 28, 2010

http://tseac.blogspot.com/2011/03/transmissible-spongiform.html


Tuesday, September 14, 2010

Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting October 28 and 29, 2010 (COMMENT SUBMISSION)

http://tseac.blogspot.com/2010/09/transmissible-spongiform_14.html


Sunday, May 10, 2009

Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)

TO : william.freas@fda.hhs.gov

May 8, 2009

Greetings again Dr. Freas, TSEAC et al,

I would kindly, once again, wish to comment at this meeting about the urgent actions that need to be taken asap, to the Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009. Due to my disability from my neck injury, I will not be attending this meeting either, however I hope for my submission to be read and submitted. ...

IN reply to ;

http://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html


Friday, June 12, 2009

vCJD-related abnormal prion protein in a person with haemophilia - an update

http://vcjdtransfusion.blogspot.com/2009/06/vcjd-related-abnormal-prion-protein-in.html


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


PDF]Freas, William TSS SUBMISSION

File Format: PDF/Adobe Acrobat -

Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary Sr. [flounder@wt.net]

Monday, January 08,200l 3:03 PM freas ...

http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf


-----Original Message-----

From: Terry S. Singeltary Sr. [mailto:flounder@wt.net]

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,

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


Tuesday, February 8, 2011

U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001

http://tseac.blogspot.com/2011/02/usa-50-state-bse-mad-cow-conference.html


Suppressed peer review of Harvard study October 31, 2002.

October 31, 2002 Review of the Evaluation of the Potential for Bovine Spongiform Encephalopathy in the United States Conducted by the Harvard Center for Risk Analysis, Harvard School of Public Health and Center for Computational Epidemiology, College of Veterinary Medicine, Tuskegee University Final Report Prepared for U.S. Department of Agriculture Food Safety and Inspection Service Office of Public Health and Science Prepared by RTI Health, Social, and Economics Research Research Triangle Park, NC 27709 RTI Project Number 07182.024

http://www.fsis.usda.gov/oa/topics/BSE_Peer_Review.pdf


Sunday, February 14, 2010

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

http://bseusa.blogspot.com/2010/02/docket-no-fsis-2006-0011-fsis-harvard.html


PLEASE SEE FULL TEXT 98 PAGES HERE ;

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf


Response to Public Comments on the Harvard Risk Assessment of Bovine Spongiform Encephalopathy

Update, October 31, 2005 INTRODUCTION The United States Department of Agriculture’s Food Safety and Inspection Service (FSIS) held a public meeting on July 25, 2006 in Washington, D.C. to present findings from the Harvard Risk Assessment of Bovine Spongiform Encephalopathy Update, October 31, 2005 (report and model located on the FSIS website: http://www.fsis.usda.gov/Science/Risk_Assessments/index.asp).

Comments on technical aspects of the risk assessment were then submitted to FSIS. Comments were received from Food and Water Watch, Food Animal Concerns Trust (FACT), Farm Sanctuary, R-CALF USA, Linda A Detwiler, and Terry S. Singeltary.

This document provides itemized replies to the public comments received on the 2005 updated Harvard BSE risk assessment. Please bear the following points in mind:

http://www.fsis.usda.gov/PDF/BSE_Risk_Assess_Response_Public_Comments.pdf


From: Terry S. Singeltary Sr.

To: FREAS@CBER.FDA.GOV

Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov

Sent: Friday, December 01, 2006 2:59 PM

Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION]

snip...

ONE FINAL COMMENT PLEASE, (i know this is long Dr. Freas but please bear with me)

THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted blood from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone.

These are the facts as i have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species. ...

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518

snip... 48 pages...page 1 starts on page 13, then come back to page 1 to finish.....tss

http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8


TSEAC JUNE 2, 1999

Welcome to the FDA traveling road show

From: TSS

snip...

CHAIRMAN BROWN: A couple of points just to bring your experimental data up to speed. Unpublished further experiments on the mouse model have produced good news and bad news.

The bad news is that we have a disappointingly large number of transmissions following intravenous inoculation of either plasma or Buffy coat. We also have a transmission using whole blood as a transfusion into these mice. So that's not good news.

The other thing that is not too good is that we have now got in this particular model a ratio of five to one, as opposed to ten to one, which was also disappointing.

The only piece of good news in that in terms of experimental data is that we found that, again, in this model, the level of infectivity during the entire incubation period is almost negligible compared to the level of infectivity during the clinical phase of illness. And that is very good news indeed. So these are data that are not yet published but ??

snip...

snip...page 154

CHAIRMAN BROWN: Well, this is exactly why we're here today. Dr. Satcher and the other groups have already decided that this is not worth significant worry with respect to classical CJD, and that new variant was an unknown. And so that's why we're considering specifically new variant because we don't have information specifically on it. I mean, everything we don't have information on becomes a subject for this committee. (Laughter.)

snip...

snip...page 218

MS. HARRELL: Well, I asked him the question, was there a deferral ?? was there deferral criteria for blood donors for classic CJD for people who have either resided or visited the UK.

CHAIRMAN BROWN: I'm sorry. Repeat that, the question.

MS. HARRELL: Is there a deferral policy for blood donors to attempt to reduce the risk of transmitting classic CJD for people who either resided or visited the UK?

DR. SCHONBERGER: The answer is no.

MS. HARRELL: And if there is no risk, if we think that there is no risk of transmitting the whatever to ?? for CJD, what makes this different, for new variant CJD much different?

CHAIRMAN BROWN: That's the first time, Stan, you'll ever hear of prion referred to as a whatever. (Laughter.)

CHAIRMAN BROWN: I mean, I've heard it referred to as a lot of different things. I'm ??

DR. PRUSINER: You've said that many times, Paul. (Laughter.)

CHAIRMAN BROWN: It may be that ??

DR. PRUSINER: Is that in the Congressional Record?

CHAIRMAN BROWN: The issue is not about sporadic CJD. That is the issue we can sort of generically say CJD. Presumably, if the blood from a patient with new variant CJD were infectious, the disease that it would transmit would be new variant CJD. So it's not ??

MS. HARRELL: Okay. So CJD is not transmitted through the blood is what you're saying?

CHAIRMAN BROWN: We have no evidence from looking at populations that that has ever happened. The question is: since we know it can happen when we use experimental models of CJD, we can take CJD blood from one animal and produce the disease in another animal.

So there is the "theoretical possibility" that this might also happen in humans, particularly with a different strain of the disease, which new variant is, about which we don't know a whole lot. That's the question.

DR. SCHONBERGER: Isn't the answer to her question that the incidence of CJD, REDS, classic CJD, is not influenced by whether or not you've lived in the UK between 1980 and 1996 ??

CHAIRMAN BROWN: Yes.

DR. SCHONBERGER: ?? but the incidence of new variant CJD is?

CHAIRMAN BROWN: Yes, 40-love. (Laughter.)


snip...


see more here ;

http://tseac.blogspot.com/2011/06/tseac-june-2-1999-welcome-to-fda.html



Saturday, January 2, 2010

Human Prion Diseases in the United States January 1, 2010 ***FINAL***

http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html


Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.

http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf


my comments to PLosone here ;

http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd


Wednesday, March 31, 2010

Atypical BSE in Cattle

To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.

