Tse Advisory Committee December 15, 2006

[flatfish]

##################### Bovine Spongiform Encephalopathy #####################

Subject: TSE ADVISORY COMMITTEE DECEMBER 15, 2006
Date: November 27, 2006 at 3:06 pm PST
Food and Drug Administration

Transmissible Spongiform Encephalopathies Advisory Committee
December 15, 2006

FDA

Disclaimer

Portions of this document have been determined to be exempt from disclosure under the Freedom of Information Act (the FOIA) (5 U.S.C. §552). These redacted portions will appear as white space on the screen or on the printed page.

Topic I: FDA's Risk Assessment for Variant Creutzfeldt- Jakob Disease (vCJD) Potentially Associated with the Use of US Licensed Human Plasma-Derived Factor VIII (pdFVIII, Antihemophilic Factor) Products, and Potential Public Health Service Responses (pdf)


http://www.fda.gov/OHRMS/DOCKETS/ac/06/briefing/2006-4271B1-01.pdf




Draft Quantitative Risk Assessment of vCJD Risk Potentially Associated with the Use of Human Plasma-Derived Factor VIII Manufactured Under United States (US) License From Plasma Collected in the US (pdf)


http://www.fda.gov/OHRMS/DOCKETS/ac/06/briefing/2006-4271B1-02.pdf




Appendex A: Supplemental Technical Information for the FDA Risk Assessment (pdf)


http://www.fda.gov/OHRMS/DOCKETS/ac/06/briefing/2006-4271B1-03.pdf




Topic II: Experimental Clearance of Transmissible Spongiform Encephalopathy (TSE) Infectivity in Plasma-derived Factor VIII (pdFVIII) Products (pdf)




http://www.fda.gov/OHRMS/DOCKETS/ac/06/briefing/2006-4271B1-04.pdf




Bibliography (pdf)


http://www.fda.gov/OHRMS/DOCKETS/ac/06/briefing/2006-4271B-bib.pdf



http://www.fda.gov/OHRMS/DOCKETS/ac/06/briefing/2006-4271b1-index.htm



TSS


#################### https://lists.aegee.org/bse-l.html ####################

[flatfish]

Subject: Re: TSE ADVISORY COMMITTEE DECEMBER 15, 2006
Date: November 28, 2006 at 9:01 am PST

DRAFFT ( ((1 111 11/ //2 221 11/ //0 006 66) ))

AGENDA

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE

Crown Plaza, 8777 Georgia Avenue, Silver Spring, MD

December 15, 2006

Friday, December 15, 2006

8:00 a.m. Administrative Remarks, TSEAC Executive Secretary

8:05 a.m. Opening Remarks, Glen Telling, Ph.D. Chairperson, TSEAC

8:10 a.m. Committee Update


- Status of FDA’s initiative on communication of the potential exposure to
vCJD risk from an investigational product, plasma derived Factor XI that was
manufactured from UK donor plasma (15’) (M. Weinstein, Ph.D., FDA)

8:25 a.m Topic I. FDA’s risk assessment for potential exposure to vCJD in
human plasma-derived

antihemophilic factor (FVIII) products and communication materials.


A. Introduction: FDA risk management strategy for potential exposure to vCJD
in plasma derivatives (D. Scott, M.D., FDA) (10’)


B. Risk assessment and interpretation (S. Anderson, Ph.D., FDA) (40’)

C. Overall risk communication approach

(M. Weinstein, Ph.D., FDA) (15’)

D. Advocacy organization perspectives (30’)


i. National Hemophilia Foundation (Val Bias) (5’)


ii. Hemophilia Federation of America (Janice Hamilton) (5’)


iii. Committee of Ten Thousand (Richard Colvin, M.D., Ph.D.) (5’)


iv. World Federation of Hemophilia (Mark Skinner) (5’)

10:10 a.m. Break

10:25 a.m. Open Public Hearing

.

