Transcript Preliminary Risk Assessment Model for U.S. Plasma Derivatives and vCJD

Preliminary Risk
Assessment Model for
U.S. Plasma Derivatives
and vCJD
Steven Anderson, PhD, MPP
Office of Biostatistics & Epidemiology
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Elements of Risk Assessment
NAS (1983)
I. Hazard identification
• Establishes causality between hazard and adverse
effects
II. Dose response
(Hazard characterization)
• Probability of response – infection or illness
III. Exposure assessment
• Frequency and level of exposure
IV. Risk characterization
• Probability of occurrence, severity of adverse effects
• Uncertainty
• Sensitivity analysis
Risk Assessment Question
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Given the recent probable transmission of
vCJD via transfusion of non-leukocyte
reduced RBC concentrates in the United
Kingdom, what is the risk of potential
exposure to the vCJD agent to the US
population(s) that have received USmanufactured human plasma derivatives?
Risk Assessment
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FDA has risk assessments underway for several
plasma derivatives
n
n
n
n
FVIII
FIX
Immune globulins
Serum albumin
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This presentation provides an overview of the
concept model and assumptions for the risk
assessments for the above products
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The risk assessments have not been completed!
I. Hazard Identification
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Two recent cases of probable transfusiontransmitted vCJD in United Kingdom
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Raise possibility of transmission of vCJD
via plasma derived products
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To date vCJD transmission via plasma
derivatives has not been observed
II. Dose response
(or Hazard characterization)
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Human data not available
– On BSE dose(s) that cause vCJD
– Quantity vCJD ID50 causes infection by blood
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Animal data limited
– Multiple dose groups needed
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Development of a dose response model
not possible at this time
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Predicting probability
of vCJD illness is extremely uncertain !
100%
50%
1
2
Quantity of agent
III. Exposure Assessment
Plasma derivatives and vCJD
Key aspects of exposure assessment:
(A) vCJD in US population and plasma pool
– Probability of agent in pool and
– Quantity (dose) TSE agent in starting pool
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(B) Plasma donation
– Probability of deferral
– Probability of agent in pool
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(C) Reduction during manufacture
– Reduction in Quantity (dose) TSE agent in product
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(C) Dose per surgery or treatment(s)
– Quantity of vCJD agent in final product
– Amount of product used by patients
US Plasma Derivatives Risk Assessment
Exposure Assessment Overview
INPUT
UK vCJD cases
US vCJD risk
dietary exposure to
BSE
Probability vCJD plasma
pool
Screening questionnaire
Plasma pool size
Infectivity in plasma
Reduction of quantity vCJD
agent during manufacture
Product yield
Percent contaminated vials
Amount vCJD agent per
unit(s)/ vial(s)
Annual dose product
MODULE
OUTPUT
Module A
Theoretical estimate of
potential annual number vCJD
cases in the United States
vCJD cases
US
Module B
Plasma
Donation
Percentage of contaminated
plasma pools
Quantity vCJD agent in
contaminated plasma pool
Module C
Processing
Percentage units/ vials with
vCJD ID50
Infectivity units/ vials with
vCJD ID50
Module D
Utilization
Annual exposure to vCJD agent
III. Exposure Assessment:
Module A: Potential vCJD cases in US
vCJD risk in US plasma donors possible
from two sources:
(1) Dietary exposure to BSE agent from US
domestic beef consumption
(2) Dietary exposure to BSE agent during extended
travel to UK and Europe
III. Exposure Assessment:
Module A: Potential vCJD cases in US
(1) Dietary exposure to BSE agent from US domestic
beef consumption
 Evaluation of USDA BSE surveillance data in US
cattle
 Currently – estimated risk of domestically acquired
vCJD in United States from this route is negligible
 Model assumes zero cases from this source
III. Exposure Assessment:
Module A: Potential vCJD cases in US
(2) Dietary exposure to BSE agent during extended
travel to UK and Europe
Approach:
Model estimates vCJD prevalence in UK population
“Relative risk” of exposure to BSE agent in relation to UK
risk is estimated for France and Europe
vCJD risk then calculated for US plasma donors with
history of extended travel to UK, France, and Europe
III.
