Draft Risk Assessment for UK manufactured Factor XI and Potential vCJD Exposure Steven Anderson,...

Draft Risk Assessment for UK manufactured Factor XI

and Potential vCJD Exposure

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 Quantity of exposure

IV. Risk characterization• Probability of occurrence, severity of adverse effects • Uncertainty • Sensitivity analysis

Quantitative Risk Assessment

l Commonly used when uncertainty about a risk is high !

l Uncertainty is pervasive in risk assessment

l FDA plasma derivative risk assessments include:n Model - FDA model is a computer modeln Document - organized according to NAS framework

Quantitative Risk Assessment

– “Link” relevant data together in a meaningful way

– Estimate potential exposure / risk

– Framework to identify critical elements where research will improve model

– Understand key elements that “drive” risk

– Risk assessment is an iterative process – updated as new data / information emerge

Draft Risk Assessment for U.K. Factor XI and

vCJD

Risk Assessment Question

l Given the recent probable transmission of vCJD via transfusion of non-leukocyte reduced RBC concentrates, what is the risk to US recipients that received human plasma derived Factor XI product from 1989 to 1997 manufactured from UK plasma?

Factor XI background

l Factor XI –clotting factor present in low concentrations in plasma

l FXI deficiency – rare

l Bleeding is less frequent that with Hemophilias A and B – does not involve joints or muscle

l Bleeding associated with surgery


I. Hazard identification

II. Dose response (Hazard characterization)

III. Exposure assessment

IV. Risk characterization

I. Hazard Identification

l In-depth review of available data and information

l Establishes causality between TSE agent in blood and infection and/or illness

I. Hazard Identification (cont’d)

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

I. Hazard Identification (cont’d)

l Factor XI Risk Assessment

l vCJD transmission via Factor XI is a potential hazard

l UK manufactured Factor XI was used in United States under investigational new drug (IND) status from 1989 to 1997

II. Dose response(or Hazard characterization)

l Relates amount of agent in dose to probability of infection or illness

Prob

abi l

ty o

f i n

fect

i on

50%

100%

1 2Quantity of agent


l Challenges for determining dose response for TSE diseasesn Human data absent

– Quantity agent in human blood? Plasma?– Variation?– Present throughout incubation period?– Genetics & susceptibility of humans

– Threshold? Or not?

– Accumulation of agent in humans?

n Animal data available– Does data approximate human situation well?


Commonly used dose terminology and metric in TSEs

One ID50 = dose necessary to initiate infection in 50% of the exposed population

– vCJD inferences based on animal TSE data !– Extrapolation of animal data to human outcomes = highly uncertain– Assumption in risk assessment: animal data approximates infection / illness in humans– We don’t know if assumption is accurate or not !

l Exposure may not lead to infection

l Infection may not lead to illness


l Dose-response (D-R) provides link to estimating risk based on exposure

l D-R is lacking – or highly uncertain for TSEs

l Therefore – predicting probability of vCJD is extremely uncertain !

Pro

babi

lity

of

infe

ctio

n

50%

100%

1 2Quantity of agent

III. Exposure Assessment

l Frequency or probability of exposure to vCJD agent

l Quantity of vCJD agent to which an individual is exposed

III. Exposure Assessment Factor XI Risk Assessment

Key aspects of exposure assessment:

l (A) vCJD ID50 in plasma pooln Probability of agent in pool and n Quantity (dose) TSE agent in starting pool

l (B) Reduction during manufacture

l (C) Dose per surgery or treatment(s)n Quantity of vCJD agent in final productn Amount of product used by patients

Percentage pool used in production Log10 reduction ID50 during processing

ivID50 per unit FXIivID50 per vialScenarios: include a pre- and post-surgery dose 20 – 50 u/kg

Module AvCJD ID50

plasma pool

Module BReduction in manufacture

Module CDose per surgery

Input Module Output

ID50 in FXI post-processingYield FXI plasma poolTotal ID50 per vial

Exposure estimate vCJD iv ID50

Exposure estimates 3 scenarios

•Total i.c. ID50 per vCJD donationTotal i.v. ID50 per plasma pool of 20,000 donations

