EDSP’s Approach to Test Protocol Validation Office of Science Coordination and Policy U.S. Environmental Protection Agency

Validation Process Statutory 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 Process Stakeholder 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 EPAOECDICCVAM ER AR BindingX SteroidogenesisX AromataseX UterotrophicX HershbergerX

Lead Organization for Validation EPAOECDICCVAM Pubertal femaleX Pubertal maleX Fish Repro ScreenX In uterolactationX

Lead Organization for Validation TestEPAOECDICCVAM Mammalian? AvianX FishX AmphibianX 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 -Recommend peer 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 GuidelineApproval by Natl Coord Joint Mtg EPOC Council Published Guideline

OECD ED Test Guideline Roles EDTA- Government and major stakeholders VMG-Eco-Technical experts VMG-Mam-Technical experts TEST GUIDELINE PROGRAM National 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 Introduction 2.1 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 Considerations 5.1 Technical requirements 5.2 Cost/time requirements 5.3 Animal welfare considerations

Detailed Review Paper 6.0 Recommended Protocol 7.0 Developmental Status of the Assay 7.1 Current status 7.2 Uncertainties, protocol issues needing resolution and data needs 7.3 Recommendation for further development and pre-validation studies 8.0 References

Pre-Validation Report 1.0 Pre-validation Study Plan 1.1 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