EDSP’s Approach to Test Protocol Validation

Office of Science Coordination and Policy

U.S. Environmental Protection Agency

Validation ProcessStatutory Requirements

• EPA must use valid screens and tests in the EDSP (FQPA)

• The EDSP must be reviewed by the FIFRA Scientific Advisory Panel or Scientific Advisory Board (FQPA)

Process Realities for EDSP

• Stakeholder involvement throughout the process

• Challenge to make process open and under the FACA procedures

• Follow ICCVAM process for validation of test protocols

• Need to develop valid test guidelines

Process Realities for EDSP

• International harmonization of guidelines through OECD

• Deadlines established in NRDC settlement agreement

• Deadlines in appropriations process

Validation ProcessStakeholder Involvement

• Standardization and Validation Task Force– Technical group made up of major stakeholders formed

after EDSTAC

– 3 expert workgroups: in vitro, mammalian, ecotoxicity

– Challenge resulted in disbandment of SVTF

– Replaced by a FACA committee

• EDMVS– Will advise EPA on standardization and validation

issues

ICCVAM Validation Process

1. Method Development

2. Prevalidation• Demonstration of relevance

• Standardization of protocol

3. Validation in multiple laboratories

4. Scientific Peer Review

5. Regulatory acceptance and implementation

Challenge: How to Meet Conflicting Requirements

• Guidelines of international interest to be developed and validated under OECD auspices

• Domestic guidelines requiring lab work to be developed and validated by EPA with advice from EDMVS

• ER/AR binding assay, not requiring lab work, to be validated by ICCVAM.

Lead Organization for Validation

EPA OECD ICCVAM

ER AR Binding X

Steroidogenesis X

Aromatase X

Uterotrophic X

Hershberger X

Lead Organization for Validation

EPA OECD ICCVAM

Pubertal female X

Pubertal male X

Fish Repro Screen X

In uterolactation X

Lead Organization for Validation

Test EPA OECD ICCVAM

Mammalian ?

Avian X

Fish X

Amphibian X

Invertebrate ?

EPA Process for Domestic Guidelines

• For domestic test guidelines, follow ICCVAM Process with EPA administration

• EDMVS will advise EPA on design and execution of validation work and validation products

• EPA will conduct literature reviews and laboratory work for methods development, pre-validation and validation through Contractor

EPA Process for Domestic Guidelines

• Involve ICCVAM through representation on FAC, consult with ICCVAM between pre-validation and validation and give opportunity to comment at peer review

• Conduct independent peer review

Process for Domestic Guidelines

FAC EPA-Method development-Prevalidation-Validation

SAP/SAB-Peer Review

Stakeholder advice

Consultation ICCVAM-Consultation-Recommendpeer reviewers-Comments to SAP/SAB

Contractor

Process for International Guidelines

• Follow ICCVAM requirements

• OECD’s Endocrine Disruptor Testing and Assessment workgroup will be primary vehicle for deliberation and stakeholder input

• EDMVS kept informed and will be asked for input for US position

Process for International Guidelines

• US will be lead country on most guidelines– Lead country coordinates technical work– US volunteering for lead country because we

have resources and are mandated to meet schedule

• Peer review

• National Coordinator comment process

OECD Test Guideline Process

MC Scientific Com Secretariat

Natl Coord Natl Coord Mtg

Detailed Review Paper *Comment

Test Guideline**Expert Mtg

Proposed Changes

Test Guideline Approval by Natl Coord

Joint Mtg

EPOC

CouncilPublished Guideline

OECD ED Test Guideline Roles

EDTA-Government and major stakeholders

VMG-Eco-Technical experts

VMG-Mam-Technical experts

TEST GUIDELINE PROGRAMNational Coordinators

KEY CONCEPTS IN EPA VALIDATION APPROACH

• Select chemicals specific to each assay, validate assay rather than battery

• More chemicals in pre-validation to establish relevance of assay and standardize the protocol than in validation phase

• Battery validation will be a paper exercise that relies on test results of individual assays

EPAValidation Process

• Method development and preparation of Detailed Review Paper (DRP)

• Pre-validation– Demonstration of relevance – Development of standardized protocol

• Determination of readiness for validation in consultation with EDVMS and ICCVAM

• Validation in multiple laboratories• Independent peer review and review by ICCVAM

Detailed Review Paper

1.0 Executive Summary

2.0 Introduction2.1 EDSP

2.2 Validation process

2.3 Purpose of DRP

2.4 Objective of the assay

2.5 Methodology used in the analysis

Detailed Review Paper

3.0 Scientific Basis of the Assay

4.0 Candidate Protocols

5.0 Implementation Considerations5.1 Technical requirements

5.2 Cost/time requirements

5.3 Animal welfare considerations

Detailed Review Paper

6.0 Recommended Protocol7.0 Developmental Status of the Assay

7.1 Current status7.2 Uncertainties, protocol issues needing

resolution and data needs7.3 Recommendation for further development and

pre-validation studies

8.0 References

Pre-Validation Report

1.0 Pre-validation Study Plan1.1 Endpoints of interest

1.2 Protocol issues needing resolution

1.3 Study design to address outstanding issues

1.4 Test substances and dose selection

1.5 Detailed protocol(s)

Pre-Validation Report

2.0 Pre-validation Study Results

3.0 Assessment of Test Method

4.0 Standardized Protocol

5.0 References

Validation Report

1.0 Validation study plan

1.1 Protocol

1.2 Selection of laboratories

1.3 Test substances and dose selection

2.0 Validation Study Results

3.0 Test Method Data Quality

Validation Report

4.0 Assessment of Test Method

5.0 Animal Welfare Considerations

6.0 Proposed Test Guideline

7.0 References

Summary Report

1.0 Introduction and Rationale for the Proposed Method

2.0 Proposed Test Method Protocol

3.0 Characterization of the Materials Tested

4.0 Reference Data Used for Performance Assessment

5.0 Test Method Data and Results

6.0 Test Method Performance Assessment

7.0 Test Method Reliability

8.0 Test Method Data Quality

9.0 Other Scientific Reports and Reviews

10.0 Animal Welfare Considerations

11.0 Other Considerations