18th Meeting of FDA TSE Advisory Committee: 31 October 2005 Summary

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18th Meeting of FDA TSE Advisory Committee31
October 2005Summary

• FDA Blood Products Advisory Committee
• 85th Meeting
• 03 November 2005
• Holiday Inn
• Gaithersburg MD
• David M. Asher, MD
• ltasher_at_cber.fda.govgt
• Laboratory of Bacterial, Parasitic and
  Unconventional Agents
• Division of Emerging Transfusion-Transmitted
  Diseases
• Office of Blood Research Review
• Center for Biologics Evaluation Research
• US Food Drug Administration

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18th FDA TSEAC Agenda

1. BSE worldwide and USA USDA update
2. TSE decontamination of surgical devices CDRH
   update
3. CBER decisional issue 1. Advice on further
   development of FDA risk assessment for vCJD and
   plasma-derived factor VIII
4. CBER decisional issue 2. Validation criteria and
   possible label claims for devices to remove TSE
   infectivity from blood components

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Recipients surviving gt3yrs post transfusion of
blood components from vCJD/CJD Donors(using data
from UK TMER and US ARC look-back studies,S.
Anderson, FDA TSEAC 14 Oct 2004)
Infection No Infection
CJD 0 116
vCJD 2 13

• Fisher's Exact Test comparing rates of infection
  after transfusions from vCJD and CJD donors
  suggests a statistically significant difference
  between the two groups (?1.2 likelihood that the
  difference occurred by chance). ?Risk of
  transfusion-transmitted vCJD gtgt sporadic CJD

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vCJD Non-UK 27cases(October 2005 UK 158)
from R. Knight/CJD SU Edinburgh

• FRANCE 15
• ITALY 1
• NETHERLANDS 1
• PORTUGAL 1
• SPAIN 1
• REPUBLIC of IRELAND 2
• REPUBLIC of IRELAND 2
• USA 1
• CANADA 1
• JAPAN 1
• SAUDI ARABIA (source uncertain) 1

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Critical elements of vCJD risk assessmentPrevale
nce of vCJD in US Plasma

• UK vCJD prevalence
• US donor travel history
• Time of travel relative to UK BSE prevalence
• Travel Source Plasma vs recovered plasma donors
• Risk reduction by donor deferral
• Effectiveness of donor deferral
• Residual risk non-deferred (short-duration)
  travelers

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Module 1 Prevalence of vCJD in United Kingdom

• Proposed Modeling Approaches
• Two sources of UK vCJD prevalence data
• 1. Predictive models based on UK vCJD cases
• 2. Surveillance data based on examination of
  appendix samples
• Problem
• Disparity 10 to 100 fold between approaches

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Module 1Prevalence of vCJD in UK

• Predictive models based on observed cases of vCJD
  and back calculation method
• ______________________________________________
• (1) Ghani et al 2003
• vCJD estimated median 100 cases (10 to 2,600 -
  95 CI)
• Median 1 in 500,000
• (2) Boelle et al 2003
• vCJD UK estimated cases 183 to 304
• (3) Llewelyn et al 2004
• vCJD UK est 1 in 15,000 to 1 in 30,000 or
  1,000-2,000 infections

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Unique Pathology of vCJD (Chazot G al. Lancet
19963471181. Will RG al. Lancet
1996347921-5. Hill AF al. Lancet
1999353183-9)
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Module 1 Prevalence of vCJD in UK

• Empirical appendix surveillance data (Hilton et
  al. 2004)
• 3 PrPres-positive samples in 12,674 samples
  tested
• mean of 1 positive in 4,225 individuals
• (mostly 20- to 30-yr-old patients)
• Approximately 13,000 vCJD infected UK individuals
  in UK
• Data should be further age-adjusted using
  reported UK vCJD case age profile
• Does not consider infected persons before
  appendix becomes positive for PrPres (e.g., last
  transfusion-transmitted infection in a
  PRNP-codon-129 met/val person)

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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• UK Prevalence Use empirical prevalence value
  based on UK PrPres tissue survey allowing for a
  pre-clinical/sub-clinical infectious state in
  donors of all PRNP-codon-129 genotypes

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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• Screening sensitivity for vCJD risk Advised
  against using estimates from analogous donor
  screening situations (showing 90-99 sensitivity
  of screening) and recommended instead 85 most
  likely
• Source Plasma donor information Encouraged
  obtaining survey data for travel by apheresis
  donors rather than extrapolating from a travel
  survey for donors of Whole Blood

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Levels of vCJD infectivity in human plasmaWhat
infectivity range (in ID50/ml) should FDA select
for human blood/plasma based on studies in
animals?During what part of the incubation
period?

• FDA proposed a triangular distribution
• Minimum 0.1
• Most likely 10
• Maximum 310
• FDA proposed assuming infectivity to be
  potentially present in blood throughout the
  entire incubation period.