This study will contribute to a correct definition of specified risk material (SRM) in atypical BSE. The incumbent of this position will develop new and transfer existing, ultra-sensitive methods for the detection of atypical BSE in tissue of experimentally infected cattle.

http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2


Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed. ***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat

snip...

http://www.neuroprion.org/en/np-neuroprion.html


http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html


14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America

update October 2009

T. Singeltary

Bacliff, TX, USA

Background:

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

Methods:

12 years independent research of available data

Results:

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

Conclusion:

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf



Thursday, February 24, 2011

The risk of variant Creutzfeldt-Jakob disease among UK patients with bleeding disorders, known to have received potentially contaminated plasma products

http://vcjdtransfusion.blogspot.com/2011/02/risk-of-variant-creutzfeldt-jakob.html


Saturday, January 22, 2011

Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/alzheimers-prion-and-neurological.html



CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.

2. Briefly, the meeting agreed that:

i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.

93/01.05/4.1tss

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf



BSE101/1 0136

IN CONFIDENCE

5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.

What are the implications for public health?

3. . The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

92/11.4/1-1

BSE101/1 0137

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832

121/YdeStss

92/11.4/1.2

http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf



http://betaamyloidcjd.blogspot.com/


Oral presentations

Oral.01: Changing Spectrum of Prions

Stanley Prusiner

University of California San Francisco, Institute for Neurodegenerative Diseases; San Francisco, CA USA

Prions are self-propagating forms of proteins found in eukaryotes. Prions are created from benign, cellular precursor proteins by a posttranslational modification that is self-perpetuating. Often the prion form of the protein is aggregated and assembles into amyloid polymers. Prions can be inherited both genetically and epigenetically. In neurodegenerative diseases, the formation of prions is heritable through mutations in the gene encoding the cellular form of the prion protein. In fungi, the prion state is epigenetically transferred from mother to daughter cells.

Historically, prions were confined to a small group of infectious CNS illnesses including Creutzfeldt-Jakob disease (CJD) and kuru of humans, scrapie of sheep, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk. CJD can present as an infectious, inherited or sporadic illness. In all three manifestations of the disease, the cellular prion protein (PrPC) refolds into the disease-causing isoform (PrPSc). A truncated form of PrPSc readily polymerizes into amyloid fibrils and forms PrP amyloid plaques. Prion strains composed of different conformers of PrPScSc have been identified. Subsequently, prions were recognized in fungi and studied extensively using yeast. Recently, self-propagation of altered proteins that cause several neurodegenerative diseases, including Alzheimer disease and the tauopathies, has been demonstrated using cultured cell and transgenic mouse models. Increasing evidence argues that the Ab peptide acts as a prion in that it stimulates the de-novo formation of more Ab peptide. Similarly, the aggregates of Tau provoke the assembly of more aggregated Tau. In addition, fetal grafts of substantia nigra in patients with advanced Parkinson’s disease exhibit Lewy bodies, arguing that a-synuclein may act as a prion. Misfolded a-synuclein is thought to transit from the patient’s neurons to those in the graft, where it stimulates the de-novo formation of aberrantly folded a-synuclein into Lewy bodies.

The spread of misprocessed proteins in the human CNS is also consistent with the Ab peptide, hyperphosphorylated Tau and misfolded a-synuclein being prions. In Alzheimer disease, Ab plaques and neurofibrillary tangles (NFTs) begin in the entorhinal cortex and spread throughout the brain. In a delayed form of traumatic brain injury, NFTs appear to spread outward from points of impact. Misfolded a-synuclein has been found along the vagus nerve where it appears to migrate retrograde into the CNS.

Increasing evidence that posttranslationally altered proteins are responsible for the major neurodegenerative diseases widens the spectrum of prion disorders. Moreover, prions with glutamine/asparagine-rich regions like those in yeast and aplysia have given unique insights into the normal function of alternatively processed, self-propagating proteins.

http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf


Wednesday, January 5, 2011

ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions

David W. Colby1,* and Stanley B. Prusiner1,2

http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html


http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html


Friday, September 3, 2010

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html


Thursday, December 23, 2010

Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom

http://betaamyloidcjd.blogspot.com/2010/12/alimentary-prion-infections-touch-down.html


Saturday, March 22, 2008

10 Million Baby Boomers to have Alzheimer's in the coming decades

snip...

Alzheimer’s disease is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years. More than 5 million Americans are estimated to have Alzheimer’s disease. Every 71 seconds someone in America develops Alzheimer’s disease; by 2050 it is expected to occur every 33 seconds. During the coming decades, baby boomers are projected to add 10 million people to these numbers. By 2050, the incidence of Alzheimer’s disease is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million persons. Significant cost implications related to Alzheimer’s disease and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (eg, caregiver lost wages and out-of-pocket expenses, decreased business productivity) costs. Not included in these figures are the estimated 10 million caregivers who annually provide $89 billion in unpaid services to individuals with Alzheimer’s disease.

snip...

http://www.alzheimersanddementia.org/webfiles/images/journals/jalz/JALZ_739.pdf



see full text and more ;

http://betaamyloidcjd.blogspot.com/2008/03/10-million-baby-boomers-to-have.html


http://betaamyloidcjd.blogspot.com/


TSS



UPDATE JULY 27, 2011


August 1, 2011 Transmissible Spongiform Encephalopathies Advisory Committee Meeting Draft Agenda (PDF - 18KB)




Posted: 7/27/2011



http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/UCM265683.pdf


August 1, 2011 Transmissible Spongiform Encephalopathies Advisory Committee Meeting: Issue Summary (PDF - 154KB)
Posted: 7/27/2011


http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/UCM265682.pdf



----- Original Message -----



From: Emery, Bryan (CBER)



To: 'Terry S. Singeltary Sr.'



Cc: Emery, Bryan (CBER)



Sent: Friday, July 22, 2011 9:47 AM



Subject: RE: TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



Hi Mr. Singeltary,



Your statement will be provided to the members and will be placed in the meetings display folder for the public to see. Come or attend via webcast.



thanks for your public participation



LCDR Bryan Emery



--------------------------------------------------------------------------------



From: Terry S. Singeltary Sr. [mailto:flounder9@verizon.net]



Sent: Wednesday, June 29, 2011 3:54 PM



To: Emery, Bryan (CBER)



Cc: Harvey, Rosanna; BSE-L@LISTS.AEGEE.ORG; CJD-L@LISTS.AEGEE.ORG; cjdvoice@yahoogroups.com; BLOODCJD@YAHOOGROUPS.COM; Advocatejr@aol.com; COTTWEST@SILCOM.COM; Dave Cavenaugh



Subject: TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



Meeting of the Transmissible Spongiform Encephalopathies Advisory Committee



Center Date Time Location



CBER August 1, 2011 9:00 a.m. - 4:30 p.m.



Hilton Washington DC/North, 620 Perry Pkwy., Gaithersburg, MD



Agenda



snip...end...TSS



Wednesday, June 29, 2011



TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



http://tseac.blogspot.com/2011/06/tseac-meeting-august-1-2011-donor.html




Bio.108: Transmission of Prion Disease by Multiple, Clinically-Relevant Blood Components Following a Single Blood Transfusion



Sandra McCutcheon,2,† Anthony R. Alejo Blanco,2 E. Fiona Houston,1 Christopher de Wolf,2 Boon Chin Tan,2 Nora Hunter,2 Valerie Hornsey,3 Ian R. MacGregor,3 Christopher V. Prowse,3 Marc Turner3, 4 and Jean C. Manson2



1The University of Glasgow; Glasgow, UK; 2The Roslin Institute and R(D)SVS, University of Edinburgh; Edinburgh, UK; 3Scottish National Blood Transfusion Service; Edinburgh, UK; 4The University of Edinburgh; Edinburgh, UK;†Presenting author; Email: sandra.mccutcheon@roslin.ed.ac.uk



Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. While the epidemic appears to be waning, there is much concern that vCJD infection may be amplified/prolonged in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported. Using the most appropriate animal model available, in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion to recipients, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components can act as potential vectors for prion transmission and highlight the importance of multiple control measures to minimize the risk of human to human transmission of vCJD by blood transfusion.



