1. Regulatory Acceptance of Alternative Methods- Pharmaceuticals in the U.S. A. Jacobs 11/07 (not an official opinion)

2. Overall ICCVAM OECD In vitro assays Flexibility in approaches ICH Combining of endpoints/considerate of the 3 Rs Implementation- the need for better alternatives

3. ICCVAM FDA is an active participant in ICCVAM –On the overall committee and most working groups on various alternatives and thus hopefully familiar with the issues

4. ICCVAM Agencies (a) Regulatory Agencies Consumer Product Safety Commission Department of Agriculture Department of the Interior Department of Transportation Environmental Protection Agency Food and Drug Administration Occupational Safety and Health Administration

5. ICCVAM Agencies (b) Research Agencies Agency for Toxic Substances and Disease Registry Department of Defense Department of Energy National Cancer Institute National Institute for Occupational Safety and Health National Institute of Environmental Health Sciences National Library of Medicine National Institutes of Health, Office of the Director

6. ICCVAMs Mission (a) To facilitate development, validation and regulatory acceptance of new and revised regulatory test methods that –reduce, refine, and replace the use of animals in testing –while maintaining and promoting scientific quality and the protection of human health, animal health, and the environment

7. ICCVAMs Duties (a ) To consider petitions from the public for review and evaluation of validated test methods To review and evaluate new, revised, and alternative test methods To submit test method recommendations to U.S. Federal agencies and make agency responses (due within 180 days) available to the public

8. ICCVAMs Duties (b) To facilitate and provide guidance on: – test method development –validation criteria and processes To facilitate: –acceptance of scientifically valid test methods Interagency and international harmonization

9. ICCVAM Acceptance Criteria (a) Fits into the regulatory testing structure Adequately predicts the toxic endpoint of interest Generates data useful for risk assessment Adequate data available for specified uses Robust and transferable Time and cost-effective Adequate animal welfare consideration (3Rs)

10. ICCVAM Acceptance Criteria (b) The proposed use of the test method will provide for equivalent or improved protection of human and/or animal health, or the environment 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

11. Regulatory Acceptance by U.S. Agencies ICCVAM does not dictate to U.S. regulatory agencies what tests or testing strategies to accept or use U.S. Agencies are bound by their regulatory mandates from the U.S. Congress

12. OECD (a) FDA and other agencies contribute to OECD expert pharm/tox working groups and guidelines For some agencies, OECD protocols/guidelines need to be followed OECD guidelines are geared toward evaluation of chemicals, not pharmaceuticals

13. OECD (b) In the U.S. for pharmaceuticals, Specific protocols are not generally required and testing strategy is different from that for chemicals for which labeling for hazard is the goal Studies conducted according to OECD guidelines will be accepted, but may not be sufficient to answer a regulatory question For cosmetics, it is the sponsors responsibility to establish safety and to determine how (what methods)

14. Worker Exposure/Drug Discovery/Lead Selection vs Drug Evaluation Many in vitro and other alternative assays may be (are) used by drug companies for screening, to help in compound discovery and selection and to assess effects of exposure to the unfinished product For high deliberate exposure of humans, however, a screening assay will probably be insufficient to support studies in humans

15. In vitro Assays (a) May be used for the active ingredient (API) of a pharmaceutical formulation but may have limitations for entire formulations At some high concentrations, the incidence of false positives increases Often interested in reversibility

16. In vitro Assays (b) Limulus bacterial endotoxin test for pyrogenicity generally used in place of rabbits and currently ICCVAM is evaluating assays in human whole blood, PBMC and monocytoid cells Validation studies can suggest assays promising to be pursued by sponsors However, it would need to be demonstrated that the assay works for a particular product since that is a safety/regulatory need, and consequences of being wrong could be dire

17. In vitro Assays (c) 3T3 assay for photoirritation accepted, but a large percentage of false positives is seen –Some formulations are incompatible with 3T3 cells –Primarily for UVA absorbing since cells cant tolerate very much UVB BCOP for severe ocular irritation accepted, but for one drug, results in one lab indicated a severe ocular irritant (a score of 126) and in another lab a nonirritant (a score of 1.3)

18. In vitro Assays (d) Experience of false positive results discourages use of an assay –Companies follow-up on positives on their own Some endpoints involve systemic interactions Need to relate effects to exposure when making a regulatory decision

19. Flexibility in What Specifically is Needed (a) Follow International Conference on Harmonization (ICH) agreements on what is needed and when in development Rather than a list of tests, consider what concerns need to be addressed during pharmaceutical development

20. Flexibility in What Specifically is Needed (b) Have potential human adverse effects at particular exposures been identified? What is a safe first dose in humans? How much toxicity is reasonable for humans at the particular stage of drug development? Is an identified adverse effect reversible?

21. Flexibility in What Specifically is Needed (c) How high is it reasonable to dose humans? What should be monitored in humans and how frequently? Is the drug reasonably safe for a person who wants to get pregnant or is pregnant What are the long-term effects of taking the drug?

22. Alternative Assays Accepted before Formal Validation (a) For pharmaceuticals, formal validation not required for an assay to be accepted for regulatory use –if adequate background data are provided to demonstrate that the assay is capable of measuring the endpoints/effects claimed – if the assay is a scientifically reasonable assay

23. Alternative Assays Accepted before Formal Validation (b) Sometimes alternatives are accepted to get data on usefulness for pharmaceuticals Examples: LLNA; 3T3; BCOP LLNA was strongly recommended to drug sponsors; false positives affected subsequent use and reliance on results; eagerly awaiting some in vitro alternatives 3T3 accepted but 7/8 positive results have turned out to be false positives

24. Alternative Assays Accepted before Formal Validation (c) BCOP accepted when direct exposure of finished product to eye not involved (e.g., dermal product on finger and eye then rubbed); experience with false positives may also affect use of this assay

25. Implementation (a) Alternatives mentioned in FDA guidances –LLNA –3T3 Photocytotoxicity assay Exploratory IND Guidance –Less animal tox needed in fewer animals at lower doses to help select drug candidates in limited studies in humans PreIND meeting with companies/ sponsors on product development plans

26. Implementation (b) Dont ask for unnecessary studies Dont ask for acute lethal tox studies Dont ask for nonclinical photoallergy studies Combine endpoints when possible

27. Implementation (c) Draize tests not necessary for pharmaceuticals –Dermal irritation is part of another tox study –Ocular irritation usually part of another tox study in which the active ingredient is diluted and is expected to be tolerated (the same material/formulation that will go into the human eye) –Ocular irritation not evaluated if product causes dermal irritation

28. Implementation (d) Monthly Pharm/Tox supervisor meetings across all 16 human drug divisions in the FDA E-mail to share information Presentations at reviewer and supervisor retreats Workshops

29. Near-Term Goal Reduce animal use whenever possible without jeopardizing human health

30. Long-Term Goal Replace All Animal Testing Need alternatives that can address the questions that need to be answered in order to make regulatory decisions

31. The Dose-Limiting Step-the Assays For pharmaceuticals The limitations and the limited utility of the currently validated alternatives is the biggest impediment If we had reliable alternatives that could better address the regulatory questions, they would be strongly encouraged and easily accepted