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Experimental TSEs infectivity in blood
? Infected
? Uninfected
(147)
(429)
(396)
(184)
(443)
(448)
(308)
(463)
(504)
(379)
(447)
(210)
(343)
(307)
________________________________
_____________________________________
__________________ 0 1 2 3 4
5 6 7 8 9 10
15 20
25
CJD in guinea pig
Manuelidis/ic inoc .1ml clinical/ 0.1ml buffy
coat ic, ip, sc, im
scrapie in mouse
(214)
(151)
(151)
(186)
(191)
(108)
(116)
(114)
(113)
(128)
(124)
(131)
(121)
(132)
(138)
________________________________
_____________________________________
_______________


1 8
16 27 41
51 60 70 80 90
100 120
scrapie in hamster
Cassacia/ 106 ip 200 ul blood equiv ic
Clinical disease
Numbers in parentheses are mean incubation times.
From Dr RG Rohwer, Baltimore VAH
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Infectivity in blood of terminally ill mice
inoculated with mouse-adapted GSS (Fu-1)
agent(Brown P et al. Transfusion
1999391169-78)
Infectivity in ic IU/ml Expt 1 Expt 2 Pool 1 Expt 2 Pool 2
Buffy coat 44 NT 106
Plasma 10 34 22
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Titers of scrapie-infected hamster bloodfrom
clinically ill animals
Infectious Doses/ml
Infectious Doses/ml
From Dr RG Rohwer, Baltimore VAH
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From Dr RG Rohwer, Baltimore VAH
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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• Infectivity level Agreed thatbased on rodent
  data10 ID50/ml blood most likely and minimum of
  0.1 ID50 prudent, but offered mixed advice on
  upper level (100 to 1000 ID50 mentioned)
• Duration of infectivity in blood relative to
  incubation period Agreed compromise advice
  estimating infectivity in last 50 of incubation
  period, modified if shown to be a critical
  parameter in sensitivity analysis

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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• Pool size Agreed with FDA-proposed bimodal
  distribution with pools of 20,000 and 60,000
  donations considered most likely
• Clearance of TSE infectivity by manufacturing
  processes Agreed with FDA proposal to use three
  different ranges for various products

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Issue 1. Plasma fractionationFDA proposes 3
ranges of estimated vCJD infectivity clearance by
manufacturing
Range of reduction (log10) Process
Likely minimum 2-3 Single step with moderate clearance
Mid-range 4-6 Single step with higher clearance or Multiple additive steps
Likely maximum 7-9 Multiple additive steps
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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• Clinical use Agreed with FDA that CDC databases
  for FVIII use (1993-98 survey of all HA pts in 6
  states and Universal Data Collection Program
  UCD) were best available (but not
  enoughespecially for von Willebrands disease)
• Additional information needed Agreed with FDA
  proposal to extrapolate from existing data to
  estimate use by year and use patient-based
  medical record data if needed to resolve
  inconsistencies

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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• Cumulative risk from repeated exposures to
  sub-infectious doses Agreed with FDA that
  experimental studies showing infection following
  frequent exposures of rodents to amounts of
  infectivity not infectious by single exposures or
  repeated at long intervals are a concern
• Risk per annum Agreed with FDA proposal to
  estimate vCJD risk per annum rather than per dose
  (but did not advise other modification to the
  risk model)

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Issue 1. Advice on Assumptions for vCJD FVIII
Risk Assessment

• Special concern risk communication
• Risk of transmission by plasma derivatives is
  theoretical. (Even in UK, no case of vCJD has
  been recognized in a recipient of a plasma
  derivative.)
• Especially difficult to communicate highly
  uncertain theoretical risks
• Notification might cause adverse effects
• Patient anxiety
• Health care provider anxiety
• Other
• Participation of patient groups helpful

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TSEAC Decisional Issue 2.Validation criteria and
possible label claims for devices to remove TSE
infectivityfrom blood components

• UK regulatory authorities plan an independent
  evaluation of CE-marked blood filters purported
  to reduce TSE infectivity
• Expect minimal ? 3 log10 reduction of spiked
  infectivity (demo by Western blot and bioassay)
  at ambient temp and 4oC
• Component (RBC) must maintain functionality at
  expiry by usual tests
• Seek surrogate markers suitable for QA
• Three manufacturers described 3 promising devices
  for clearing TSE agents (one CE-marked)

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TSEAC Decisional Issue 2.Validation criteria and
possible label claims for devices to remove TSE
infectivityfrom blood components

• TSEAC suggested modifications to FDAs proposed
  criteria
• ? 3 log10 reduction of spiked infectivity
  (demonstrated by Western blot and bioassay)
• Remove all detectable infectivity from
  endogenously infected animal blood
• ? 2 animal models and 2 strains of TSE agent
• ? 1 agent strain derived from cow with BSE or
  human with vCJD (rodent-adapted)
• Filtered blood components should maintain
  functionality at expiry by usual tests

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TSEAC Decisional Issue 2.Validation criteria and
possible label claims for devices to remove TSE
infectivityfrom blood components

• TSEAC suggested modifications to FDAs proposed
  criteria for validation (continued)
• Desirable to demonstrate that device removes all
  detectable endogenous TSE infectivity from whole
  units of blood of large animals (sheep
  scrapie/BSE ?? primatesnot yet available)
• Since bioassays for residual infectivity by
  transfusing of animals of the same species, while
  ideal, are generally not feasible, may test in
  susceptible transgenic mice (although sensitivity
  relative to large animals not known)

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TSEAC Decisional Issue 2.Validation criteria and
possible label claims for devices to remove TSE
infectivityfrom blood components

• TSEAC suggested modifications to FDAs proposed
  criteria for validation (continued)
• While reproducibility of results at separate
  study sites is desirable, it may be difficult to
  arrange for two labs with required equipment and
  TSE expertise
• Study should be large enough for statistical
  validity
• Studies described might support label claims for
  reduction of TSE infectivity (small animal
  models), ?? prevention of transfusion-transmitted
  TSE (only after large animal study)

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