1. 1 Imaging Community Critical Need #1: Standardized and Harmonized Multisite Imaging George Q. Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics

2. 2 Discussion today will include comments and references to [F-18] FLT: an Investigational, non-FDA approved, PET Imaging Agent Enabling Investigational & Approved PET Imaging in Large Multicenter Clinical Trials

3. 3 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 can not effectively implement PET imaging in large multi- center therapeutic clinical trials

4. 4 Results: Multiple IND Design Solutions Regulatory CMC Imaging Standardization SNM Assessment Efforts

5. 5 Solution Centralized Investigational PET Imaging IND: Oct. 2008 Will enable therapeutic developers’ multi-center therapeutic clinical trials Solution: SNM Centralized IND

6. 6 Presentation - Solution Topics 1.Clinical Trials Network (CTN) Sites Registry 2.Distributed Manufacturing of PET agents – CMC 3.Imaging Standardization 4.[F-18] FLT selection

7. 7 International Registry - Investigators’ Sites – Industry necessity & reality – “Pick list” to match therapeutic sites  Registry criteria to enable industry review & site selection Enrollment & qualifications Location Equipment – hardware & software Personnel Access to investigational imaging agents Participation: phantom program – clinical trials Topic 1: Clinical Trials Sites - Registry

8. 8 International PET imaging sites & PET manufacturers

9. 9 Distributed Multi-center Manufacturing of PET Imaging FDA – Anticipates - “single, GMP product” ―PET production ― Multi-center methods of production of the investigational PET product ― Multiple “similar” PET products by end-product specifications Topic 2: Distributed Manufacturing of PET Agents

10. 10 Solution - Centralized IND Submission  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” [F-18] FLT

11. 11 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 Drug Master File (DMF)

12. 12 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

13. 13 CMC information must be submitted in centralized IND – CMC may be directly submitted to IND submission or – CMC may be submitted through a letter of cross-reference to an existing DMF filed with FDA Key Point

14. 14 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

15. 15 Solutions Clinical imaging with a standardized protocol hardware/software - International imaging clinical site registry Clinical trials educational programs for multi-center trials Pre-clinical imaging standardization - Phantom Program –Oncology / CNS / Cardiovascular Topic 3: Imaging Standardization

16. 16 [F-18] FLT fillable phantoms Qualitative & Quantitative (SUV) VA system —Torso: Oncology —Head: CNS —Cardiac SNM Imaging Phantom Program

17. 17 Presentation - Solution Topics 1.Clinical Trials Network (CTN) Sites Registry 2.Distributed Manufacturing of PET agents – CMC 3.Imaging Standardization

18. 18 Disclosures: Consultant to SNM (Society of Nuclear Medicine) Employee: PAREXEL/Perceptive Informatics - CRO Thank You George Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics george.mills@perceptive.com

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