PPPM.18: Induction of Ab Amyloidogenesis In Vivo by Blood Transfusion



Rodrigo Morales,1,† Claudia Duran-Aniotz,1, 2 Akihiko Urayama,1 Lisbell Estrada,3 Diego Morales-Scheihing1, 2 and Claudio Soto1



1University of Texas Health Science Center at Houston; Houston, TX USA; 2Universidad de Los Andes; Santiago, Chile; 3Universidad Catolica de Chile; Santiago, Chile†Presenting author; Email: Rodrigo.MoralesLoyola@uth.tmc.edu



Alzheimer disease (AD) is the most common type of senile dementia. Disease manifestation is characterized by progressive impairment of memory and cognition which is triggered by synaptic dysfunction and neuronal loss. Compelling evidence suggests that misfolding and aggregation of Ab is a hallmark event in the disease pathogenesis. An important unanswered question related to AD involves its etiology since over 90% of the AD cases arise sporadically. Interestingly, misfolding and aggregation of proteins is the main feature of other diseases -termed Protein Misfolding Disorders (PMDs)] which include Transmissible Spongiform Encephalopathies (TSEs), among others. Convincing experimental evidences have shown that the only component of the infectious agent in TSEs is the misfolded form of the prion protein. Strikingly, the molecular mechanisms responsible for prion replication are very similar to the process of amyloid formation in all PMDs, suggesting that all these diseases have the inherent capability of being transmissible. Recent reports have shown that intra-cerebral and intra-peritoneal administration of brain homogenates containing Ab aggregates can accelerate the generation of senile plaques in mice models of AD. However, it remains to be demonstrated if this phenomenon can occur by more relevant routes of administration. The aim of this study was to assess whether AD pathogenesis can be induced intravenously, mimicking the know transmission of prion diseases through blood transfusion. For this purpose we used young tg2576 mice which were injected with blood obtained from 12 months old tg2576 mice (AD-blood) that contains a substantial quantity of cerebral Ab deposits. Mice were sacrificed at 250 days old, a time in which these animals scarcely develop Ab deposits. Interestingly, we observed that infusion of AD-blood induces substantial Ab accumulation in animals that without treatment or injected with wild type blood would barely have any detectable Ab lesion. Plaque deposition was mainly present in cortex and hippocampus, being more abundant in the former. In addition, we observed a decrease in memory in mice challenged with AD-blood. Other features such as brain inflammation and synaptic integrity were also measured. Importantly, similar results were obtained in a second and independent experiment performed in a double transgenic mouse model that develops AD plaques as early as 4 months old. Our results indicate that an AD-like pathogenesis can be induced by intravenous administration of AD-blood, presumably through induction of protein misfolding in a similar way as prion diseases. These findings may open a new avenue to understand the origin of sporadic AD and may provide new strategies for disease intervention and prevention.



http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf





Tuesday, July 26, 2011



Irhad Rizvo Durakovic has lost his fight to nvCJD R.I.P.



http://creutzfeldt-jakob-disease.blogspot.com/2011/07/irhad-rizvo-durakovic-has-lost-his.html



http://transmissiblespongiformencephalopathy.blogspot.com/



http://vcjdtransfusion.blogspot.com/



http://creutzfeldt-jakob-disease.blogspot.com/




Wednesday, July 27, 2011



HIQA says vCJD blood filter not justified



[Posted: Wed 27/07/2011 http://www.irishhealth.com/]





http://vcjdtransfusion.blogspot.com/2011/07/hiqa-says-vcjd-blood-filter-not.html




----- Original Message -----



From: "Terry S. Singeltary Sr."



To:



Sent: Wednesday, June 29, 2011 2:54 PM



Subject: [CJD-L] TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



Meeting of the Transmissible Spongiform Encephalopathies Advisory Committee



Center Date Time Location



CBER August 1, 2011 9:00 a.m. - 4:30 p.m.



Hilton Washington DC/North, 620 Perry Pkwy., Gaithersburg, MD



Agenda



On August 1, 2011, in the morning, the committee will discuss donor deferral for time spent in Saudi Arabia to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue-based products.



SNIP...



Wednesday, June 29, 2011



TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



http://tseac.blogspot.com/2011/06/tseac-meeting-august-1-2011-donor.html





TSS

TSEAC JUNE 2, 1999 Welcome to the FDA traveling road show

From: TSS

Subject: TSEAC JUNE 2, 1999 Welcome to the FDA traveling road show

Date: October 15, 2007 at 3:18 pm PST

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY COMMITTEE MEETING Thursday, June 2, 1999

CHAIRMAN BROWN: My name is Dr. Paul Brown. Welcome to the FDA traveling road show. We are asked yet once more by the FDA to consider a question of theoretical risk in the absence of sufficient knowledge on which to base any firm conclusion.

The issue before us today is that of excluding categories of American blood donors who have either visited or resided for longer periods of time in Great Britain. The issue is sufficiently delicate, as you see that we have been moved outside the Beltway. (Laughter.)

snip...

"Dr. Alan Williams is employed by the American Red Cross, Holland Labs, and is Scientific Adviser for the Florida Blood Services and Canadian Blood Services. In addition, he has financial interests in firms that could be affected by the general discussions.

"Dr. Richard Race has financial interests in firms that could be affected by the general discussions and is a public health science researcher. "In the event that the discussions involve specific products or specific firms for which FDA participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement. And their exclusion will be noted for the public record. A copy of the waivers is available by written request under the Freedom of Information Act. "With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon."

So ends the reading of the conflict of interest statement. Dr. Brown, I turn the meeting over to you.

snip...

DR. JACOBS: Thank you, Dr. Brown, and welcome to members of the Committee. Today we are again bringing the question of deferral from blood donation of persons with possible foodborne exposure to bovine spongiform encephalopathy, BSE, as a precautionary measure to reduce the risk of blood transmission of new variant Creutzfeldt Jakob disease. And we are asking the Committee at this time, as we did in December, to consider this in the light of possible shortages.

Next, the current status. So far there have been no cases of either BSE or new variant CJD reported in the U.S. We're aware and we discussed in December the precautionary measures which have been taken in the U.K. First, they are not using U.K.?sourced plasma; and, secondly, they are implementing universal leukoreduction.

snip...

Next. In December, we asked the Committee to vote on two votes. I'm going to go through what those votes were. The first one is: Should FDA recommend new deferral criteria for blood donors to attempt to reduce a theoretical risk for transmitting new variant Creutzfeldt Jakob disease be excluding donors potentially exposed to the agent of bovine spongiform encephalopathy? The Committee voted nine yes and six no.

Next overhead. Should FDA recommend excluding donors who have resided in the United Kingdom or other BSE countries? The Committee voted 15 yes, unanimous, to remove "or other BSE countries."

snip...

I want to just put on the record and mention the other votes which were taken in December. Should FDA recommend withdrawal for blood components based on these donor deferral criteria? The vote was seven yes, five no. And should FDA recommend withdrawal for plasma derivatives based on these donor deferral criteria? Voted eleven no, one yes.

