Evolution of ICCVAM

1. 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 Evolution of ICCVAM

2. 1994 1997 1997 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 Evolution of ICCVAM (cont.)

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 ToxicologicalTest Methods1 • 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 ______________________________________ 1Validation 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 Methods1 • 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 1Adopted 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 ValidationInvolve? • 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 Validation1 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 ________________ 1Adopted 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 Acceptance1 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) ____________________ 1Adopted 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 Stage Outcome Identify needs for new and/or improved testing methods Review Risk Assessment Methods Research Understand toxic mechanisms Development Incorporate new science and technology into test methods Prevalidation Optimize standardized transferable protocol Validation Further determination of reliability and relevance Peer Review Independent peer review evaluation of validation status Acceptance Determination of acceptability for regulatory risk assessment Implementation Effective use of new methods by regulators/users

11. ICCVAM Test Method Submission Guidelines1,2 • 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 1Evaluation of the Validation Status of Alternative Toxicological Methods: Guidelines for Submission to ICCVAM, NIEHS, 1999; iccvam.niehs.nih.gov 2Federal 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 Test Sponsor Submission of Test Method NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) Advisory Committee on Alternative Toxicological Methods Peer Review Panels Expert Workshops Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) ICCVAM InteragencyWorking Groups Agency Decisions/Actions Test Recommendations to Agencies

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