preliminary risk assessment model for u.s. plasma derivatives and vcjd steven anderson, phd, mpp...
DESCRIPTION
Risk Assessment Question l 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 US- manufactured human plasma derivatives?TRANSCRIPT
Preliminary Risk Assessment Model for U.S. Plasma Derivatives and vCJD
Steven Anderson, PhD, MPP
Office of Biostatistics & EpidemiologyCenter for Biologics Evaluation and Research
U.S. Food and Drug Administration
Elements of Risk AssessmentNAS (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
l 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 US-manufactured human plasma derivatives?
Risk Assessmentl FDA has risk assessments underway for several plasma
derivativesn FVIII n FIXn Immune globulinsn Serum albumin
l This presentation provides an overview of the concept model and assumptions for the risk assessments for the above products
l The risk assessments have not been completed!
I. Hazard Identification
l Two recent cases of probable transfusion-transmitted vCJD in United Kingdom
l Raise possibility of transmission of vCJD via plasma derived products
l To date vCJD transmission via plasma derivatives has not been observed
II. Dose response(or Hazard characterization)
l Human data not available– On BSE dose(s) that cause vCJD– Quantity vCJD ID50 causes infection by blood
l Animal data limited – Multiple dose groups needed
l Development of a dose response model not possible at this time
l Predicting probability of vCJD illness is extremely uncertain !
Prob
abili
ty o
f inf
ectio
n
50%
100%
1 2Quantity 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
l (B) Plasma donation– Probability of deferral– Probability of agent in pool
l (C) Reduction during manufacture– Reduction in Quantity (dose) TSE agent in product
l (C) Dose per surgery or treatment(s)– Quantity of vCJD agent in final product– Amount of product used by patients
Probability vCJD plasma pool Screening questionnairePlasma pool sizeInfectivity in plasma
Reduction of quantity vCJD agent during manufactureProduct yield
Percent contaminated vialsAmount vCJD agent per unit(s)/ vial(s) Annual dose product
Module AvCJD cases
US
Module BPlasma
Donation
Module CProcessing
Module DUtilization
INPUT MODULE OUTPUT
Percentage of contaminated plasma poolsQuantity vCJD agent in contaminated plasma pool
Percentage units/ vials with vCJD ID50
Infectivity units/ vials with vCJD ID50
Annual exposure to vCJD agent
Theoretical estimate of potential annual number vCJD cases in the United States
UK vCJD cases US vCJD risk dietary exposure to BSE
US Plasma Derivatives Risk AssessmentExposure Assessment Overview
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 > 3 months - 1980 – 1996 France, Europe > 5 years - 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) - relative risk 1UK < 5 years - 1980 to 1996
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 0.05Europe >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 historyModel 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
Age (in yrs)Percentage plasma donors by age
< 25 42 %
25 - 34 28 %
35 - 44 19 %
> 45 11 %
(1) Model uses estimated age specific Source Plasma donation rates
0
5
10
15
20
25
9 20-24
30-34
40-44
50-54
60-64
70-74
80-84
Age group
UK vCJD
(2) Age specific vCJD rates- Model assumes vCJD for US -similar age demographics to UK- Based on UK data (Knight et al 2004)
III. Exposure Assessment: Module B Plasma Donation
III. Exposure Assessment: Module B Plasma Donation
(3) Probability of vCJD donation per plasma pool Model uses equation to estimate vCJD donations per pool:
n = number donations Dpool = Total donations per pool DC-prev = prevalence vCJD donation(s)
),,(Pr Pr evCpoolnD DDnBINOMDISTobvCJD
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 variesReduction based on processing stepsHigh purity – immunopurified product
Intermediate purity - alcohol precipitation, chromatography, etc.
III. Exposure Assessment: Module C
Processing: Example using Factor VIIIReduction during Manufacturing
ParameterLog10 reduction
Minimum Most Likely Maximum
High purity FVIII 3.0 5.0 6.0Intermediate purity FVIII 2.0 3.0 4.0
III. Exposure Assessment: Module D Utilization: Example using Factor VIII
l Probability and Quantity of exposure influenced by patient utilization of product(s)
l Number sources of product utilization by patients
l Three categories of Hemophilia A disease severity:n Severen Moderaten Mild
III. Exposure Assessment: Module D Utilization: Example using Factor VIII
TreatmentRegimen for Severe
Disease
Mean 5th percentile
95th percentile
Prophylaxis 236,800 u 158,800 u 314,600 u
Episodic 95,200 u 63,800 u 126,400 u
III. Exposure Assessment: Module D Utilization of other plasma derivativesFactor IX, immune globulins, albumin
l Concepts for utilization similarl Probability and Quantity of exposure influenced
by patient utilization of product(s)
l Number sources of product utilization by patients
l Severity of disease and utilizationl Frequent usel One or few occasions of use (albumin)
Exposure Assessment: Other plasma derivatives
Factor IX, immune globulins, albumin
l Many concepts in model similar:– Probability of vCJD in US– Probability contaminated plasma pool– Effectiveness screening questionnaire
l Some processes vary:– 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:• Prevalence of vCJD in UK, USA, etc.• Amount vCJD agent present in human blood & plasma• Progression of vCJD and variability of levels of infectivity in blood &
plasma• Variability in reduction of vCJD agent during various processing
steps• Plasma product utilization• Many other parameters
Acknowledgements
• Hong Yang, OBE
• Dorothy Scott, OBRR• David M. Asher, OBRR• Rolf Taffs, OBRR• Mark Weinstein, OBRR
• Other Hematology and OBRR staff