Next one, please. In addition to these questions on deferral of donors, in December we also asked the Committee to consider the actions that FDA would take if there were a report of a possible case of new variant CJD. We're going to refer those to CDC, but considering our precautionary withdrawal policy for new variant CJD, we asked: Should FDA recommend precautionary quarantine or withdrawal for plasma derivatives to which a possible new variant CJD donor contributed pending confirmation of the clinical diagnosis?

The Committee voted eight yes, one no, one abstained, but they asked us to revisit this question of our operational definition of a possible new variant CJD case. And in the second part of today's deliberations, after the vote on deferral, we will go back to that question.

The Committee also voted that a tonsil biopsy negative for protease?resistant prion would not be sufficient to make product withdrawals unnecessary.

snip...

We now have a presentation by Dr. Philip Comer, who will give us the Det Norsk Veritas risk assessment. Dr. Comer?

MR. COMER: Thank you very much, Chairman, and thank you for the opportunity to come and talk about the study that we were asked to do by the Department of Health in the United Kingdom as a result of a recommendation from the United Kingdom's Spongiform Encephalopathy Advisory Committee.

snip...

I am just going to go very quickly over the evidence for infectivity in blood. I think probably that will have already been looked at significantly by this Committee, but it was very much part of the background for what we were doing in the study that we did.

If we look at blood transfusions, we know that all attempts to transmit infectivity of blood, blood transfusion, so across a species barrier, have failed and that within animal models, as far as I am aware, the one case which has been reported by Bob Rohwer is still the only case that I have heard of in which there has been a positive transmission by the i/v route within an animal model.

Epidemiology studies have shown that's from sporadic CJD. There is no evidence that there has been any transmission through the blood route. And when we look at blood from human CJD cases, primarily sporadic CJD cases and certainly no variant CJD cases, and look at that, their infectivity through the i/c route into animal models, there have been a few experiments which have shown positive infectivity into rodents but negative results from a significant number of studies into primates and other species. And there have been some questions asked about ?? these cases, these experiments all involve very small numbers of animals and some sort of significant questions asked about those and, in particular, the fact that it is a bit odd that we have got no positive infections in the primates, which you might have expected would be more susceptible than the rodents. Then when we look at actually within animal models themselves, there have been quite a number of cases, experiments where positive infections have been reported from animals infected with some form of TSE and have been through the i/c route infected in the same species, so again with no species barrier.

snip...page 89

CHAIRMAN BROWN: A couple of points just to bring your experimental data up to speed. Unpublished further experiments on the mouse model have produced good news and bad news.

The bad news is that we have a disappointingly large number of transmissions following intravenous inoculation of either plasma or Buffy coat. We also have a transmission using whole blood as a transfusion into these mice. So that's not good news.

The other thing that is not too good is that we have now got in this particular model a ratio of five to one, as opposed to ten to one, which was also disappointing.

The only piece of good news in that in terms of experimental data is that we found that, again, in this model, the level of infectivity during the entire incubation period is almost negligible compared to the level of infectivity during the clinical phase of illness. And that is very good news indeed. So these are data that are not yet published but ??

snip...page 105

CHAIRMAN BROWN: Right, right. And, as I say, if it turns out to be the case with the human disease, ?? and I'm guessing it probably will be ?? with you, I think the likelihood of disease, natural disease, whether it be scrapie in sheep, BSE in cattle, or CJD in humans, is going to be quite a lot less virulent than the experimentally induced disease.

Even under the experimental conditions I mentioned, however, infectivity in all components of the blood during the incubation period is so low that it virtually poses I think no risk, at least in terms of plasma derivatives.

snip...page 106

Dr. Chan

snip...

So the issue that we dealt with in early May was "do variants of CJD pose a risk to blood safety?" And we sort of divided it into the classic variant and others. The others came out of, I'm sure you're all aware, of the scare that we all had over the Utah donor was this a possible chronic wasting disease, etc.

So we just put that issue on the table and let's see where it went. Our process -- we circulated a notice widely to all associations, consumer groups. We've sort of got a mailing list that's growing.

snip...page 129

And thirdly, the question was: What is the biological plausibility, from our experimental data, that there will be other variants of CJD? I won't go into the attempts of answering these.

snip...page 135

The rest of the recommendations I'll go through very briefly. Health Canada had not standardized its -- not finalized its policy on classic CJD, and we advised that they do so.

The blood services should provide clear statements about the reasons for believing that there are no longer concerns regarding the classic sporadic CJD; that Health Canada and the blood services provide communication regarding all aspects of product quarantine.

And that was because there's considerable confusion over the Utah donor case. Health Canada identify and provide information that all products that contain trace amounts of blood products -- this was interesting. Many of the physicians did not even know which products that were being distributed contained blood products. We thought this was an important issue. All products can be tracked in the event of an infected donor. And that they take steps to discourage manufacturers from using blood products in the production or formulation of other products.

That mechanisms are developed to ensure that -- oh, this is the surveillance for CJD. That criteria have to be established to determine between classic and variant forms, which I know is the topic that you are going to be discussing this afternoon.

snip...page 138

CHAIRMAN BROWN: This afternoon's program will begin with several presentations as a part of the open public hearing.

snip...page 145

CAPTAIN RUTHERFORD: Good afternoon.

The Department of Defense would like to thank you for allowing us to offer public comment.

I am Captain Bruce D. Rutherford, Medical Service Corps, United States Navy, the present Director of the Armed Services Blood Program. On 5 February, 1999, Dr. Sue Bailey, the Assistant Secretary of Defense for Health Affairs, forwarded a letter to Vice Admiral David Satcher, Public Health Service, the Surgeon General of the United States.

In that letter, Dr. Bailey expressed her opposition and the opposition of the Surgeon Generals of the Army, Navy and Air Force on deferring individuals as blood donors based on "perception" of a "possible" risk of transfusion transmission of the agent for "new variant" CJD. There has not been a single case, repeat, single case of transfusion transmitted new variant CJD or classical CJD reported in the world in more than 55 years since transfusion of blood products became widely accepted as a treatment regime.

In November of 1991, the Department of Defense issued an advisory recommending that individuals participating in Operation Desert Storm be deferred as blood donors after a number of Desert Storm troops were identified with cutaneous and visceral Leishmania tropica. Knowing that Leishmania donavani was transfusion transmissible, and now knowing the extent of infection rate of the "at risk" population, the DOD decided to defer those individuals as blood donors who participated in country in the Persian Gulf.

It was not until December of 1993, or two years later, that the DOD stopped asking leishmaniasis related questions of its blood donors. The cessation was due to a concentrated effort by the military health system in identifying an extremely small number of infected individuals and the follow-on screening questions' ability in identifying an extremely small number of donors with symptoms where leishmaniasis could have been a possibility.

However, a study in the survivability and infectivity of viscerotropic Leishmania tropica in human blood donors from ODS participants was later shown to support our concern and was published in the American Journal of Tropical Medicine and Hygiene in 1993.

Transfusion transmission by Leishmania species was a known, not theoretical. We know the calculatable risk of being injured in a car accident, yet millions of individuals a day drive their cars with hundreds of thousands being injured per year and tends of thousands killed each year. It is the same with airplanes, lightening and other activities.

In theory, anything is possible. I remember back a few years ago when the Institutes of Medicine came out with this HIV report. Yes, hindsight was better, but that has always been true.

I think in this case we have hindsight, 55 years of hindsight. We do not need to institute a UK deferral policy which will only lead to further crippling of our nation's blood supply and more product shortages.

snip...page 148

CHAIRMAN BROWN: Thank you, Captain Rutherford. Are there any questions that any of the panel would wish to address to Captain Rutherford?

