Phases of Therapeutic Development

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; 1-828-349-0247

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 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) Virinder Nohria/ASENT_NT Symposium

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

7. Full Prescribing Information (1) • Indications and Usage • Dosage and Administration • Dosage Forms and Strengths • Contraindications • Warnings and Precautions • Adverse Reactions • Drug Interactions • Use in Specific Populations Virinder Nohria/ASENT_NT Symposium

8. Full Prescribing Information (2) 9. Drug Abuse and Dependence • Overdosage • Description • Clinical Pharmacology • Non-clinical Toxicology • Clinical Studies • References • How Supplied/Storage and Handling • Patient Counseling Information Virinder Nohria/ASENT_NT Symposium

9. Full Prescribing Information - Lyrica 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 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 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 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 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 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) 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 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 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 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 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 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) 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 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 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 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 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 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 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 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 Patientswhile Maximizing Shareholder Value Virinder Nohria/ASENT_NT Symposium