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

1

• 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

2
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

3
Risk Assessment Question

• 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?

4
Risk Assessment

• FDA has risk assessments underway for several
  plasma derivatives
• FVIII
• FIX
• Immune globulins
• Serum albumin
• This presentation provides an overview of the
  concept model and assumptions for the risk
  assessments for the above products
• The risk assessments have not been completed!

5
I. Hazard Identification

• Two recent cases of probable transfusion-transmitt
  ed vCJD in United Kingdom
• Raise possibility of transmission of vCJD via
  plasma derived products
• To date vCJD transmission via plasma derivatives
  has not been observed

6
II. Dose response(or Hazard characterization)

• Human data not available
• On BSE dose(s) that cause vCJD
• Quantity vCJD ID50 causes infection by blood
• Animal data limited
• Multiple dose groups needed
• Development of a dose response model
• not possible at this time
• Predicting probability
• of vCJD illness is extremely uncertain !

100
Probability of infection
50
1
2
Quantity of agent
7
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
• (B) Plasma donation
• Probability of deferral
• Probability of agent in pool
• (C) Reduction during manufacture
• Reduction in Quantity (dose) TSE agent in product
• (C) Dose per surgery or treatment(s)
• Quantity of vCJD agent in final product
• Amount of product used by patients

8
US Plasma Derivatives Risk Assessment Exposure
Assessment Overview
9
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

10
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

11
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

12
Exposure Assessment Module A

• (2) Dietary exposure to BSE agent during
  extended travel to UK and Europe
• Calculation US donor vCJD risk based on
• Prevalence vCJD in UK
• Relative risk of UK, France, Europe for BSE/vCJD
• Percentage US donors with travel history UK,
  France Europe
• 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

13
III. Exposure Assessment Module A (2)
Potential vCJD cases in US due toBSE dietary
exposure during travel

• 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

14
Exposure Assessment Module A (2) Potential
vCJD cases in US due toBSE dietary exposure
during travel

• (b) Relative risk of UK, France, Europe for
  BSE/vCJD
• UK gt 3 months - 1980 1996
• France, Europe gt 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

15
III. Exposure Assessment Module A (2)
Potential vCJD cases in US due toBSE 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 gt 5 years (1980 to 1996) -
  relative risk 1
• UK lt 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 gt5 years (since 1980) -
  relative risk 0.05
• Europe gt5 years (since 1980) -
  relative risk 0.015

16
III. Exposure Assessment Module A (2)
Potential Potential vCJD cases in US BSE dietary
exposure during travel

• 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

17
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

18
III. Exposure Assessment Module B Plasma
Donation

• US donors with travel history
• Model incorporates information on
• Age specific plasma donation rates
• Age specific vCJD rates
• Probability of vCJD donation per plasma pool
• (4) Quantity iv ID50 per plasma donation
• (5) Probability of donor deferral

19
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
lt 25 42
25 - 34 28
35 - 44 19
gt 45 11
20
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)

21
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)

22
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

23
III. Exposure Assessment Module B Plasma
Donation

• (5) Probability of donor deferral
• Model assumes donor questionnaire is
  90 - 95 effective

24
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.

25
III. Exposure Assessment Module C
Processing Example using Factor VIIIReduction
during Manufacturing
Parameter Log10 reduction Log10 reduction 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
26
Exposure Assessment Module D Utilization
Example using Factor VIII

• Probability and Quantity of exposure influenced
  by patient utilization of product(s)
• Number sources of product utilization by patients
• Three categories of Hemophilia A disease
  severity
• Severe
• Moderate
• Mild

27
III. Exposure Assessment Module D
Utilization Example using Factor VIII
Treatment Regimen 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
28
III. Exposure Assessment Module D Utilization
of other plasma derivativesFactor IX, immune
globulins, albumin

• Concepts for utilization similar
• Probability and Quantity of exposure influenced
  by patient utilization of product(s)
• Number sources of product utilization by patients
• Severity of disease and utilization
• Frequent use
• One or few occasions of use (albumin)

29
Exposure Assessment Other plasma
derivativesFactor IX, immune globulins, albumin

• Many concepts in model similar
• Probability of vCJD in US
• Probability contaminated plasma pool
• Effectiveness screening questionnaire
• Some processes vary
• Plasma pool size
• Reduction vCJD ID50 during manufacture
• Product package sizes and amounts dispensed
• Product utilization by patients

30
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

31
Acknowledgements

• Hong Yang, OBE
• Dorothy Scott, OBRR
• David M. Asher, OBRR
• Rolf Taffs, OBRR
• Mark Weinstein, OBRR
• Other Hematology and OBRR staff