1. Phases of Therapeutic Development by Virinder Nohria, MD, PhD Presented at ASENT Annual Meeting Symposium on Neurotherapeutics Arlington, VA March 6, 2008 Contact Information: vnohria@aol.com; 1-828-349-0247vnohria@aol.com

2. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 2 Agenda  Definitions  Overview of Drug Development  Objectives of Drug Development Program  Contents of Package Insert  Strategy of Drug Development  Pre-clinical Testing  Phases of Clinical Development

3. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 3 Definitions  Sponsor – Organization sponsoring the study  CDER - Center for Drug Evaluation and Research  CBER – Center for Biologicals Evaluation and Research  CDRH - Center for Devices & Radiological Health  IND – Investigational New Drug  NDA – New Drug Application  BLA – Biological Licensing Application  510 (k) – Approval for devices etc.  IRB – Institutional Review Board  EMEA – European Medicines Evaluation Agency  ICH – International Commission on Harmonization  GCP – Good Clinical Practice (ICH – E6)

4. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 4 An Overview of Drug Development Idea Exploration Lead Finding Lead Optimization Drug Candidate Confirmation Human Pharmacology Phase I IND Filing Strategy & Research Pharmacology Synthesis, Toxicology & ADME Therapeutic Exploration Phase II (Proof of Concept) Therapeutic Confirmation Phase III (Pivotal Studies) NDA Preparation & Filing (6-9 months) 2 years 6-12 months 3 months 12-18 months 1-2 years 2-3 years

5. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 5 Objectives of Development Program  Gain regulatory approval –support package insert  Provide clinically meaningful information –comparator data –cost effectiveness –clinical utility basic efficacy and safety –quality of life (QOL)

6. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 6 Package Insert Contents  Highlights of Prescribing Information  Full Prescribing Information –Has 17 numbered sections referring to detailed information –This new format was proposed in 2006 and is now being implemented for all new approvals

7. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 7 Full Prescribing Information (1) 1.Indications and Usage 2.Dosage and Administration 3.Dosage Forms and Strengths 4.Contraindications 5.Warnings and Precautions 6.Adverse Reactions 7.Drug Interactions 8.Use in Specific Populations

8. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 8 Full Prescribing Information (2) 9.Drug Abuse and Dependence 10.Overdosage 11. Description 12.Clinical Pharmacology 13.Non-clinical Toxicology 14.Clinical Studies 15.References 16.How Supplied/Storage and Handling 17.Patient Counseling Information

9. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 9 Full Prescribing Information - Lyrica

10. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 10 Corporate Strategy for Drug Development  Unmet medical need  Market size  Competitor advantage - franchise  Complexity and cost of development program  Serendipity  Molecules looking for diseases  Niche markets - orphan drugs  Me too’s

11. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 11 Generation of “Lead Candidate(s)”  New understanding of pathophysiology - designer drugs –molecular biology, –computer modeling, –combinatorial chemistry –high through put screening  Structure activity relationship and pro-drugs  Serendipity  Partnership with academia (licensing-in)  Molecules looking for diseases  Reformulation

12. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 12 Lead Optimization/Candidate Confirmation  Testing in in-vitro/in-vivo disease models  Toxicology - acute and subacute  Pharmacokinetics-pre-clinical - in-vivo –absorption –distribution –metabolism –Excretion

13. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 13 Investigational New Drug Application (IND)  2000-3000 page document containing –investigators brochure –ADME-preclinical –Chemistry, manufacturing, & control –Proof of concept (animals) - rationale –toxicology - integrated summary –proposed protocols –previous human experience

14. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 14 Phase I Studies  Initial introduction of investigational new drug to humans  Determination of metabolism, pharmacologic actions and side-effects  Usually healthy volunteers, but may be patients; e.g. development of oncolytics

15. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 15 Objectives of Phase I Studies  Human safety and tolerability  Pharmacokinetics (PK)  Pharmacodynamics  Correlation between PK & PD ( dose - response curve)  Drug interactions  Maximum tolerated dose (MTD)  Minimally effective dose (MED)

16. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 16 Phase II Studies  Carried out in patients  Establish PK & PD in patients  Determine MED and MTD in patients  Determine effective and safe dose range –determine optimal dose  Proof of concept studies

17. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 17 Design of Early Phase II Studies  Similar to phase I studies and often carried out in major academic centers (e.g GCRC) or purpose built units  Primarily PK, safety & tolerability in patients  Often include efficacy measures

18. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 18 Design of Late Phase II Studies  These are usually proof of concept studies  Double-blind, placebo-controlled (may be comparator controlled)  Usually dose ranging – multiple dose groups  Strict inclusion/exclusion criteria  Statistically water-tight - p < 0.05, 80-90% power

19. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 19 Design of Late Phase II Studies (2)  Efficacy parameters - crisp & clinically meaningful; may include surrogate markers  Plasma levels are monitored  Usually requires 150-300 patients  Treatment duration is 12-24 weeks  Often have independent safety data monitoring boards  Phase II takes 12-24 months

20. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 20 Phase III Studies  Pivotal studies - need at least two independent studies  Confirm what was observed in phase II studies  Determine product label/primary indication

21. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 21 Design of Phase III Studies  Double-blind, placebo-controlled (may be comparator controlled), parallel group  Multi-center, multi-national  Broader inclusion/exclusion criteria  Multiple doses, 100s of patients  Statistically powered to show difference from placebo (rarely from comparator)

22. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 22 Design of Phase III Studies (2)  Need to have long-term extensions in order to accrue 300 patients exposed for 6 months and 100 patients exposed for 1 year (minimum long term safety requirement by ICH agreement)  Efficacy parameters should be clinically relevant and accepted by the regulatory authorities  May include QOL scales  Phase III takes 2-3 years

23. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 23 Phase IV Studies  Additional indications  Post marketing surveillance  Health economics  Clinical utility  Practice guidelines  Publication studies  Marketing studies  Safety studies

24. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 24 Rate-limiting Steps in Drug Development  Lack of resources - human and financial  Company bureaucracy and lack of decision making and strategy  Long-term toxicology studies  IRB approvals/institutional bureaucracy  Lack of study coordinators at sites  Patient recruitment  Data cleaning and harmonization

25. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 25 Drug Development - Decision Points and Milestones  Lead generation  Identification of the candidate  Intellectual property protection  Scaling up of synthesis  Safety assessment - Toxicology  IND filing  Completion of phase I

26. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 26 Drug Development - Decision Points and Milestones (2)  Marketable dosage form  Cost of manufactured goods  Completion of phase II  Clinical safety and efficacy review  Completion of phase III  NDA preparation and filing  Product launch

27. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 27 Common Pitfalls in Drug Development  Drug development is a process and there are no short cuts  However common pitfalls are –Starting phase I/ phase II studies too late/ too early –Not defining the dose range in well controlled phase II studies before moving to phase III – too high a dose leads to too many side effects and too low a dose may lead to a negative study(ies) and the drug not be approved –Poor study designs (wrong endpoints, wrong inclusion/exclusion criteria, wrong assumptions

28. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 28 Common Pitfalls in Drug Development (2)  Too many sites, too heterogeneous a patient population leads to increased variability and reduction/loss of effect size  Inadequate investigator training  Not listening to regulatory authorities – a ongoing dialogue is important – e.g. pre-IND meeting, EOP-2 meeting, pre-NDA meeting in the US and similar meetings with other authorities  Emotion/investor driven development rather than process driven development

29. March 06, 2008 Virinder Nohria/ASENT_NT Symposium 29 Mission Statement for a Drug Development Program Reduce Time to Market by providing Quality Data On Time (QDOT) in order to bring More Effective Therapies to Patients while Maximizing Shareholder Value Reduce Time to Market by providing Quality Data On Time (QDOT) in order to bring More Effective Therapies to Patients while Maximizing Shareholder Value