George Q. Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics

1. Workings of the SNM Clinical Trials Network Centralized IND for FLT George Q. Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics

2. Discussion today includes background information, comments and references to the SNM Clinical Trials Network Centralized IND Selection of [F-18] FLT: an Investigational, non-FDA approved, PET Imaging Agent

3. FDA / IOM Meeting – October 2007 Therapeutic Drug Developers Comments • PET imaging desired for Multi-center Therapeutic Trials …but ... numerous deficiencies with PET imaging ISSUES • Lack of qualified & experienced imaging centers for large (200+ sites) multi-center Phase 3 clinical trials • Limited supply of known/desired investigational PET agents • No standardized PET imaging acquisition protocols • No harmonized PET imaging report output • Industry could not effectively implement PET imaging in multi-center therapeutic clinical trials

4. SNM Assessment Efforts Multiple Discussions: • Therapeutic Developers • Participating PET Imaging Centers • FDA: Pre-IND Process Results: • Multiple IND Design Solutions • Regulatory • CMC • Imaging Standardization

5. Solution Topics • Clinical Trials Network (CTN) Sites Registry • Selection of IND biomarker – [F-18] FLT • Distributed Manufacturing of PET agents – CMC • Imaging Standardization

6. Topic 1: Clinical Trials Sites Registry • International Registry - Investigators’ Sites • Industry necessity & reality • “Pick list” to match therapeutic sites • Criteria to enable industry review & site selection • Enrollment & qualifications • Location • Equipment – hardware & software • Personnel • Access to investigational imaging agents • Participation: phantom program – clinical trials

7. International PET imaging sites & PET manufacturers

8. Areas of Interest • Selection: [F-18] FLT (Oct. 2008) Topic 2: Centralized IND Selection 8

9. Selection Criteria for [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 for lung, breast, esophageal, GI, brain, lymphoma PRE-TX 22 days 113 days

10. Topic 3: Distributed Manufacturing of PET Agents Distributed Multicenter Manufacturing of PET Imaging • FDA: Anticipates “single GMP product” • PET production • Multicenter methods of production of the investigational PET product • Multiple “similar” PET products by end-product specifications

11. Using the SNM Centralized IND for [F-18] FLT • FDA must review CMC for all manufacturing sources & methods • CMC from all manufacturers supplying [F-18] FLT to trials must be submitted directly to IND or through letter of cross-reference to a filed DMF • FDA defines acceptable ranges for [F-18] FLT by end-product specifications • FDA accepted [F-18] FLT products = “single IND GMP product”

12. Drug Master File (DMF) DMF = Efficient CMC submission tool for manufacturers Drug Manufacturer’s Submits Information – Chemistry, Manufacturing and Controls (CMC) of a drug product or a component of a drug product to FDA file room to permit the FDA to review this information upon request only and in support of a specific submission

13. FDA Regulatory DMF Background Five Types • I: Plant information • II: Drug substance, drug product, intermediates and material used in their manufacture • III: Packaging • IV: Excipients • V: Other clinical, toxicology

14. Key Point CMC information must be submitted in centralized IND • CMC may be directly submitted in IND submission or • CMC may be submitted through a letter of cross-reference to an existing DMF filed with FDA

15. Letter of Authorization (LOA) - Enables FDA review of DMF • The DMF Holder (manufacturer) MUST submit an LOA (2 copies) to the DMF and route a separate copy to the IND Applicant • The Applicant submits LOA in their IND submission… the mechanism to enable review of the DMF by FDA • The DMF will be reviewed ONLY when it is referenced in an IND submission • In Europe, the LOA is called a Letter of Access

16. Topic 4: Imaging Standardization Solutions • Clinical imaging with a standardized protocol • International imaging clinical site registry – hardware/software • Clinical trials educational programs for multicenter trials • Pre-clinical imaging standardization - Phantom Program • Oncology / CNS / Cardiovascular

17. SNM Imaging Phantom Program [F-18] FLT fillable phantoms • Qualitative & Quantitative (SUV) • VA system • Torso: Oncology • Head/Brain: CNS • Cardiac

18. Plans for Future Centralized IND • FDG • FLT • FDOPA • FAZA • FMISO • Ga-68 octreotide • FES • FHDT • C-11 acetate

19. Review: Solution Topics • Clinical Trials Network (CTN) Sites Registry • Selection of IND biomarker – [F-18] FLT • Distributed Manufacturing of PET agents – CMC • Imaging Standardization

20. Thank You George Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics george.mills@perceptive.com Disclosures: • Consultant to SNM (Society of Nuclear Medicine) • Employee: PAREXEL/Perceptive Informatics - CRO