The 3Rs principles for safety testing of human and veterinary medicines A view on the EU regulatory developments in 3Rs (replacement, reduction, refinement) over the last years Ellen-Margrethe Vestergaard

Overview of presentation Use of animal models as regulators Definition of accuracy and precision Tissue specific genes in man and mouse Use of experimental animals for regulatory purposes Presentation of the JEG3Rs Output from the 3Rs expert group on human and veterinary medicinal product testing approaches 24. november 2018

3Rs in safety testing – human pharmaceuticals Use of animal models implemented during a period of observations of complex adverse effects e.g. Thalidomide as teratogen, 1961- resulted in testing methods to be developed/established. Animal studies are needed to support short term and long term use of a product assessment of reproductive risks assessment of carcinogenic risks Animal studies have no value if under-powered (e.g. small sample sizes) a balance is needed to avoid too few OR too many animals in experimental design 24. november 2018

3Rs in testing of veterinary pharmaceuticals and immunologicals Animal models are used in basic research and early drug development studies. Animal studies are also used to demonstrate pharmaceutical product safety and efficacy in the target species. Laboratory safety studies are performed in animals during pharmaceutical product development to establish maximum residue limits for food safety to consumers. Laboratory safety studies are also performed in animals to address product user safety concerns and the absence of harmful toxicological effects in animals treated with the product. For immunological products (mainly vaccines), animal tests are often needed for batch release to demonstrate the potency/activity of a batch before release onto the market. Field studies in the target species. 24. november 2018

References to slides 6, 7, and 8 An integrated enclyclopedia of DNA elements in the human genome: Nature, 6. September 2012, Vol. 489, 57-73. A comparative encyclopedia of DNA elements in the mouse genome: Nature, 20. November 2014, Vol. 515, 355-364. Comparison of the transcriptional landscapes between human and mouse tissues: PNAS, 2. December 2014, No. 48, 17224-17229. 24. november 2018

Use of animals for regulatory purposes in EU 2011 experimental animals used in EU: Regulatory testing for human and veterinary medicinal products 4.4 % Quality Batch Control testing of human medicinal products 10.9 % Quality Batch Control testing of veterinary medicinal products 4.0 % 24. november 2018

24. november 2018

3Rs and batch release (European Pharmacopoeia) progress in the reduction of animal testing Veterinary Deletion of safety tests – in mice and guinea pigs (abnormal toxicity test, LABST) and Target Animal Batch Safety Test (TABST) Potency testing – Rabies vaccine (inactivated) for veterinary use - Replacement of challenge in mice by serology (refinement) Human Deletion or replacement of safety tests – Safety in mice and guinea pigs (Abnormal toxicity test) is deleted from the Ph.Eur. Limulus Amoebocyte Lysate test and Monocyte Activation test are introduced to replace the Rabbit Pyrogen Test Potency testing – Replacement and refinement of challenge tests by serology for vaccines against tetanus, diphteria, rabies 24. november 2018

JEG3Rs established in 2010 replaced by J3RsWG from 2017 Joint expert group for human and veterinary medicines with representatives from almost all working parties giving input to CHMP and CVMP (Commitees for human and veterinary medicinal products) Output EMA Guideline on regulatory acceptance of 3Rs (replacement, reduction, refinement) testing approaches – adopted by December 2016 EMA Guideline for individual laboratories for transfer of quality control methods validated in collaborative trials with a view to implementing 3Rs – public consultation,end Q1 2017 2 x reflexion papers providing an overview of the current regulatory testing requirements for veterinary/human medicinal products and opportunities for implementation of the 3Rs Review and update of EMA guidelines to implement best practise with regard to 3Rs - report on actions taken (living document) 24. november 2018

Guideline on acceptance of 3Rs (EMA/CHMP/CVMP/JEG-3Rs/450091/2012) Criteria for regulatory acceptance of 3Rs testing approaches Demonstration of method validation (e.g. by formal validation as described by EURL- ECVAM, ICCVAM, OECD) Demonstration that the new or substitute method or testing strategy provides either new data that fill a recognised gap or data that are at least as useful as, and preferably better than those obtained using existing methods Demonstration of adequate testing of medicinal products under real-life conditions (human and veterinary)which can be generated through the ”safe harbour” concept 24. november 2018

Procedure for submission of a proposal for regulatory acceptance of 3Rs approaches Assessment of the new 3R testing approaches will be performed according to the criteria in collaboration with the relevant 3Rs experts from CHMP/CVMP working parties The outcome of the assessment can entail the following recommendations: New 3R testing approaches is based on sufficient data and can be recommended for regulatory acceptance to the relevant working parties New 3R testing approaches needs a real-life data collection period under safe harbour provisions New 3R testing approaches is rejected because it is immature 24. november 2018

Thank you for the attention