1. Evolution of ICCVAM 1978 1993 ◊National Toxicology Program Develop and validate improved test methods ◊NIH Revitalization Act: P.L. 103-43 Develop and validate test methods for acute and chronic safety testing, including alternative methods that can reduce or eliminate the use of animals Establish criteria for validation and regulatory acceptance Develop process for regulatory acceptance of scientifically valid methods

2. Evolution of ICCVAM (cont.) 1994 1997 1998 ◊ad hoc ICCVAM ◊Report of the ad hoc ICCVAM ◊ICCVAM established Replaced ad hoc ICCVAM Implemented NIEHS directives: P.L. 103-43 ◊NTP Advisory Committee on Alternative Toxicology Methods ◊NTP Interagency Center for the Evaluation of Alternative Toxicological Methods

3. National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) ◊ Located at NIEHS ◊ Functions ICCVAM operational/technical support Test method peer reviews and workshops Information dissemination Communication with stakeholders Partnerships with stakeholders Validation studies ◊ http://iccvam.niehs.nih.gov

4. ICCVAM and NICEATM Goals ◊To promote the scientific validation and regulatory acceptance of new alternative test methods that: are more predictive of human health and ecological effects than current methods refine, reduce, and replace animal use where scientifically feasible ◊To contribute to improved public health  Improved risk assessments  Improved risk management  Prevention of injury and disease!

5. Validation and Regulatory Acceptance of Toxicological Test Methods 1 ◊Prepared by the ad hoc ICCVAM 15 Federal agencies Broad stakeholder involvement ◊Provides: criteria for validation and regulatory acceptance process for regulatory acceptance ◊http://iccvam.niehs.nih.gov/ validate.pdf ______________________________________ 1 Validation and Regulatory Acceptance of Toxicological Test Methods: A Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods; NIH Pub. No. 97-3981, 1997, NIEHS, Research Triangle Park, NC.

6. Prerequisites for Using New Methods 1 ◊ Scientific Validation Determination of the usefulness and limitations of a test method for a specific purpose Determination of relevance and reliability ◊ Acceptance for Regulatory Use Determination that the proposed use of data from the new test method will provide for comparable or better level of protection of human health or the environment than the current method or approach 1 Adopted from: Validation and Regulatory Acceptance of Toxicological Test Methods: A Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods; NIH Pub. No. 97-3981, 1997, NIEHS, Research Triangle Park, NC. http://iccvam.niehs.nih.gov/fraiccre.htm

7. What does Scientific Validation Involve? ◊ Determination of Relevance The extent to which a test method will correctly predict or measure the biological effect of interest —e.g., accuracy, sensitivity, specificity, false negative rate/ false positive rate ◊ Determination of Reliability The extent to which a test can be performed reproducibly within and among laboratories over time.

8. Criteria for Test Method Validation 1 1. Clear statement of proposed use 2. Biological basis/relationship to effect of interest 3. Formal detailed protocol 4. Reliability assessed 5. Relevance assessed 6. Limitations described 7. All data available for review 8. Data quality: Ideally GLPs 9. Independent scientific peer review ________________ 1 Adopted from: Validation and Regulatory Acceptance of Toxicological Test Methods: A Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods; NIH Pub. No. 97-3981, 1997, NIEHS, Research Triangle Park, NC. http://iccvam.niehs.nih.gov/validate.pdf

9. Criteria For Test Method Acceptance 1 1. Fits into the regulatory testing structure 2. Adequately predicts the toxic endpoint of interest 3. Generates data useful for risk assessment 4. Adequate data available for specified uses 5. Robust and transferable 6. Time and cost-effective 7. Adequate animal welfare consideration (3Rs) ____________________ 1 Adopted from: Validation and Regulatory Acceptance of Toxicological Test Methods: A Report of the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods; NIH Pub. No. 97-3981, 1997, NIEHS, Research Triangle Park, NC. http://iccvam.niehs.nih.gov/validate.pdf

10. Evolution Process for New Testing Methods StageOutcome Incorporate new science and technology into test methods Further determination of reliability and relevance Independent peer review evaluation of validation status Optimize standardized transferable protocol Effective use of new methods by regulators/users Identify needs for new and/or improved testing methods Understand toxic mechanisms Determination of acceptability for regulatory risk assessment Acceptance Validation Peer Review Prevalidation Development Research Review Risk Assessment Methods Implementation

11. ◊Outlines format for test method background review document ◊Background review documents Provide data and information needed to assess a test method’s current validation status Provide basis for decisions on standardized protocols and validation study designs ◊http://iccvam.niehs.nih.gov/ subguide.doc ICCVAM Test Method Submission Guidelines 1,2 ICCVAM Test Method Submission Guidelines 1,2 1 Evaluation of the Validation Status of Alternative Toxicological Methods: Guidelines for Submission to ICCVAM, NIEHS, 1999; iccvam.niehs.nih.gov 2 Federal Register: December 2, 1999 (Volume 64, Number 231, Page 67570-67580) [wais.access.gpo.gov]

12. ICCVAM Submission Guidelines ◊Purpose To describe the data and information needed by agencies to adequately assess a test method’s current validation status To provide a standard outline and format for test method submissions and background review documents For methods in development and validation phases, to provide an outline for describing the rationale for standardized protocols and validation study design To supplement NIH Pub. No. 97-3981: Validation and Regulatory Acceptance of Toxicological Test Methods: A Report on the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods

13. ICCVAM Test Method Evaluation Process NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) Test Sponsor Submission of Test Method Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Test Recommendations to Agencies Peer Review Panels Expert Workshops Advisory Committee on Alternative Toxicological Methods Agency Decisions/Actions ICCVAM Interagency Working Groups

14. ICCVAM Working Groups 1. Experts/participants from ICCVAM agencies 2. Review submission for completeness 3. Recommend experts for peer review panel Consider public nominations 4. Develop questions to be addressed by Panel 5. Attend peer review panel meeting 6. Prepare draft test recommendations for ICCVAM

15. ICCVAM/NICEATM Scientific Peer Review Panels ◊Panel of international experts ◊Public meetings; public comments invited ◊Comprehensive review of all available data and information ◊Evaluate extent to which the validation and acceptance criteria have been addressed ◊Develop consensus on usefulness and limitations of the test method ◊Product: Panel report