Probability vCJD in UK Number vCJD donations per pool ID50 per ml plasma

Factor XI Risk AssessmentExposure Assessment Overview

III. Exposure Assessment : (A) vCJD ID50 in plasma pool

l Probability vCJD ID50 in pool or product – directly related to prevalence of vCJD in population

l Disparity in scientific literature between mathematical models and surveillance data

l Mathematical models:l (1) Ghani et al 2000

l vCJD estimate 70 to 236,000 clinical casesl Or 1 in 840,000 to 1 in 500

(2) Ghani et al 2003 l vCJD estimate median 100 cases (10 – 2,600 - 95% CI)l Median 1 in 500,000

l (3) Llewyn et al 2004l vCJD infection 1 in 15,000 to 1 in 30,000


l Surveillance data:l Hilton et al 2004

Surveillance study tonsil/appendices (Hilton, et al. 2004) – 3 prion positive samples in 12,674 samples tested

237 positives per million individuals Model assumes mean vCJD prevalence

of 1 in 4,224

l FDA rationale for use of surveillance datan Represent “real” data of possible incubating casesn Conservative – but uncertain estimate of prevalencen Model data – mostly estimate clinical vCJD casesn Non-clinical or asymptomatic infections have potential for

transfusion transmission


l Estimate prevalence vCJD in donor population to estimate probability of vCJD ID50 in plasma pool

l United Kingdom: (1) Mathematical modeling results (2) Surveillance study – tonsil & appendices

l United States:l Possible sources vCJD dietary exposure to BSE agent:l (1) History extended travel/residence in UK or Europe

(2) Domestic dietary exposure of US residents (3) Others – dietary supplements, etc.

III. Exposure Assessment: (A) vCJD ID50 in plasma pool

Factor XI Risk Assessment

Probability of exposure - Prevalence vCJD determines number vCJD donations per pool!

(1) Prevalence of vCJD in UK population Surveillance study tonsil/appendices (Hilton, et al. 2004) – 3 prion positive

samples in 12,674 samples tested

Mean of 1 positive in 4,225 individuals or 237 positives per million individuals

(2) Number vCJD donations per pool Average of 4.7 donations per pool of 20,000 donations

U.K. vCJD prevalence & Number vCJD donations per plasma pool


Prevalence UK PopulationvCJD cases per million

Mean 95% confidence interval

237 49 to 692

Triangular distributionParameters

Mean Range

UK Plasma poolNumber vCJD donations

per 20,000 donations

~ 5

(Most likely = 2)

0 to 14

Prevalence x 1 million20,000

1

50


l What is the Quantity TSE agent in starting plasma pool?

l Amount infectivity per donation and pooln Estimates of infectivity in human blood derived from

animal data

l Number TSE donations per pool(s)n Higher prevalence/incidence of TSE disease – greater

chance of multiple donations containing TSE agent in pool



Quantity of vCJD ID50 present - per ml plasma

Intercerebral (i.c.) ID50 per ml blood Minimum 0.1 Most likely 10 Maximum 1,000

Model assumes 58% associated with plasma (Gregori, et al. 2004)

Assume adjustment 5 to 10 fold reduced efficiency of intravenous vs. intracerebral route of exposure

III. Exposure assessment: Module B Reduction during manufacture

Parameter Minimum Most Likely Maximum

Log10 reductions vCJD agent 0 2.0 4.0

Factor XI Risk AssessmentLog10 reduction ID50 during processing

Reduction based on processing stepsVariability in processing and level(s) of reduction achieved

Assumption used in model:

III. Exposure Assessment: Module C: Dose per surgery or treatment(s)

l Package size (vial, vial size, # units, etc.)

l TSE ID50 per package

l One-time or chronic /multiple use of product

l Utilization may vary by severity of disease

l Estimate of utilization - precise as possible

III. Exposure assessment: Module C: Dose per surgery or treatment(s)


Utilization of UK-manufactured FXI in USA by patients

Scientific literature indicates common dosing with Factor XI Surgery-related dose(s) of 20 – 50 u/kg

Three possible dose scenarios range in the following:

Scenario 1: 3,000 u ( 1 treatment 60kg x 50 u ) Scenario 2: 9,000 u ( 3 treatments 60kg x 50 u ) Scenario 3: 15,000 u ( >3 treatments )

IV. Risk Characterization

l Integration of exposure and dose response information to estimate risk

l TSE dose response information lacking – Not possible to precisely estimate risk

l TSE risk assessments – characterize exposurel Really are TSE exposure assessments

l Can draw limited qualitative conclusions about risk – Low level of exposure – low level of risk, etc.