10:55 a.m. FDA Questions for the Committee

11:05 p.m. Open Committee Discussion and Recommendations

12:00 p.m. Lunch

2

1:00 p.m. Topic II. Levels of TSE clearance in the manufacture of
plasma-derived FVIII


A. Summary of 18 September 2006 TSEAC discussion (D. Scott, M.D., FDA) (15’)


B. Updated information from manufacturers (T. Kreil, Ph.D., PPTA Baxter
Bioscience) (20’)

1:35 p.m. Open Public Hearing

2:05 p.m. FDA Questions for the Committee (10’)

2:15 p.m. Discussion (45’)

3:00 p.m. Adjourn


http://www.fda.gov/ohrms/dockets/ac/06/agenda/2006-4271A(draft)%20.pdf


Greetings,

i see the media picked up on this as a 'low risk', from what the gov. agency
perceived to be to them;


http://www.newsday.com/news/health/ats-ap_health14nov27,0,7955259.story?coll=ny-leadhealthnews-headlines


however, i seem to disagree. from my primitive ciphering, i see it another
way. this is a huge catastrophic risk. 3 in 160 is 1.9%. so call that 2%
which is 1 in 50 or twenty per thousand or 20,000 per million. also, what
about the mixed genotypes/mixed susceptibility? what about the silent
carriers that donated tainted blood? what about the sporadic CJDs of UNKNOWN
strain or phenotype? this risk assessment is just more BSe to me. just
another in a long line of industry fed crap. i pray that my assessment is
the one that is wrong. but it is THEY who roll the dice with your life. it
is THEY who refuse to regulate an industry that has run amok...TSS

[flatfish]

----- Original Message -----
From: Terry S. Singeltary Sr.
To: FREAS@CBER.FDA.GOV
Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov
Sent: Wednesday, November 29, 2006 1:24 PM
Subject: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION]



November 29, 2006


Greetings FDA, DHH, Dr. Freas, and Dr. Harvey et al,



a kind and warm Holiday Greetings to you all.


i kindly wish to submit the following to the TSE advisory committee for the meeting December 15, 2006,
about the assessment for potential exposure to vCJD in human plasma-derived antihemophilic factor (FVIII) products
manufactured from U.S. plasma donors and related communication material ;


http://a257.g.akamaitech.net/7/257/2422/01jan20061800/edocket.access.gpo.gov/2006/E6-20251.htm



i see the media picked up on this as a 'low risk', from what the gov. agency
perceived to be to them;


http://www.newsday.com/news/health/ats-ap_health14nov27,0,7955259.story?coll=ny-leadhealthnews-headlines



however, i seem to disagree. from my primitive ciphering, i see it another
way. this is a huge catastrophic risk. 3 in 160 is 1.9%. so call that 2%
which is 1 in 50 or twenty per thousand or 20,000 per million. also, what
about the mixed genotypes/mixed susceptibility? what about the silent
carriers that donated tainted blood? what about the sporadic CJDs of UNKNOWN
strain or phenotype? this risk assessment is just more BSe to me. just
another in a long line of industry fed crap. i pray that my assessment is
the one that is wrong. but it is THEY who roll the dice with your life. it
is THEY who refuse to regulate an industry that has run amok. just from a
recall aspect of potentially tainted blood, and these are just recent recalls ;


snip................


PLEASE READ my full submissions to the TSE Advisory committee part I and part II at urls below, much too long to post here ;



TSE ADVISORY COMMITTEE DECEMBER 15, 2006 [TSS SUBMISSION] - TSS 11/30/06 (1)


http://www.vegsource.com/talk/madcow/messages/1001062.html

Re: TSE ADVISORY COMMITTEE DECEMBER 15, 2006 [TSS SUBMISSION PART II] - TSS 11/30/06 (0)

http://www.vegsource.com/talk/madcow/messages/1001064.html


TSS

[flatfish]

----- Original Message -----
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 PART III]


Lancet Neurology DOI:10.1016/S1474-4422(06)70413-6

Predicting susceptibility and incubation time of human-to-human transmission of vCJD


MT Bishop a, P Hart b, L Aitchison b, HN Baybutt b, C Plinston b, V Thomson b, NL Tuzi b, MW Head a, JW Ironside a, RG Will a and JC Manson b

Summary
Background
Identification of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion has caused concern over spread of the disease within the human population. We aimed to model iatrogenic spread to enable a comparison of transmission efficiencies of vCJD and bovine spongiform encephalopathy (BSE) and an assessment of the effect of the codon-129 polymorphism on human susceptibility.

Methods
Mice were produced to express human or bovine prion protein (PrP) by direct replacement of the mouse PrP gene. Since the human PrP gene has variation at codon 129, with MM, VV, and MV genotypes, three inbred lines with an identical genetic background were produced to express human PrP with the codon-129 MM, MV, and VV genotypes. Mice were inoculated with BSE or vCJD and assessed for clinical and pathological signs of disease.

