1. Entrepreneurship in Biotechnology Columbia University Graduate School of Arts and Sciences BIOT 4180 Columbia University GSAS BIOT 4180

2. Week 10 Product Development: Clinical Development Columbia University GSAS BIOT 4180

3. Development Process Columbia University GSAS BIOT 4180

4. Decrease in productivity Columbia University GSAS BIOT 4180

5. Academia and Private Sector Columbia University GSAS BIOT 4180

6. Risk mitigation Columbia University GSAS BIOT 4180

7. Process Phase 1: safety – IND: Investigational New Drug – Apply to FDA for human dosing – FDA has 30 days to object IRB approval Small number of subjects, one dose – Records adverse events, monitor physiologic process – Efficacy signals in oncology, infectious disease Columbia University GSAS BIOT 4180

8. Phase 2 trial IIA: dosing IIB: efficacy – Target dose for pivotal – Target indication, study design Can do one at a time or many phase 2 trials – Small biotech companies do a minimum – Large pharma do wide range of studies Rarely file NDA/BLA based on phase 2 data Columbia University GSAS BIOT 4180

9. Phase 3 Typically 2 trials per indication, multicenter N=hundreds to thousands Why do trials fail? – Poor design Difficult identification of treatment group or endpoint Poor statistics: gaussian distribution, power Placebo groups perform better than historical Poor oversight – The drug does not work Columbia University GSAS BIOT 4180

10. Phase 3 considerations Physiologic or made-up endpoint – ADAS-COG and other cognition tests – Pain scores – How reproducible is the entity being measured? Surrogate endpoints: accelerated approval process Dealing with drop-outs – Intent to treat vs per protocol Ease of enrollment Columbia University GSAS BIOT 4180

11. Post phase 3 Successful trial – Second trial (unless oncology, unmet need) – If works: NDA, then PDUFA date (6-9 months) – If approved, marketing and phase 4 studies Unsuccessful trial – Data review/ data mining – Await concurrent study completion – Tough to kill a molecule Columbia University GSAS BIOT 4180

12. Decrease in # approved drugs Columbia University GSAS BIOT 4180

13. Increase in orphan designations Columbia University GSAS BIOT 4180

14. Orphan Designation Columbia University GSAS BIOT 4180

15. Definitions Accelerated approval: surrogate endpoint Fast track designation: FDA facilitated communication Priority review: 6 vs 10 months SPA Special Protocol Assessment PDUFA IND process NDA Columbia University GSAS BIOT 4180