# Presentation: 764373

## Risk Assessments:

***Models for Estimating the Risk of Transmitting TSE by Human Tissue Intended for Transplantation****** ***
**Rolf E. Taffs, Ph.D.**
**Center for Biologics Evaluation and Research**
**U.S. Food and Drug Administration**

## Background (1)

- BfAr.M, (Fed. Inst. for Med. Supplies and Medicinal Products), Public notice regarding approval and registration of medicinal products. Protection against medicinal risks, Grade II. Federal Publicity No. 210-09.11.1995, S.11604 (25 September 1995).
- Bader F. et al. Pharmaceutical Research and manufacturers of America (PhRMA) BSE committee.  Assessment of risk of bovine spongiform encephalopathy in pharmaceutical products.  Biopharm 1998, 11 (1)20-31, and 11(3):18-30.

## Background (2)

- EC Health and Consumer Protection Directorate-General, Directorate C - Scientific Opinions. First Report on the Harmonisation of Risk Assessment Procedures Part 1: Report of the Scientific Steering Committee's Working Group on Harmonisation of Risk Assessment Procedures in the Scientific Committees Advising the EC in the Area of Human and Environmental Health, 26-27 October 2000.
- Kennedy, R.H. et al. Eye banking and screening for Creutzfeldt-Jakob disease. Arch Ophthalmol. 2001. 119:721-6.

## Risk Analysis

***A comprehensive, structured approach to dealing with risk***
** **
**Assessment**
**Management**
**Communication**

## Elements of Risk Assessment

**Hazard identification**
***Source(s) of risk and quantitative description of the adverse effect***
**Exposure assessment**
***Level and duration of exposure to the risk***
**Hazard characterization**
***Mechanisms and dose-response relationship***
**Risk characterization**
***Probability of occurrence, severity of adverse effects, attendant uncertainties, sensitivity analysis (also called importance analysis)***

## Objectives of Risk Modeling

**Quantitate the relative contributions of  parameters in the model**
**Identify critical elements for additional research in order to improve the model**
**Provide accurate information for making regulatory decisions**

## Objectives of Sensitivity (“Importance”) Analysis

**To evaluate effects of changes in risk models by varying model parameters such as the underlying assumptions about CJD and vCJD in the donor pool**
***- Used as a tool to examine the assumptions, variability, and uncertainty of the model and their effect on risk estimation***

## Components of CJD Risk Assessment Models

***Prevalence of CJD in the donor pool***
***Donor availability and utilization***
***Sources of uncertainty in the model***
***Potential impact of infection***
***diagnosed cases of CJD and vCJD***
***undiagnosed symptomatic cases***
***asymptomatic cases***

## Data Inputs for the Model

**population by age**
**age-specific all-cause deaths**
**age-specific CJD deaths**
**age-specific tissue donations**
**rational assumptions regarding screening, processing, and cross-contamination**

## Examples of Information Sources

**CJD Incidence in the U.S.: Holman et al. Emerging Infectious Diseases 2:333-337. Oct.-Dec. 1996.**
**Age-specific mortality rates: CDC. National Vital Statistics Reports. 47(19), 1999.**
**Population estimates: U.S. Bureau of the Census, P25-1127, 1995.**
**Cornea donors: EBAA Report, 1998**

## Age Distributions of Sporadic CJD

## Cornea Donor Age Distribution

## Model Variables (1)

**symptomatic cases diagnosed but missed by current screening procedures**
**symptomatic cases prior to diagnosis**
**asymptomatic cases (incubation period)**
**disease prevalence**
**specificity of additional donor screening procedures**

## Model Variables (2)

**extent of decontamination of tissues**
**effect of cross-contamination or commingling during processing steps**
**batch size**
**numbers of donors, recipients, and grafts used in a given transplant procedure**

## Exposure Assessment

**Dynamics**

**Recovery / Processing**

**Therapeutic **
**Applications**

**Donor**
**Screening**

**Tissue**
**Recovery**

**Tissue**
**Processing**

**Transplant**
**Procedures**

**Risk **
**Characterization**

**Risk**
**Factors**

**Population **
**Characteristics**

- Risk
- Characterization

## Model Parameters: Assumptions

## CJD Risk: Model Comparisons

**Probability distributions for number of exposures per year under different model assumptions (based on 25,000 donors)**
**Medical history (75% reviewed)**
**Commingling**
**No commingling**
**Medical history (100% reviewed)**
**Commingling**
**No commingling**

## Likelihood of Exposure (Model 1)

## Likelihood of Exposure (Model 2)

## Likelihood of Exposure (Model 3)

## Likelihood of Exposure (Model 4)

## Comparative Models: Summary Table

## Sensitivity Analysis

**Comparisons under different model assumptions**
**Medical history (100%)**
**Commingling**
**No commingling**

## Sensitivity Analysis (Model 3)

## Sensitivity Analysis (Model 4)

## Data Gaps

**More data are needed on:**
**the amount of CJD agent that is present in or could contaminate tissues during procurement from a CJD-infected donor.**
**the progression of CJD and the infectivity of different tissues during the course of the disease.**
**the extent of reduction of CJD agent that might occur during processing of tissues from a CJD-infected donor.**
**donor utilization and allograft implantation practices for different tissues.**** **
**the extent of cross-contamination by instruments or equipment that might occur during processing.**

## Conclusions

**Probabilistic risk assessment allows detailed examination of the likelihood of exposure under differing model assumptions.**
**Different tissues and processing methods have unique models and must be assessed separately.**
_**Cross-contamination is a major driver in the CJD risk model.**_
**Other parameters such as number of transplanted tissues are also significant drivers in the model.**
**Additional data are needed to provide accurate estimates of exposure to infected tissues.**

## Acknowledgements

**David M. Asher**
**Steven A. Anderson**