1. The SNM Centralized IND & Clinical Trials Network Enabling Implementation Investigational & Approved PET Imaging in Multicenter Clinical Trials George Q. Mills, MD, MBA Vice President, Medical & Regulatory Affairs Perceptive Informatics, Inc. June 13, 2009

2. Page 2 Initial development - October 2007 Washington, DC Institute of Medicine (IOM) Meeting FDA – NCI - Imaging & Therapeutic Developers Presentations Advocating Investigational & Approved PET Imaging Biomarkers

3. Page 3 PET imaging for Multicenter Trials Desired…but…numerous deficiencies… lack of… 1. Supply of investigational PET agents 2. Standardized PET imaging acquisition protocols 3. Harmonized PET imaging report output 4. Qualified imaging centers large (200+ sites) multicenter clinical trials  Industry could not effectively implement PET imaging in multicenter therapeutic clinical trials Therapeutic Drug Developers Comments

4. Page 4 FDA IOM Meeting Assessment “Critical Path” Initiative… Needs for Therapeutic Drug Development Enable the Development of Diagnostic Investigational & Approved PET Imaging r

5. Page 5 Assessment Efforts - SNM & FDA  Therapeutic Developers  Participating PET Imaging Centers  FDA – Pre-IND Process Results – Solution Design Centralized Investigational PET Imaging IND to Enable Therapeutic Developers’ Multicenter Therapeutic Clinical Trials

6. Page 6 Today’s topics Overview – Key Elements – Centralized IND Delivered Timeline – First year - Centralized IND Clinical Trials Network – Resources – Sites Registry – Phantom Program – Education & Training Program F-18 FLT selection criteria

7. Page 7 Overview – Key Elements SNM Centralized IND Concepts – Demonstration Project - Future development INDs – F-18 FLT – first choice – available – broad potential 1. Regulatory 2. CMC 3. Imaging Standardization

8. Page 8 Regulatory facilitated PET use & improve administrative implementation  Letter of cross-reference to diagnostic IND improve access for therapeutic developers  Enable effective safety & efficacy reporting Diagnostic IND  Adverse events reports  Annual reporting  Final reports

9. Page 9 Regulatory – multicenter IND manufacturing CMC – Investigational F-18 FLT Multiple production sites & multiple methods “Distributed manufacturing” = multiple end-product specs SNM Centralized IND F-18 FLT FDA review – defining through review processes acceptable ranges for end-product specifications

10. Page 10 Imaging standardization 1. Pre-clinical Imaging Standardization SNM Imaging Phantom Program Oncology – CNS - Cardiovascular 2. Clinical imaging - Standardized imaging acquisition protocol 3. International imaging clinical site registry (217 sites) documentation of equipment & demonstrated capabilities 4. Clinical Trials Educational programs – Multicenter Trials

11. Page 11 Timeline - Achievements Pre-IND – 3 FDA meetings & multiple t-con May – August 2008 Centralized IND submitted to FDA for F-18 FLT August 2008 SNM’s Clinical Trials Imaging Network August 2008 Centralized IND F-18 FLT FDA Approved September 2008 SNM Phantom imaging program implementation October 2008 Clinical Sites Registry October 2008 Clinical Trials Symposium – Mid-Winter Meeting February 2009 Standardized Phantom program – 4 – 10 – 10 centers March 2009 Network Education training programs June 2009

12. Page 12 SNM Clinical Trials Network Enabling Multicenter Clinical Trials

13. Page 13 Investigator international site registry Forming “Pick List” of available imaging centers for therapeutic developers  Enrollment & qualifications  Location Geography Patient population access  Equipment – hardware & software  Personnel  Access to investigational imaging agents  Participation – phantom program – clinical trials Clinical Trials Network - Registry

14. Page 14 Network Registries (Jun 09)

15. Page 15 World wide interest - imagers & manufacturers

16. Page 16 Four sites: U. Iowa, Mayo Clinic, U. Utah & U. Penn – Separate, independent F-18 FLT INDs - Experienced – Participation - SNM’s imaging phantom program Next thresholds – Multicenter trial Imaging participation – Demonstration & implementation Multicenter clinical trial protocol compliance Imaging acquisition standardization Harmonization of imaging output Clinical Trials Sites - Centralized IND

17. Page 17 F-18 fillable phantoms – Qualitative & Quantitative (SUV) – VA system Torso – Oncology  Head – CNS Cardiac SNM Imaging Phantom Program

18. Page 18 SNM Educational & Training Programs Clinical Trials February Mid-winter – Clearwater, Fl 1½-day symposium June Annual Meeting – Toronto, Canada Full-day categorical

19. Page 19 Selection - F-18 FLT Investigational PET imaging biomarker Literature reports of “potential” for demonstrating tumor proliferation Potential as a surrogate marker for evaluating investigational oncology therapeutics as well as existing therapeutics Broadly applicable to lung, breast, esophageal, GI, brain, lymphoma PRE-TX 22 days 113 days

20. Page 20 Therapeutic Developers Current Goals for Investigational F-18 FLT Phase 1 – 2 Clinical Trials  Assess potential as imaging surrogate  Document & Report - safety & efficacy  “Promising vs. Not So Promising”

21. Page 21 Topics - Reviewed Overview – Key Elements – Centralized IND Deliverables Timeline – First year - Centralized IND Clinical Trials Network – Resources – Sites Registry – Phantom Program – Education & Training Program F-18 FLT selection

22. Page 22 Regulatory – multicenter IND manufacturing CMC – Investigational F-18 FLT Multiple production sites & multiple methods “Distributed manufacturing” = multiple end-product specs SNM Centralized IND F-18 FLT FDA review – acceptable ranges for end-product specifications

23. Page 23 Thank you George Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics george.mills@perceptive.com

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