The next presentation will be by Kay R. Gregory of the American Association of Blood Banks.

MS. GREGORY: Good afternoon.

snip...page 148

In conclusion, AABB notes that there is no evidence that nvCJD is transmitted by blood transfusion. There are no cases of nvCJD in the United States. It is unknown whether travel to Great Britain correlates with exposure to or infection with the agent of BSE.

And there is no evidence that any proposed criteria will decrease the theoretical risk of acquiring nvCJD from transfusion. In contrast, there is good evidence that even a one to two percent loss of donors due to new deferral criteria will have a significant impact on blood availability and, hence, on the safety of those transfusion recipients who cannot tolerate a delay in receiving blood products.

The country should contemplate nvCJD deferral criteria only when it is apparent that such a policy would improve blood safety more than the loss of donors and the associated decrease in blood availability would compromise blood safety.

Thank you.

CHAIRMAN BROWN: Thank you, Ms. Gregory.

The word theoretical has been used many, many, many times this morning and will continue to be used, and it's being used correctly. I'd just point out that, for ten years, between 1985 and 1995, the risk of new variant CJD from BSE was also theoretical.

The next speaker is Dave Cavenaugh from the Government Relations Committee of Ten Thousand.

MR. CAVENAUGH: I'm the government relations person at the Committee of Ten Thousand. The organization is the Committee of Ten Thousand. CHAIRMAN BROWN: Yes, that's fine. Thank you.

MR. CAVENAUGH: Okay, COTT, which is the Committee of Ten Thousand, is gravely concerned about the industry logic favoring UK donors over additional U.S. replacement donors even with the survey, and even with the lack of data on paid and unpaid high volume pheresis donors. This morning's discussion showed a glaring omission in the analysis to date of the impact of excluding well paid, highly educated, non-incentive provided pheresis donors in addition to the larger, understood group of paid pheresis donors.

We've heard quite a bit in terms of the studies and in terms of some of the questions about the likely blood borne nature of this never documented entity of prion and its ability to be transmitted by blood.

There's a perceived link between new variant and beef that's been raised based on proximity, but the BSE classical CJD link should not be forgotten. It should be entertained at the minimum. Living in the United Kingdom in the late '80s seemed to be a major factor, for example.

What was it about living there, that's proximity. Both statistic presenters showed clear risk of new variant in the blood, not even enlarging the scope to include classical CJD. There are no nv cases in the U.S., but plenty of classical -- arguably, much more than the one in one million rate alleged.

Just ask CJD Voice, the patient-family support group which spoke before you 18 months ago. Small then, its numbers have mushroomed. Something is getting transmitted. Can it all be through beef? But most disturbing is the recent news confirming a second mutated form of prions also causing death in under a year.

This doubling of the number of ways prions can be malformed with fatal results raises our concern levels considerably. The explanation that it is spontaneous sounds like an early catch all. With an entity so new, so unknown and so dangerous, the committee should be providing every protection possible, not bowing to arguments of relative risk.

Thank you.

CHAIRMAN BROWN: Thank you.

snip...page 154

CHAIRMAN BROWN: Well, this is exactly why we're here today. Dr. Satcher and the other groups have already decided that this is not worth significant worry with respect to classical CJD, and that new variant was an unknown. And so that's why we're considering specifically new variant because we don't have information specifically on it. I mean, everything we don't have information on becomes a subject for this committee. (Laughter.)

snip...page 213

DR. LEITMAN: We seem to be extrapolating the partitioning data of classical CJD -- the agent of classical CJD to the agent of new variant CJD. That may or may not be okay.

I'd like to ask Dr. Prusiner if we can at all extrapolate the lack of transmissibility through blood components of classical CJD agent to new variant?

DR. PRUSINER: I don't know that I'm qualified to answer this. I can only tell you that the little bit of work that we've done now on new variant CJD says that it is a dramatically different strain of prion. That means that the confirmation of PRP scrapie is dramatically different than anything else we've studied.

So let me give you an example. We've looked at 40 different cases of sporadic CJD, and we know that there's several different confirmations there at least. And all of these are transmissible in about 200 days to either mice that have a human PRP gene or have a chimeric mouse human PRP gene. If you look at new variant CJD, it takes more than 500 days and only about 60 percent of the animals get sick. Now, as I said before, if we take new variant CJD and we passage it into a mouse that expresses a bovine PRP gene on a null background, then all the mice are getting sick in 240 days. The piece of data I don't have that you want is you want to know if I take sporadic CJD or familial CJD cases and passage those into mice with a bovine PRP gene, do they get sick? And the answer is I don't know yet.

snip...page 218

MS. HARRELL: Well, I asked him the question, was there a deferral ?? was there deferral criteria for blood donors for classic CJD for people who have either resided or visited the UK.

CHAIRMAN BROWN: I'm sorry. Repeat that, the question.

MS. HARRELL: Is there a deferral policy for blood donors to attempt to reduce the risk of transmitting classic CJD for people who either resided or visited the UK?

DR. SCHONBERGER: The answer is no.

MS. HARRELL: And if there is no risk, if we think that there is no risk of transmitting the whatever to ?? for CJD, what makes this different, for new variant CJD much different?

CHAIRMAN BROWN: That's the first time, Stan, you'll ever hear of prion referred to as a whatever. (Laughter.)

CHAIRMAN BROWN: I mean, I've heard it referred to as a lot of different things. I'm ??

DR. PRUSINER: You've said that many times, Paul. (Laughter.)

CHAIRMAN BROWN: It may be that ??

DR. PRUSINER: Is that in the Congressional Record?

CHAIRMAN BROWN: The issue is not about sporadic CJD. That is the issue we can sort of generically say CJD. Presumably, if the blood from a patient with new variant CJD were infectious, the disease that it would transmit would be new variant CJD. So it's not ??

MS. HARRELL: Okay. So CJD is not transmitted through the blood is what you're saying?

CHAIRMAN BROWN: We have no evidence from looking at populations that that has ever happened. The question is: since we know it can happen when we use experimental models of CJD, we can take CJD blood from one animal and produce the disease in another animal.

So there is the "theoretical possibility" that this might also happen in humans, particularly with a different strain of the disease, which new variant is, about which we don't know a whole lot. That's the question. DR. SCHONBERGER: Isn't the answer to her question that the incidence of CJD, REDS, classic CJD, is not influenced by whether or not you've lived in the UK between 1980 and 1996 ??

CHAIRMAN BROWN: Yes.

DR. SCHONBERGER: ?? but the incidence of new variant CJD is?

CHAIRMAN BROWN: Yes, 40-love. (Laughter.)

snip...page 240

CHAIRMAN BROWN: I agree. We're starting to vote, and we'll start with Larry. Hold on. All right. The question is: should FDA recommend new deferral criteria for donors of transfusable components, to attempt to reduce the theoretical risk of transmitting new variant CJD from transfusions based on donor exposure to BSE in the UK?

DR. SCHONBERGER: Yes.

CHAIRMAN BROWN: Incidentally, just to remind the committee, it is possible to vote punt; that is to say, you can vote yes, no, or no vote ?? abstain.

DR. HUESTON: Well, for my own benefit, I suppose, to walk through the logic ?? and maybe for the benefit of Barbara because I think she raises a good point about how we proceed ?? we have a situation with a small number of known cases of variant Creutzfeldt Jakob, all but one of which are in the UK.