Exposure Assessment:
Module A
(2) Dietary exposure to BSE agent during extended travel to
UK and Europe
Calculation US donor vCJD risk based on:
(a) Prevalence vCJD in UK
(b) Relative risk of UK, France, Europe for BSE/vCJD
(c) Percentage US donors with travel history UK, France & Europe
(d) Duration of US traveler stay
Potential cases vCJD in US
= [(UK Prev vCJD) x (Rel Risk UK) x (% US donors) x (duration in UK)]
+ [(Fr Prev vCJD) x (Rel Risk Fr) x (% US donors) x (duration in Fr)]
+ [(EU Prev vCJD) x (Rel Risk Eu) x (% US donors) x (duration in EU)]
+ others
III. Exposure Assessment: Module A
(2) Potential vCJD cases in US due to
BSE dietary exposure during travel
(a) Prevalence of vCJD in UK population
 Tonsil/appendix surveillance study (Hilton, et al. 2004)
 3 prion positive samples in 12,674 samples tested
 Mean of 1 positive in 4,225 individuals
III.
Exposure Assessment: Module A
(2) Potential vCJD cases in US due to
BSE dietary exposure during travel
(b) Relative risk of UK, France, Europe for BSE/vCJD
 UK
 France, Europe
> 3 months > 5 years
-
1980 – 1996
1980 - present
 Model uses concept of “relative risk” presented at TSEAC at
past meetings
 to evaluate vCJD risk for US plasma donors with history of
extended travel
 Donor travel risk is evaluated in relation to UK vCJD risk
III. Exposure Assessment: Module A
(2) Potential vCJD cases in US due to
BSE dietary exposure during travel
(b) Relative risk of UK, France, Europe for BSE/vCJD
vCJD risk of UK citizens is assumed – equal to 1
Other country exposures are a fraction of the UK relative risk
Based on potential exposure to BSE, vCJD prevalence, etc.
US donor travel stay in UK:
UK > 5 years
(1980 to 1996)
UK < 5 years - 1980 to 1996


-
relative risk 1
Risk for stay for 3 months to 5 years pro-rated on a per year basis
Relative risk apportioned equally for each of 17 years between 1980 - 1996
US donor travel stay in France and Europe:
France >5 years
(since 1980) - relative risk 0.05
Europe >5 years (since 1980) relative risk 0.015
III. Exposure Assessment: Module A
(2) Potential Potential vCJD cases in US
BSE dietary exposure during travel
(c)Percentage US donors with travel history UK,
France & Europe
~ 6% US residents - history of travel to UK and Europe
during 1980s and 1990s
~ 3% US residents Military and dependents history of
travel to UK and Europe
1.7% traveled to UK (1980 – 1996) for 3 month period
0.2% traveled to France since 1980 for 5 year period
0.7% traveled to Europe since 1980 for 5 year period
III. Exposure Assessment: Module A
(2) Potential Potential vCJD cases in US
BSE dietary exposure during travel
(d) Duration of travel to UK, France and Europe
 Travel history and duration of travel data was collected for
blood donors using blood center surveys
 Model assumes blood donor travel history data is same for
plasma donors
 However, plasma donors less likely to have history of travel
to UK and Europe
 Model may slightly overestimate vCJD risk for US plasma donors
III. Exposure Assessment: Module B
Plasma Donation
US donors with travel history
Model incorporates information on:
(1) Age specific plasma donation rates
(2) Age specific vCJD rates
(3) Probability of vCJD donation per plasma pool
(4) Quantity iv ID50 per plasma donation
(5) Probability of donor deferral
III. Exposure Assessment: Module B
Plasma Donation
(1) Model uses estimated age specific Source Plasma
donation rates
Age (in yrs)
Percentage plasma
donors by age
< 25
42 %
25 - 34
28 %
35 - 44
19 %
> 45
11 %
III. Exposure Assessment: Module B
Plasma Donation
(2) Age specific vCJD rates
- Model assumes vCJD for US -similar age demographics to UK
- Based on UK data (Knight et al 2004)
UK vCJD
25
20
15
10
5
0
9
2024
3034
4044
5054
6064
Age group
7074
8084
III. Exposure Assessment: Module B
Plasma Donation
(3) Probability of vCJD donation per plasma pool
 Model uses equation to estimate vCJD donations per
pool:
Pr ob
DvCJD  n
