European Partnership for Alternative Approaches to Animal Testing Acute Toxicity Testing: Analysis Across Sectors

1. European Partnership for Alternative Approaches to Animal TestingAcute Toxicity Testing: Analysis Across Sectors

2. Acute Toxicity as a EPAA horizontal project Overview of pharmaceutical company initiative

3. Why Acute Toxicity ? Acute toxicity testing conducted in most sectors Association with lethality/substantial effects Often limited data provided Quote from 2007 EPAA conference, Dagmar Roth-Behrendt: �Why are acute toxicity studies required for cosmetics but not for drugs ?�

4. Acute Toxicity & EPAA Added value of EPAA is sharing best practice across sectors Challenged the requirement for acute toxicity within pharmaceutical sector � may lead to questions about possibilities in other sectors (cf quote from 2007 conference) Opportunity to be proactive & analyse scientific drivers across sectors and make recommendations on what is possible or not possible in different sectors

5. Acute Toxicity in Pharmaceutical Sector Regulatory requirement worldwide for all new drugs Usually in rodents using two routes of administration Perception by industry that data was of limited value in terms of human safety assessment Working group established (2003) Shared data on objectives, study design, timings, how data was used Aim: to identify opportunities for the application of the 3Rs

7. Pharmaceutical: Scientific Drivers Preclinical: Dose setting for other animal studies Clinical: To support the first clinical trials in humans To support overdose in humans

10. Data analysed from >70 compounds demonstrated acute toxicity study data Was NOT used for dose setting for other animal studies Was NEVER used to stop a compound in development either in the preclinical or clinical stages Was NEVER used to set the doses or exposure limit for first clinical trials, or to identify target organs of concern or parameters for monitoring in humans and that there was NO preclinical or clinical benefit from the use of an additional route to the clinical route

11. Recommendations Acute toxicity studies should not be required prior to the first clinical trials Any short term data that is currently used for dose setting in other animal studies should be acceptable to allow assessment of acute toxicity and this should be by the clinical route only. These studies in rodents and non-rodents are already an integral part of drug development and include parameters in the study design that assist risk assessment In situations where overdosing may be a cause for concern establish, by reviewing both the pre-clinical and clinical dataset, whether additional high dose information is necessary. In the majority of cases an acute toxicity study should not be required as the data generated above will be adequate. Discussed at regulatory workshop in 2006, the first draft of the revision of ICH M3 has incorporated the recommendations made by the group.

13. Summary Sharing of best practice � significant reductions in animal numbers (estimate15,000 across Europe) Limited value of acute toxicity study for human risk assessment for new medicines ICH revision will incorporate the recommendations Will ultimately lead to replacement by redundancy through use of other data that is generated as part of drug development

14. Proposals for an EPAA horizontal project Establish a Task Force under the auspices of WG4 with invitation to other WGs for their respective areas of expertise Overview of regulatory and scientific drivers across each sector conducting acute toxicity tests (e.g. chemical, agrochemical, cosmetics) Sectoral sharing of data on study designs, no.s of animals used Arrange a workshop to overview the cross-sectoral analysis and investigate opportunities for application of the 3Rs Publish output

15. Types of questions that should be addressed What guidelines are there for acute toxicity testing ?�Is there a consensus within each sector on which guideline is used Is just the route of exposure tested Are all products tested or just certain types ? and at what stage are they tested What information is provided from the tests Minimum lethal dose (or similar) Maximum non-lethal dose (or similar) anything else ??? Are the following assessed Clinical pathology, micropathology, systemic exposure � � � Are other tests conducted that might provide information that could replace acute toxicity testing (e.g. data from dose-range finding studies) How are the acute toxicity data used in assessment of risk to humans What is each sectors view on the value of acute toxicity testing 

16. Timelines Identify at least one representative/expert from each sector conducting acute toxicity to form a Task Force First stage analysis (regulatory and scientific drivers), workshop and recommendations Follow up work (if required) within sectors 2009 and beyond

17. Participants in project NC3RS Sanofi AventisECVAM DowSolway EvonikBayer HenkelNovozymes Novartis (animal health) Covance HLSAstraZeneca BASF Humane Society International