Findings
BSE was transmitted to the bovine line but did not transmit to the human lines. By contrast, vCJD was transmitted to all three human lines with different pathological characteristics for each genotype and a gradation of transmission efficiency from MM to MV to VV.

Interpretation
Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.

Affiliations

a. National CJD Surveillance Unit, Bryan Matthews Building, Western General Hospital, Edinburgh, UK
b. Institute for Animal Health, Neuropathogenesis Unit, King's Buildings, Edinburgh, UK

Correspondence to: Prof J C Manson, Institute for Animal Health, Neuropathogenesis Unit, Ogston Building, King's Buildings, West Mains Road, Edinburgh EH9 3JF, UK


snip...


Discussion

Although the cattle BSE epidemic in the UK has
amounted to more than 180 000 cases since the 1980s,
the extent of the human vCJD epidemic has so far
remained limited with the total number of cases
worldwide currently at 190. One explanation for this
apparent discrepancy is that there exists a significant
species barrier between cattle and human beings, which
limits the susceptibility of the human population to
BSE. The data shown here suggest that this could
indeed be the case since BSE was readily transmissible
to the bovine transgenic mice but not to the human
transgenic mice. However, once BSE has passed
through human beings in the form of vCJD, the
transmissibility of this TSE strain is altered for the
human population.

All the human transgenic lines inoculated with BSE
were negative for TSE transmission, which suggests that
either the human transgenic lines are relatively resistant
to transmission of BSE or the incubation time is longer
than the length of the experiment (approximately
700 days). BSE transmission previously observed by
others, in human transgenic lines overexpressing the
human prion protein, could be due to overexpression of
the PrP gene and may not therefore give a true reflection
of the species barrier between BSE and human
beings.15,25,26 This apparent resistance of human transgenic
mice to BSE could be explained by a large species barrier
and this in turn could explain the low number of vCJD
cases in the human population.

vCJD was transmitted to all three human lines with
different pathological characteristics for each genotype,
and a gradation of transmission efficiency from MM to
MV to VV. The greater transmission efficiency in HuMM
mice suggests that homozygosity for methionine at
codon 129 leads to earlier onset of TSE-related
pathological features and clinical disease than for the
other two genotypes. The differences in PrPSc deposition
in the HuMM and HuMV lines suggest that the codon-
129 polymorphism in human beings is likely to affect
the distribution of PrPSc deposition in the brain.
Moreover, the similar numbers that scored positive for
PrP deposition in each of the MM and MV groups (11/15
and 11/13 respectively) suggest that the two genotypes
might be equally susceptible to vCJD, but with different
incubation periods. Titration experiments are needed to
fully compare the susceptibility of each line. The single
HuVV mouse positive for PrPSc shows that VV
individuals may be susceptible to vCJD with very long
incubation times, including a lengthy subclinical phase.
Transmission studies from all three genotype mice are
now underway to examine the infectious nature of the
disease and determine any alterations in the strain
characteristics on passage through human transgenic
mice. By contrast with published data suggesting that
VV individuals cannot propagate the vCJD biochemical
phenotype,15 the data presented here suggest that the

PrPSc type will remain a useful diagnostic feature of
secondary vCJD infection irrespective of codon-129
genotype, as has been observed for the two extant cases
of transfusion-associated vCJD infection. 5,27

Transmission of vCJD to the three lines of human
transgenic mice indicates that the human population
could be at significantly heightened risk of developing
disease after iatrogenic exposure to vCJD. Secondary
transmission of vCJD has partly removed the cattle-to-
human species barrier and has resulted in an agent that
can be transmitted from human to human with relative
efficiency. Transmission studies in cynomolgus macaques
provide further evidence for this agent adaptation as they
show reduction in incubation times after serial passage
of BSE.28 Our BSE inoculation at 10-1 dilution was
compared with vCJD inoculation at 10-2 because the latter
inoculum was found to be toxic to the mice at 10-1. Use of
a higher dose ofvCJD inoculum would have maintained
or increased the transmission efficiency of vCJD and
enhanced the current findings.