Key Parameters in TSE Plasma Model

Parameter Minimum Most Likely Maximum

# vCJD donations per pool 20,000 donations

0 2(mean ~5)

14

Pool Size 20,000 donors

Recovered plasma 200 ml

vCJD Blood ic ID50 / ml 0.1 10 1,000

% infectivity in plasma 58 %

Adjustment efficiency ic route vs intravenous route administration

5 10

Log10 reduction vCJD agent

0 2.0 4.0

Total yield FXI from pool (units / L plasma)

150 units 180 units

FXI units per vial 1,000 units

Results Factor XI Risk Assessment Model: Exposure to vCJD iv ID50 via Factor XI

Scenario Quantity Factor

XI Utilized

Mean vCJD

iv ID50 5th

percentile

95th

percentile

A single unit FXI 1 u 2 x 10-5 6.8 x 10-7 7.0 x 10-5

One vial FXI 1,000 u 2 x 10-2 6.8 x 10-4 7.0 x 10-2 Scenario 1:

1 Treatment 60 Kg person

3,000 u 6 x 10-2 2.1 x 10-3 0.21

Scenario 2: 3 Treatments 60 Kg person 9,000 u 0.17 6.2 x 10-3 0.6

Scenario 3: >3 Treatments

per person 15,000 u 0.28 1.0 x 10-2 1.0

IV. Risk Characterization (cont’d)

l Model:l Reflects mathematical approximation of realityl Predicted risk is product of UNCERTAINTY in data and

assumptions

l Probabilistic model– uses statistical distributions

l Monte Carlo method – randomly chooses values from distributions used in model and estimates risk

l Repeats process thousands of iterations– Software - @Risk, Crystal Ball, Analytica, etc.


l Uncertainty:l Arises from lack of information

l Express uncertain outcomes from model using l measures central tendency – mean, median, etc.

l Express uncertainty with confidence intervals– 95% CI , 5th and 95th percentiles, etc.


l Sensitivity Analysis :l Determines what factors in model have greatest

influence on risk estimate

l Done by varying parameters in model by percentages (25%, 50%, etc.) and observing impact on risk estimates

l Can be done for multiple outcomes

l Identifies factors in model where additional information may improve risk estimate

IV. Risk Characterization (cont’d) Sensitivity Analysis

l Factor XI risk assessment

l Two major factors influence risk:

l (1) Number of vCJD donations per plasma pool– Risk reduction measures – donor deferrals

l (2) Log10 reduction of vCJD agent during manufacture of product

– Risk reduction measures – manufacturing processes that reduce vCJD agent in product

– Additional validated processing steps may further reduce risk


l Model Validation : l Emerging situations – epidemiological data on outcomes may not be

available– Uncertainty about risk high – risk assessment used to estimate risk

l Lack of Epidemiological data - formal model validation may not be possible

l “Anchor” components of model with data– Known levels of TSE clearance– Utilization, etc.

l Empirical data / Epidemiological data preferred over model or risk assessment estimates !

Objectives of Risk Assessment

• Address a specific policy question for decision making• Is there a risk? • Magnitude of risk?• Risk Reduction measures?

• Identify data gaps and research priorities

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

• Many other parameters

Conclusions: Factor XI Risk Assessment

l Potential exposure to vCJD agent in Factor XI manufactured in the U.K. and used under IND in the U.S. from 1989 to 1997 was estimated in this probabilistic risk assessment.

l It is possible that FXI product manufactured from U.K. plasma may have been manufactured from plasma pools that contained a plasma donation(s) from an individual that was incubating vCJD.

l To date, no recipients of plasma derivatives in the U.K. or elsewhere have been diagnosed with vCJD.

l Given the potentially prolonged incubation times for human TSEs, it is still theoretically possible that such transmissions occurred are yet to be identified.

Acknowledgements

• Hong Yang, OBE• Dorothy Scott, OBRR• Mark Weinstein, OBRR• David M. Asher, OBRR• Rolf Taffs, OBRR• Pedro Piccardo, OBRR• Other OBRR Staff

Draft Risk Assessment for UK manufactured Factor XI and Potential vCJD Exposure Steven Anderson,...

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