However, we know there is a potential for widespread exposure to BSE that has already occurred. Therefore, we expect more cases, but we really don't have a good idea of the magnitude of the epidemic that we're going to expect.

Part number 2 says, "While there is no known whole blood or blood product transmission of classical CJD in humans, variant Creutzfeldt Jakob differs substantially from classical CJD." So we recognize that there is the potential for transmission of some of the transmissible spongiform encephalopathies via blood, albeit controversial We have an animal model, and we can identify infectivity in lymphoid tissues with variant Creutzfeldt Jakob, which is different from classical Creutzfeldt Jakob.

At the same time, it has been pointed out many times by a number of people that there have been no observed risk ?? or no observed cases at this point of transfusion or blood product related variant Creutzfeldt Jakob cases in the UK. I think that's a little premature. One might say the absence of evidence is not evidence of absence.

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At the same time, there are look-back studies in place in the UK, and there is a natural experiment ?? a huge natural experiment ongoing in the United Kingdom, where if, in fact, there is a risk, I believe that the risk will first be apparent in the United Kingdom far before we would see it anywhere else.

At the same time, in looking at the precautionary principle ??

CHAIRMAN BROWN: Is this the preamble for a vote?

DR. HUESTON: Yes, sir. You got it. (Laughter.)

DR. HUESTON: If our goal is to be precautionary, but at the same time we have to preclude having more negative impacts for any action that we take, then positive ?? in other words, impacts on the blood supply. And I have struggled through the whole time, but I'm going to vote no at this time.

CHAIRMAN BROWN: Could I urge the remaining members of the committee ?? (Laughter.)

CHAIRMAN BROWN: ?? to vote rather than ?? I appreciate it, and I let Will, you know, chatter on because he hasn't said a whole lot, and I wanted to hear what he had to say. And so thank you, but we'll never get through if we continue to explain the reasons for our votes, each one and all. So, Susan?

DR. LEITMAN: I take the opportunity to disagree with what you just said. I think the vote at this table is so critical, it will have such a huge impact potentially on the way America collects its blood, that if we go beyond our designated time it's worth it.

And I was influenced, and it was helpful to hear the last speaker's discussion. So I think if any of us have discussions or points to mention now, they might be valuable.

The deliberations of this committee are among the most difficult of any advisory committee I've ever been on because there are simply inadequate data upon which to base a decision. For myself, in the absence of data suggesting or, rather, documenting risk, I cannot vote yes based on assumptions, perceptions, possibilities, uncertainties, theoretical risks, and potential risks.

On the other hand, there are tangible measurable data that deferral of any percentage of donors, whether it's half, one and a half, two percent, will lead to replacement by donors by a small proportion of donors that are at increased risk for measurable diseases such as hepatitis B and C. So I vote no.

CHAIRMAN BROWN: Dr. Leitman votes no.

Dr. Prusiner?

DR. PRUSINER: I would like to vote yes, and I would like to say I have 23 points that I want to go through. (Laughter.)

DR. PRUSINER: I only want to say very quickly that I don't think that economics and the availability of donors is a reason to vote yes or no in this. I think that the economy has a way of solving these problems, and I think that will happen. I think the real problem here lies that we have a very imperfect data set, and we're dealing with a disease which is universally fatal. This is really the problem that we face.

CHAIRMAN BROWN: Dr. Prusiner votes yes. Dr. Roos?

DR. ROOS: I think we're dealing with a situation in which we have no evidence of any transfusion that has transmitted either classical or new variant Creutzfeldt. And we have a situation where there are risks involved with blood transfusions that the donors accept at this point.

That is, we were informed about ?? I guess about 14 percent of individuals do donate blood that have I guess the recipients. About 14 percent of individuals that donate blood have some risky behavior. And maybe I might include living in UK part of that risky behavior.

And so I kind of accept this as, at the moment, acceptable risk for donated blood and I am awaiting evidence to prove that there is more danger involved. So I'm voting no here.

CHAIRMAN BROWN: Dr. Roos votes no. Dr. Belay?

DR. BELAY: I'm concerned about two issues. The first one is the studies that showed the presence of the new variant CJD agent in lymphoreticular tissues. And the second concern I have is the absence of evidence against blood-borne transmission of new variant CJD. The kind of data that's available for classic CJD is not available for new variant CJD, so I vote yes.

CHAIRMAN BROWN: Dr. Belay votes yes. Dr. Lurie?

DR. LURIE: Really, what we're doing is balancing one risk against two others. The two risks are the problem of the replacement donor, which is not zero but it is probably very small, given that we're only talking about one, two perhaps, percent replacement of donors here, depending on what happens in B if we get that far.

The second has to do with the diminution in the blood supply itself. And, again, there are scenarios available to us under B that allow us to minimize that. So we really have, on the one hand, two small risks that can more or less be quantified, and on the other hand we have another risk, which may itself be small, but if we are wrong could be very, very large. And that's really the benefit ?? the risk benefit calculation that we're making. For me, there remain too many uncertainties, and so I vote yes.

CHAIRMAN BROWN: Dr. Lurie votes yes. Dr. Hoel?

DR. HOEL: Yes. I'm changing my vote from last time, and I'm going to vote yes, mainly because of what I see in the epidemiology data of the cases in England and the modeling work. I think this needs to be monitored further to see how it comes in because the risks could be quite large, and so I would vote yes.

CHAIRMAN BROWN: Dr. Hoel votes yes. Dr. Bolton?

DR. BOLTON: I believe that there is insufficient documentation of the risk at this time. And in light of that, I can't ?? I don't think that the information warrants changing the current policy. I vote no.

CHAIRMAN BROWN: Dr. Bolton votes no. Dr. Nelson?

DR. NELSON: Well, this is a pretty difficult vote. Last time I voted no, and I'm going to vote no again, although I am ?? really, it's disturbing that there is no really good data at this point.

And I am impressed with a comment that was made earlier, and that is that there is an experiment in the UK of many people who have been exposed to UK donors over a period of many years. And I am somewhat reassured that there have been no cases, and I'm also reassured with the quality of the epidemiologic surveillance and data from the UK.

I think that that has been well done, carefully done, and presumably it will continue to be closely monitored. You know, if a single case had occurred, we would really need to change our policy immediately. That's number one.

But the other problem I have is if I voted yes, then I would have to make a decision on 1B. And the only ?? (Laughter.)

DR. NELSON: ?? the only reasonable decision on 1B would be to remove ?? to exclude all donors who had lived in the UK. I see no basis for any arbitrary decision. Once you go down that route, then you have to exclude anybody from the UK or who visited the UK or Ireland during this period. I don't see any alternative.

CHAIRMAN BROWN: Dr. Nelson votes no. Dr. McCullough?

DR. McCULLOUGH: I agree with Susan. This is one of the most difficult groups I have had to deal with. I'm impressed by the epidemiologic data. I'm also impressed by having sat through in 1983 and 1984 discussions of there ain't been a case reported yet, and also that we are concerned about the impact on the blood supply.

hrms/dockets/ac/99/transcpt/3518t1.rtf???????????

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVIS

And possibly also, I'm influenced by having been the fodder for congressional hearings and 60-minute expose on things that might have been done differently at some of those times. So I'm going to vote yes. I have tremendous confidence in the blood systems of this country that they will be able to ?? not easily ?? respond if changes are made.

CHAIRMAN BROWN: Dr. McCullough votes yes. Dr. Brown votes yes. Dr. Ewenstein?