Our findings raise concerns relevant to the possibility
of secondary transmission of vCJD through blood
transfusion, fractionated blood products, or contaminated
surgical instruments. For this study mice were injected
intracerebrally, whereas the probable human exposure to
these agents is by peripheral routes (eg, oral or
intravenous), and thus human-to-human exposures
might be significantly less efficient. However, it is difficult
to know for sure what the practical implications might be
in human beings. Peripheral route challenge is in
progress; however, BSE transmission studies in primates
have shown the intravenous route to be as efficient as the
intracerebral route, with an extension of the incubation
time.28

Although all cases of vC]D up to now have been
observed in the MM genotype, this model of human-to-
human vCJD transmission suggests that other genotypes
are also susceptible. In our experimental setting, all
PRNP codon-129 genotypes are susceptible to vCJD
infection; however, progressive development of
pathological TSE features (vacuolation and PrP
deposition) is more rapid in the MM-genotype mice. An
explanation for this finding might be provided by in-vitro
conversion of recombinant human PrP by BSE and vCJD
agents, which has shown that PrP with methionine at
position 129 is more efficiently converted than PrP with
valine, and that conversion by vCJD is significantly more
efficient than by BSE.29 Long incubation periods during
which PrPSc is deposited predicts that, in human beings,
infection could be present in all genotypes for a significant
period before clinical onset. Incubation periods of more
than 30 years have been reported in the human TSE
disease kuru.30

The possibility that an MV or VV genotype could result
in a phenotype distinct from that recognised in vCJD
draws attention to the importance of systematic
assessment of the clinical, genetic, pathological, and

biochemical features of all human prion diseases. Our
findings indicate that for human-to-human vCJD infection

it should be assumed that all codon-129
genotype individuals (not just MM) can be infected, that
long incubation times can occur, and that a significant
level of subclinical disease might be present in the population.

Contributors

MTB, PH, and CP did immunocytochemical and western blot analysis;

JCM, NT, HNB, and LA produced the transgenic mouse lines; JWI
supplied vCJD case material and reviewed the neuropathology; VT did
the mouse inoculations; and MTB, PH, MWH, RGW, JWI, and JCM
prepared the manuscript.

Conflicts of interest

We have no conflicts of interest.

Acknowledgments



snip... end


http://www.thelancet.com/journals/laneur/article/PIIS1474442206704136/abstract?isEOP=true


TSS

[flatfish]

The Lancet 2006; 368:2061-2067

DOI:10.1016/S0140-6736(06)69835-8

Articles

Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report

Stephen J Wroe FRCP a b, Suvankar Pal MRCP a b, Durrenajaf Siddique MRCP a b, Harpreet Hyare FRCR a b, Rebecca Macfarlane MRCS a b, Susan Joiner MSc b, Jacqueline M Linehan BSc b, Sebastian Brandner MRCPath b, Jonathan DF Wadsworth PhD b, Patricia Hewitt FRCPath c and Prof John Collinge FRS a b

Summary
Background
Concerns have been raised that variant Creutzfeldt-Jakob disease (vCJD) might be transmissible by blood transfusion. Two cases of prion infection in a group of known recipients of transfusion from donors who subsequently developed vCJD were identified post-mortem and reported in 2004. Another patient from this at-risk group developed neurological signs and was referred to the National Prion Clinic.

Methods
The patient was admitted for investigation and details of blood transfusion history were obtained from the National Blood Service and Health Protection Agency; after diagnosis of vCJD, the patient was enrolled into the MRC PRION-1 trial. When the patient died, brain and tonsil tissue were obtained at autopsy and assessed for the presence of disease-related PrP by immunoblotting and immunohistochemistry.

Findings
A clinical diagnosis of probable vCJD was made; tonsil biopsy was not done. The patient received experimental therapy with quinacrine, but deteriorated and died after a clinical course typical of vCJD. Autopsy confirmed the diagnosis and showed prion infection of the tonsils.

Interpretation
This case of transfusion-associated vCJD infection, identified ante-mortem, is the third instance from a group of 23 known recipients who survived at least 5 years after receiving a transfusion from donors who subsequently developed vCJD. The risk to the remaining recipients of such tranfusions is probably high, and these patients should be offered specialist follow-up and investigation. Tonsil biopsy will allow early and pre-symptomatic diagnosis in other iatrogenically exposed individuals at high risk, as in those with primary infection with bovine spongiform encephalopathy prions.

Affiliations

a. National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
b. MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
c. National Blood Service, London, UK

Correspondence to: Prof John Collinge



http://www.thelancet.com/journals/lancet/article/PIIS0140673606698358/abstract





TSS