This presentation outlines the process for dealing with adverse preclinical / nonclinical events in order to 1) optimize the chances of successful drug development, or 2) to create a scientific basis for early termination of drug development. Conclusion: There is no single answer for all problems.

4. No Single Answer for all Problems

15. Risk Evaluation Using Weight of Evidence (WoE) Analysis Does MOA of drug candidate lead to observed APE? Is MOA potentially relevant for man? Continue development Sufficient safety factor? Continue development with risk management D evelopment depends upon further WoE analyses No or partially Yes No MOA = mechanism of action; APE = adverse preclinical event Ettlin et al. J. Toxicol. Pathol. 2010; 23:189-211.

20. Cynthia J. Davenport, Ph.D. www.tigertox.com [email_address] Questions and Discussion