1. EPAA Annual conference November 2007 1 Regulatory acceptance of alternative approaches for pharmaceuticals Jean-Marc Vidal Safety & Efficacy of Human Medicines Pre-Authorisation Evaluation Unit EMEA

2. EPAA Annual conference November 2007 2 Regulatory acceptance of alternative approaches for pharmaceuticals Outline Legal and Regulatory Background for Pharmaceuticals Criteria of regulatory acceptance of 3Rs approaches How to increase the use of 3Rs methods in regulatory testing

3. EPAA Annual conference November 2007 3 Regulatory acceptance of alternative approaches for pharmaceuticals Legislation Annex I to Directive 2001/83/EC. Introduction and general principles §(10): Member States shall also ensure that all tests on animals are conducted in accordance with Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulation and administrative provisions of the Member States regarding the protection of animals for experimental and other scientific purposes.

4. EPAA Annual conference November 2007 4 Regulatory acceptance of alternative approaches for pharmaceuticals Regulatory Background for Pharmaceuticals Key areas of non-clinical safety testing are regulated by ICH guidelines, implemented in the 3 regions (Europe, Japan and USA) EU-specific guidelines belong to specialised areas, e.g. photosafety, microdose in humans etc. Requirements described in the guidelines always allow flexibility on the choice of the methods/protocol. Preparation of a guideline –consultation procedure allows to take into consideration all stakeholders (Industry, other Regulatory bodies, any Organisation). –Specific interactions FDA-EMEA on ad-hoc basis.

5. EPAA Annual conference November 2007 5 Regulatory acceptance of alternative approaches for pharmaceuticals Criteria for regulatory acceptance of 3Rs approaches 1.The use of in vitro methods is recommended in guidelines 2.The alternative approach is not part of a guideline but is scientifically robust and fit for the purpose 3.The method is used and known by regulators

6. EPAA Annual conference November 2007 6 Regulatory acceptance of alternative approaches for pharmaceuticals Criteria for regulatory acceptance of 3Rs approaches (1) Several guidelines recommend the use of in vitro methods, for example: –Replacement of Animal Studies by In Vitro Models(CPMP/SWP/728/95 adopted February 97)CPMP/SWP/728/95 –Note for Guidance on Photosafety Testing (CPMP/SWP/398/01 adopted June 2002)CPMP/SWP/398/01 –Points to Consider on the Need for Assessment of Reproductive Toxicity of Human Insulin Analogues (CPMP/SWP/2600/01 adopted March 2002)PMP/SWP/2600/01

7. EPAA Annual conference November 2007 7 Regulatory acceptance of alternative approaches for pharmaceuticals Criteria for regulatory acceptance of 3Rs approaches (2) Factors to consider for regulatory acceptance of an in vitro method : –Clear domain of applicability (endpoint, substances) –Biological basis for the effect to demonstrate –Limits and place within the integrated risk assessment are understood –Formal validation if available (reliable, recognised)

8. EPAA Annual conference November 2007 8 Regulatory acceptance of alternative approaches for pharmaceuticals Criteria for regulatory acceptance of 3Rs approaches (3) Experience of use of the method – Known by the scientific community (publication, scientific forum etc.) – Known by the regulators (included in the submitted dossiers) – Experience gained with time

9. EPAA Annual conference November 2007 9 Regulatory acceptance of alternative approaches for pharmaceuticals How to increase the use of 3Rs methods in regulatory testing Recent initiatives in relation to the 3 Rs –ICH initiative: cVAM representation on ad-hoc basis for safety topics –Early involvement of regulators in the validation process of in vitro testing (e.g. ReProTect) –CVMP initiative to encourage the implementation of 3 Rs methods (review of guidelines, review approaches for 3 Rs implementation)

10. EPAA Annual conference November 2007 10 Regulatory acceptance of alternative approaches for pharmaceuticals Way forward Identify areas where new 3Rs methods are applicable Increase early cooperation with regulators during the validation process Encourage use and submission of alternative approaches Develop cross-sector fertilisation (cosmetics, chemicals etc.) through EPAA. Obtain International agreement between main regions (ICH)

11. EPAA Annual conference November 2007 11 Regulatory acceptance of alternative approaches for pharmaceuticals THANK YOU