DR. EWENSTEIN: Yes. I'm impressed by the modeling data. I believe that we have biologic data as well as at least the potential epidemiology coming out of England to suggest that this is a new disease and on that basis should be handled with a lot more caution, because we don't have the comfort that we have with the long-standing classical CJD. And so I'm going to vote yes.

CHAIRMAN BROWN: Dr. Ewenstein votes yes. Dr. Detwiler?

ORY COMMITTEE MEETING Thursday, June 3, 1999???????http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3518t2.rtf DR.

DETWILER: I'm going to vote yes, because with these diseases, a long incubation and the lack of a pre-clinical screening test, that the day you find out there is transmission you're already years too late, and you can't easily clean up the problem. And I think they found out that even with the human transmission because that was based on there is no theoretical ?? or it's only a theoretical risk until 1996.

CHAIRMAN BROWN: Dr. Detwiler votes yes. Dr. Piccardo?

DR. PICCARDO: I would vote yes because all of the data from classical CJD cannot be extrapolated into the new variant.

CHAIRMAN BROWN: Dr. Piccardo votes yes. Dr. Williams?

DR. WILLIAMS: I'm going to vote no. I think that this is truly a balancing act, and it's a tradeoff between a known problem, I believe related to the blood supply, and the problems that may follow from a reduced supply and the perception of a risk of new variant CJD.

And I completely agree that an experiment is going on right now. Those data are going to come in, and, obviously, there is going to be close attention paid to those data, and that surely this committee and FDA will respond should information indicate that we need to take another look at the issue.

CHAIRMAN BROWN: Dr. Williams votes no. Dr. Hollinger?

DR. HOLLINGER: I'm voting no also, for the same reasons that have been addressed. I think there is ?? by doing something now doesn't mean that everything is going to be turned around and you don't have to worry about it, if you do have a long incubation situation and one can wait to see if there is some risk down the line, and I think we do have those things going on ?? natural and experimental ?? in England. So I'm voting no. CHAIRMAN BROWN: Dr. Hollinger votes no. Ms. Harrell?

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Case Report of V MS. HARRELL: Okay. Sitting next to my ex-learned colleague ?? (Laughter.)

MS. HARRELL: Okay. I'm voting to be prudent, and I think that this will buy us time to get the data in and have it analyzed from the UK. But right now, we don't have time, and so I vote yes.

CHAIRMAN BROWN: Ms. Harrell votes yes. Dr. Cliver?

DR. CLIVER: No.

CHAIRMAN BROWN: Dr. Cliver votes no. Dr. Burke?

DR. BURKE: This is a balancing act, and I can ?? there are measurable negatives here. In the face of a theoretical, I vote no.

CHAIRMAN BROWN: Dr. Burke votes no. Dr. Tramont?

DR. TRAMONT: I vote yes.

CHAIRMAN BROWN: Dr. Tramont votes yes. Twelve yes. Nine no. Well, at the least, Dr. Epstein can come away from the day with the understanding that he has not been given a mandate. (Laughter.)

DR. FREAS: Can I just make a comment? I did verify the count. There are 21 voting people at the table. Dr. Roos is a non-voting participant. And the total does add up to 21.

Excuse me. I apologize. Dr. Rohwer is ??

CHAIRMAN BROWN: I don't have to ask Bob what he would have voted, had he been allowed to vote. (Laughter.)

CHAIRMAN BROWN: But I will if you'd like to put it on the record. This is simply a question to Bob, since he's at the table. Were his vote to be counted, what would it have been?

DR. ROHWER: I'll use this soapbox opportunity.

CHAIRMAN BROWN: Uh-oh. (Laughter.)

DR. ROHWER: I am very concerned that we may be facing the grave possibility of an epidemic of new variant CJD, an epidemic that, if it occurs, could be made much worse through the mechanism of interspecies transmission, such as would occur through blood products. But I recognize the real risks of insufficient supply.

However, I am impressed by Dr. Donnelly's warning that if the feed ban in the case of BSE had been delayed just one year, the epidemic would have been vastly worse than it was. And, therefore, I feel we should take whatever opportunities for implementing mitigating measures that we can that do not simultaneously jeopardize the supply unduly.

So I recognize that what we have ?? the opportunity we have here is very, very imperfect, but I feel like it is possible to do something, and we should do it.

CHAIRMAN BROWN: Jay, you wanted a recount, or just a reexpression? DR. EPSTEIN: Just a reexpression.

CHAIRMAN BROWN: Okay. The vote on question 1A is 12 votes yes, nine votes no. Therefore, the committee is obliged now to consider what deferral criteria might be recommended. And presumably, based on the evidence, the only deferral criteria that are offered us that make any sense are duration of residence in the UK.

snip...258

Dr. Scott

skip

In addition, we do know, as Dr. Prusiner has pointed out several times, that the new variant agent is biologically different from the classical CJD agent, so we can't necessarily extrapolate all of the information that we have on classical CJD to new variant.

For example, he talked about the differences in the protein and its behavior, and we also know that there is enhanced expression of the new variant agent in lymphoid tissues compared with CJD. And we don't know much about its virulence or infectivity compared with the classical CJD. And, of course, we haven't had time to get or enough patients or subjects or transfused people to get the kind of epidemiologic data that we have which tells us that transmission of classical CJD by blood or blood products at worst is rare and may not occur.

So, currently, the diagnosis of new variant CJD is based upon neuropathology, and these are the three most characteristic features ?? numerous widespread kuru type amyloid plaques, which obviously can occur in a few other kinds of CJD but are quite common in new variant CJD; spongiform change, which is predominant in certain areas of the brain; and a high density prion protein accumulation, especially the cerebrum and the cerebellum by immunohistochemistry, and tonsillar biopsy may ultimately play a role in this diagnosis as well as analysis of prion glycoforms.

Current age, if alive, or age at death, less than 55. Since the typical age of a new variant patient is about late 20s, and the typical age of a classical CJD patient is about 65, this is one criteria that is useful. And new variant patients tend to have persistent painful sensory symptoms early in presentation and/or psychiatric symptoms.

I can go into this further if people want to know about it. But there were a couple of articles published in the Lancet from the CJD surveillance unit in September 1997, which goes into this in great detail.

In addition, the patient must have dementia and a delayed development of neurologic symptoms, particularly movement disorders, about a four-month delay. And, again, this is somewhat different from classical CJD in its course. They may have a normal or abnormal EEG, but not the diagnostic EEG, which is a pseudo periodic sharp wave that's often seen in classical CJD. The duration of illness should be greater than six months. Again, this is in marked distinction to most cases of classical CJD which average four to four and a half months of duration. Whereas, the new variant case typically is around 14 months duration, although there is a spread.

In addition, routine investigations will not suggest an alternate diagnosis. And this is a criteria, really, for the U.S. There should be history of possible exposure to BSE; that is, consumption of local beef products as resident or traveler to a BSE-affected country.

And there is only two more. No history of iatrogenic exposures that are related to development of classical CJD, and, finally, of course, such a patient, if they had a prion protein gene mutation, it was associated with familiar CJD. That would not fall under ?? that would not be a patient that we would worry about new variant CJD in.

page...284

DR. ROOS: Thanks, Dr. Scott. So we're not asked to take a vote, but just to discuss these issues. Yes?

DR. NELSON: I'm concerned a little bit about the explanation for the age criteria, and I can see that this is very useful because the one thing you do know, when somebody gets sick, you can estimate what their age is. And so that's an easy ?? you know, an easy early marker for a possible case that's not classical.

