1. Proposal for End-of-Phase 2A (EOP2A) Meetings Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 17-18, 2003 Lawrence J. Lesko, Ph.D., FCP Office of Clinical Pharmacology and Biopharmaceutics, CDER, FDA

2. New Drug Development

3. What Problems Need Solving? Costs $800 million to develop a new drug Almost 50% of phase 3 trials don’t succeed Only 20% of new drugs entering clinical testing are approved

4. FDA Strategic Plan New Drug Development: A Need for Greater Productivity “Steps to reduce the time, cost and uncertainty of developing new drugs is an important public health priority”

5. Proposal: End-of-Phase 2A Meeting Hypothesis –meetings with sponsors early in the drug development process will focus greater attention on analysis of exposure-response information and will improve dose selection and study design for later clinical trials Prior discussions –Dr. McClellan (4/03), Drs. Woodcock and Jenkins (5/03), OND Office Directors (7/03), OND Division Directors (9/03) and CDER All-Hands Guidance Training (10/03)

6. Philosophy Driving Hypothesis “There is more to do with regard to dose choice from E-R studies and there is much to gain from better use of biomarkers (PD) and more efficient study designs” Dr. Robert T. Temple, CDER Associate Director for Medical Policy, DIA Annual Meeting, June 16, 2003

7. Guidances Driving Hypothesis Exposure-Response Relationships: Study Design, Data Analysis and Regulatory Applications (2003) Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998) Dose-Response Information to Support Drug Registration (1995)

8. Data Driving Hypothesis Informal review of E-R data in over 100 NDAs submitted between 1995-2001 –identified important missing data related to the quality of submission and approval rates Prospective evaluation of over 10 NDAs submitted in 2002-2003 –evaluated the impact of review including the re- analysis of E-R information –could this review been carried out early in the IND period and would it have saved costs and time in drug development?

9. Results of E-R Re-Analysis Avoided potential requests for sponsors to conduct additional clinical trials Approved lower doses or different dosing regimens than proposed by sponsor Identified missing data on specific doses or in special populations that impacted review times

10. Additional Goal Efficient and Effective Use of Resources Interactions with sponsors early in the drug development process provides an opportunity for FDA to assist sponsors and provide advice on the development of information on E-R and other clinical pharmacology issues, rather than identify important missing data or studies during the review of NDAs.

11. Timing of Meeting Pre-IND EOP2Pre-NDA NDA Submission Labeling Action Letter EOP1EOP2A PreclinicalPhase 1Phase 4Phase 2APhase 2BPhase 3 Phase 1

12. Rationale for Meeting Time Complete information on preclinical pharmacology and E-R Complete dose-tolerance (safety) data in healthy volunteers Initial efficacy (proof-of-concept) and safety data in patients Prior to so-called “registration or label studies” on special populations, drug interactions and food studies Discuss study designs using emerging technologies such as pharmacogenetics

13. Opportunity to Apply Mechanistic and Quantitative Methods Modeling and simulation to analyze all E-R data and explore dose choices Design of studies using computer-assisted clinical trial simulation Design of PPK studies to efficiently identify co-variates affecting E-R Discuss therapeutic equivalence boundaries based on E-R to interpret special population studies

14. End of Phase 2 Meeting: Differences Final decision made on choice of doses and/or dose range Formal meeting to discuss study design, endpoints and statistics of phase 3 AWC efficacy studies as basis for approval Special population and drug interactions studies complete

15. Which Drug Development Programs Would Benefit the Most? Limited resources - first-in-class or significant therapeutic advancement - well-understood pathophysiology and pharmacology - completeness of EOP2A background package - experience of sponsor in drug development

16. Plan Draft guidance for industry* –background, objectives, examples of topics, procedure for requesting meetings, information package, process for conducting meetings, documentation Meetings are voluntary, relatively informal and interdisciplinary Evaluation of impact after years of experience * Concept paper in the background package

17. Summary: Goals of EOP2A Meeting Decrease uncertainty in further drug development, e.g., phase 3 Quantitative analysis of E-R data to suggest dose ranges for clinical study Identify missing or discuss necessary information prior to submission Improve informational quality and minimize delays in NDA review

18. Input from CPSC Do you consider the goals of the EOP2A meeting appropriate and what do you see as obstacles to achieving those goals? Comment on the analytic methods used in examples of E-R to be presented; how can these approaches be improved? What metrics can be used to measure the impact or success of this initiative?