# Presentation: 836509

## Minimizing the Risks of TSE Agents in Human Tissues

- Melissa A. Greenwald, M.D.
- Division of Human Tissues
- Office of Cellular, Tissue and Gene Therapies; CBER
- TSEAC 12-13 February 2004

## Introduction

- Human tissue safety will be discussed in the context of three general approaches to reduce the risk of TSE transmission:
- Careful screening of donor for TSE and risk factors of TSE (testing if and when validated)
- Control of recovery and processing to prevent contamination/cross-contamination
- Use of steps during manufacturing to remove or inactivate (clear) TSE agents (currently, no known validated methods for Human Tissues)

## Introduction

- FDA’s Regulatory Approach to TSE Transmission (actual and potential) by Human Tissues
- Current Regulations (Rules)
- Current Recommendations (Guidance)
- Proposed Regulations (Draft Rules)
- Proposed Recommendations (Draft Guidance)

## Current Regulations

- 21 CFR part 1270—Human Tissues Intended for Transplantation (1997)
- Screening and testing of potential donors for HIV, HBV, and HCV (TSE not included)
- Written procedures and recordkeeping
- Inspection and enforcement provisions
- Validated procedures to prevent infectious disease contamination or cross-contamination by tissue during processing – 1270.31(d)

## Current Recommendations

- (1) Guidance for Industry:  Screening and Testing of Donors of Human Tissue Intended for Transplantation (1997)—defer donors with:
- Risk factors for CJD
- Does not include vCJD risk factors

## Current Recommendations, cont.

- (2)  Guidance for Industry:  Validation of Procedures for Processing of Human Tissues Intended for Transplantation (3/2002)—clarifies 1270.31
- Infectious disease contamination includes viral, bacterial, fungal and TSE agents
- Validated methods available to prevent contamination by viruses, bacteria and fungi
- Currently there are no validated methods to prevent contamination by TSE agents

## Current Recommendations, cont.

- (3) Guidance for Industry and FDA Staff—Class II Special Controls Guidance Document:  Human Dura Mater (12/2003) – Center for Devices and Radiological Health **(CDRH)**
- Discusses additional deferral criteria beyond those for CJD/vCJD
- States that donor screening for CJD and vCJD should follow published blood donor criteria (includes travel history questions)

## Current Recommendations, cont.

- Dura Mater Special Controls Guidance (**CDRH**), cont.
- Defer potential donors who have:
- Classic CJD risk factors (listed in document)
- Degenerative/demyelinating diseases or other neurologic diseases (e.g., senile dementia, Alzheimer’s disease)
- Died in neurological/psychiatric hospital

## Proposed Regulations

- (1) Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule (9/30/99)
- Screening (including medical history interview) for risk factors for and clinical evidence of relevant communicable diseases, including HIV, HBV, HCV, TSEs
- Testing for relevant communicable diseases, including HIV, HBV, HCV, syphilis

## Proposed Regulations, cont.

- (2) Current Good Tissue Practice for Manufacturers of HCT/Ps; Inspection and Enforcement; Proposed Rule (1/2001)
- Includes requirements for controls over facilities, personnel, equipment, environment, incoming materials, labeling, storage, process controls, process validation, record keeping, adverse reaction and product deviation reporting, tracking

## Proposed CBER Regulations, cont.

- (2)  Proposed GTPs (cont.)
- Inspection and enforcement
- Requirement to archive appropriate specimens from each donor of dura mater
- Specific requirement for dura mater to be processed using validated method to reduce TSEs
- Prohibition of pooling (placing in physical contact or mixed in a single receptacle)
- Exemption or alternative from any GTP requirement—submit with valid data

## Proposed Recommendations	

- Draft Guidance for Industry:  Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)—June 2002
- Presented to TSEAC 26 June 2002

## CJD/vCJD Draft Guidance, cont.

- Donor screening recommendations for vCJD are based on the “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products” (1/2002)
- Recommended donor screening criteria for Human Tissues are the same as those listed in the blood guidance document

## Recommended vCJD Screening Criteria for Human Tissues

- Determine ineligible any donor who:
- Diagnosed with vCJD
- Diagnosed with dementia or other similar CNS diseases of unknown etiology
- Has spent >/= 3 months in UK
- US military/employees spending >/= 6 months at military base in Europe
- Lived >/= 5 years in Europe
- Received blood/products from UK
- Injected bovine insulin

## Anticipated Proposed Recommendations

- Donor Eligibility Draft Guidance Document to accompany the Donor Eligibility Rule
- Anticipate publication as a draft guidance in the general timeframe as the DE Final Rule
- Plan to finalize the DE Guidance as one document to include CJD and vCJD measures described in 2002 draft guidance document
- Until the DE Final Rule publishes, there are no requirements for vCJD screening

## Interim Final Rule 

- Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing (1/27/2004)
- Requires all establishments that manufacture HCT/Ps to register and list
- Excludes manufacturers of human dura mater and heart valves, which will continue to be regulated as medical devices
- Plan to revoke the interim rule when the Donor Eligibility and Good Tissue Practice Final Rules are published, when both products will be regulated as HCT/Ps

## Any Questions from the Committee?

## References

- Available in order of publication date at _[http://www.fda.gov/cber/tissue/docs.](http://www.fda.gov/cber/tissue/docs.htm)__[htm](http://www.fda.gov/cber/tissue/docs.htm)_ unless otherwise noted
- Draft Guidance for Industry: Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)- 6/14/2002
- Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for Transplantation - 3/8/2002

## References, cont.

- FEDERAL REGISTER Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement; Proposed Rule - 1/8/2001
- FEDERAL REGISTER Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule - 9/30/1999
- Guidance for Industry - Screening and Testing of Donors of Human Tissue Intended for Transplantation - 7/29/1997

## References, cont.

- FEDERAL REGISTER Human Tissue Intended for Transplantation; Final Rule - 7/29/1997
- Class II Special Controls Guidance Document: Human Dura Mater; Guidance for Industry and FDA 12/18/2003 _[http://www.fda.gov/cdrh/ode/guidance/054.html](http://www.fda.gov/cdrh/ode/guidance/054.html)_
- FEDERAL REGISTER Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing; Interim Final Rule; Opportunity for Public Comment - 1/23/2004

## Melissa A. Greenwald, MD(greenwald@cber.fda.gov)melissa.greenwald@fda.hhs.gov