And I assume that probably the reason for the classical CJD patients being much older is that the incubation period is so long that they probably had an exposure much longer. But as this epidemic ?? or as the ?? if it's exposure to the BSE agent from the epidemic, it seems like over time this age criteria will probably change, and that the under 55 may no longer be a useful criteria 10 years from now or 40 years from now.

And I just wonder if Larry or anybody could comment on that.

DR. SCHONBERGER: We definitely agree, and it underscores the evolving nature of these diagnoses. All I can say is the age is an excellent and easy criteria for us to use now. All cases, as you know, in the world of new variant CJD have been under age 55. In fact, I think the oldest was ?? I think the median age is like 29 or so, 28 at onset and 29 at death. So that's why that particular criteria came into existence.

However, obviously, if the epidemic should change and we should start seeing older cases, then, obviously, we would have to change.

There is some semantic problems. We actually investigate every case under 55. So, in a sense, all cases under 55 in the United States could be regarded as under investigation or possible. We have not used the word "probable," in part because that's the word they use in the United Kingdom, and they count those cases as amongst the cases of new variant CJD that we count.

The 40 cases in the UK, I think, includes one, is it? One probable? That was a case in a teenager whose brain tissue was unavailable for study. And they indicate that it's too early in the epidemic. Their experience is too small for them to be absolutely sure about that, but they're willing to ?? at this point to call it a case.

And I've been told that with these new MRI criteria, and so on, that maybe we'll be able to call cases without necessarily having the tissue, depending on what they find the specificity and sensitivity of those to be. So all cases essentially under 55 right now are under investigation.

Plus, we have established amongst pathologists the concept that any case that has the pathology of new variant CJD, regardless of age, or even regardless of whether they've diagnosed it as CJD, should be reported. And those two would count as new variant even though they are not under 55. DR. ROOS: Just a quick question, Larry. What is your timeframe of reporting, or what is the goal here? Obviously, with respect to these new guidelines, you want to identify these cases fairly quickly and make some disposition as far as blood products.

DR. SCHONBERGER: Precisely because we are looking at all cases under 55, I was encouraging FDA to encourage the blood establishments ?? or the first to identify these cases at least, and that has been the history ?? to report to us any case of CJD under 55.

Once we get that report, it may be very easy for us and very quickly making it ?? to very quickly make a determination that we're dealing with, say, a dura mater case or a human growth hormone case. But then, another part of FDA will probably become interested in that.

So we think it's worth the blood establishments reporting all of their cases in donors. There just are not that many CJD cases that are going to occur among donors that the blood establishment is going to be able to identify that quickly. But if they do, we want it reported right away. DR. ROOS: Just a quick question. So, I mean, how about if this patient donates to some large blood pool or has donated whole blood? It doesn't go back to the blood establishment. It goes to a neurologist, gets diagnosed, etcetera. What's the timeframe then?

DR. SCHONBERGER: Well, frequently, our experience with the withdrawals ?? and I'll use the Utah case as an example as that came out ?? we handled that very, very rapidly. But even handling it very, very rapidly, you'll find that huge, huge numbers of recipients were exposed to this donor's blood products.

So the withdrawal program is relatively inefficient, compared to what we just did, which was to get deferral criteria. And I think that's why it was important to try to be preemptive in a sense and have the deferral criteria up front.

The withdrawal procedure, even when you do it very quickly as in the Utah case, I would not encourage people to depend on that for considerable safety. What we will do is we will modify and ameliorate the situation. But it certainly won't eliminate even the majority of the risk.

DR. ROOS: I just think it might be good to publicize these new policies widely to the neurological community, so that they alert you, Larry, or the FDA quickly. The Utah case, in fact, was kind of a very aberrant case. It could be that there are other cases that get less sophisticated care. And if you really want to identify things in a timely manner, you obviously have to publicize the program and new policies to the neurological community. DR. SCHONBERGER: Well, let me clarify that the primary group doing the surveillance on this are blood establishments. And if this group wants to recommend that blood establishments, you know, provide blood donors with cards or something that would, you know, speed up any type of reporting, that's possible.

The surveillance that CDC is conducting is not designed for that type of rapid turnaround or rapid identification in reporting. That's another weakness of the system and relying on this withdrawal system for tremendous protection of the population.

DR. ROOS: Peter?

DR. LURIE: My question/concern is whether or not requiring all nine of these criteria is too restrictive a set of criterion. I guess the data question that I have is: of the 30-odd new variant CJD cases in Britain, how many of them have met all nine of these criteria?

DR. SCOTT: Well, could I also respond to that question?

DR. LURIE: Yes, please do.

DR. SCOTT; I don't know the answer to how many have had all nine of those criteria, but most. However, the CJD surveillance unit has somewhat altered their criteria with time such that the current organization is similar to this but not the same. And most critically, they have gotten rid of the age criteria and added an MRI criteria. But this is not yet published material, and it's very recent. We just got that information on May 31st. And I think the other thing to mention is that we weren't considering only using all nine criteria. But, really, that's the purpose of the third way, if I can say it, which is to have a very low threshold for identifying even potential cases and then to make a rapid decision on a case-by-case basis. But what we're anticipating is probably what you're thinking, that not all of those criteria are going to be met, just due to a lack of information, time hasn't passed, we don't have material to analyze. And so I think what we're anticipating is that we would be ?? we would err on the side of caution unless investigation showed us that it was most unlikely that this was a new variant case.

snip...page 292

DR. HUESTON: You don't know to what you've been exposed. So it's ?? the second thing is it draws ?? I think it gives a false sense of security and directs, potentially, attention to the wrong products, because the average person thinks of beef as primal cuts of beef. And that's, at this point, the least likely of the sources of exposure, given meat products. The third comment is that I personally am very concerned about the proposed ?? this criteria of possible new variant CJD by FDA. And I have two major reasons for that. The first is that I see the potential for conflict arising between FDA and CDC, where FDA is stepping forward or making a pronouncement of possible new variant CJD, and at the same time CDC says, "We're still investigating; you know, it's premature." And I think that puts the FDA in a very awkward position, and I think an inappropriate ?? Larry is telling me that they are investigating 25 ?? DR. SCHONBERGER: There's about 25 cases under 55 a year. DR. HUESTON: So my fear ?? here is my fear based on my experience. Item number 2 says, "Donor has physician's clinical or pathologic diagnosis of CJD."

DR. SCHONBERGER: They're not all donors, by the way. Very few of them are donors. Okay?

DR. HUESTON: Okay. Fair enough. But once you get a terminology like this established, my concern is that it's going to spread further, that people are going to say, "Well, the FDA would have called this a possible case." Number 2 says, "Has a physician's clinical or pathologic diagnosis," it doesn't say anything about the physician. And no offense to my distinguished colleagues, but there are a number of physicians that are simply not in the position to make a clinical diagnosis or a pathologic diagnosis of Creutzfeldt Jakob. That has not precluded some of these same physicians from making a proclamation.

Third, I think that the public health and the risk communication implications of this are potentially massive. And having been on the firing ?? you know, on the other end of trying to deal with these, you know, the press grabbing hold of a case and blowing it totally out of proportion and creating a great deal of concern, I don't see why you need another term. I think you coordinate with the CDC, you coordinate your investigation when it comes back from a blood collection center that you have a donor less than 55 years of age, where you have some suspicion of Creutzfeldt Jakob Disease. You go through the same CDC workup, and you base ?? on a case-by-case basis, you base your decision on that coordination with CDC.

snip...page 296

see full text and all voting results

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TSEAC MEETING JUNE 3 1999

http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3518t2.rtf


http://transmissiblespongiformencephalopathy.blogspot.com/