 BINOMDIST (n, D pool , DC  Prev )
 n = number donations
 Dpool = Total donations per pool
 DC-prev = prevalence vCJD donation(s)
III. Exposure Assessment: Module B
Plasma Donation
(4) Quantity iv ID50 per plasma donation
 ic ID50 per ml blood
 Minimum 0.1
 Most likely 10
 Maximum 1,000
 Model assumes 58% associated with plasma
(Gregori, et al. 2004)
 Model assumes source plasma donation is 800 mls
 Assume adjustment 5 to 10 fold for efficiency of
intravenous vs. intracerebral route exposure
III. Exposure Assessment: Module B
Plasma Donation
(5) Probability of donor deferral
 Model assumes donor questionnaire is
90% - 95% effective
III. Exposure Assessment: Module C
Processing
Effect of processing on vCJD infectivity
(1) Log10 reduction ID50 during processing
Processing varies
Reduction based on processing steps
High purity – immunopurified product
Intermediate purity - alcohol precipitation,
chromatography, etc.
III. Exposure Assessment: Module C
Processing: Example using Factor VIII
Reduction during Manufacturing
Log10 reduction
Parameter
Minimum Most Likely Maximum
High purity FVIII
3.0
5.0
6.0
Intermediate purity FVIII
2.0
3.0
4.0
III.
Exposure Assessment: Module D
Utilization: Example using Factor VIII
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Probability and Quantity of exposure influenced
by patient utilization of product(s)
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Number sources of product utilization by
patients
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Three categories of Hemophilia A disease
severity:
n
n
n
Severe
Moderate
Mild
III. Exposure Assessment: Module D
Utilization: Example using Factor VIII
Treatment
Regimen for Severe
Disease
Mean
5th
percentile
95th
percentile
Prophylaxis
Episodic
236,800 u
158,800 u
314,600 u
95,200 u
63,800 u
126,400 u
III. Exposure Assessment: Module D
Utilization of other plasma derivatives
Factor IX, immune globulins, albumin
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Concepts for utilization similar
Probability and Quantity of exposure influenced
by patient utilization of product(s)
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Number sources of product utilization by
patients
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Severity of disease and utilization
Frequent use
One or few occasions of use (albumin)
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Exposure Assessment:
Other plasma derivatives
Factor IX, immune globulins, albumin
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Many concepts in model similar:
– Probability of vCJD in US
– Probability contaminated plasma pool
– Effectiveness screening questionnaire
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Some processes vary:
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–
–
–
Plasma pool size
Reduction vCJD ID50 during manufacture
Product package sizes and amounts dispensed
Product utilization by patients
Data Gaps
More data are needed on:
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Prevalence of vCJD in UK, USA, etc.
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Amount vCJD agent present in human blood & plasma
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Progression of vCJD and variability of levels of
infectivity in blood & plasma
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Variability in reduction of vCJD agent during various
processing steps
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Plasma product utilization
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Many other parameters
Acknowledgements
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Hong Yang, OBE
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Dorothy Scott, OBRR
David M. Asher, OBRR
Rolf Taffs, OBRR
Mark Weinstein, OBRR
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Other Hematology and OBRR staff
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