1. The SNM Centralized IND & Clinical Trials Network Enabling Implementation Investigational & Approved PET Imaging in Large Multicenter Clinical Trials George Q. Mills, MD, MBA September 9, 2009

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

3. Page 3 SNM – Assessment Efforts  Therapeutic Developers  Participating PET Imaging Centers  FDA – Pre-IND Process Results - Design solutions Centralized Investigational PET Imaging IND to Enable Therapeutic Developers’ Multicenter Therapeutic Clinical Trials Distributed Manufacturing Investigational PET imaging Agents

4. Page 4 SNM Centralized IND – Demonstration Project - Future development INDs – F-18 FLT – first choice – available – broad potential 1. Regulatory 2. CMC 3. Imaging Standardization

5. Page 5 Investigator international site registry Forming “Pick List” - 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 Sites Network - Registry

6. Page 6 World wide interest - imagers & manufacturers

7. Page 7 Regulatory – multicenter IND manufacturing Multicenter INDs - “Single source” – investigational product CMC – Investigational F-18 FLT sources Multiple production sites & multiple methods “Distributed manufacturing” = multiple end-product specs SNM Centralized IND F-18 FLT FDA CMC review of all sources – acceptable ranges for end- product specifications

8. Page 8 Review through submission to IND file directly or through Drug Master File (DMF) “a submission tool of efficiency for manufacturers” Information concerning the Chemistry, Manufacturing and Controls (CMC) of a drug product or a component of a drug product to permit the FDA to review this information upon request in support of a submission

9. Page 9 Types of DMFs Five Types I: Plant information II: Drug substance, drug product, intermediates and material used in their manufacture III: Packaging IV: Excipients V: Other clinical, tox Five Types I: Plant information II: Drug substance, drug product, intermediates and material used in their manufacture III: Packaging IV: Excipients V: Other clinical, tox

10. Page 10 Who must file a DMF? CMC information must be available for IND review: CMC must be in an IND submission or in a DMF – There is no legal or regulatory requirement to file a DMF (submission by Holder, … ref by applicant or authorized party) – Applicant submits a Letter of Authorization (LOA) from the Holder with their IND submission CMC information must be available for IND review: CMC must be in an IND submission or in a DMF – There is no legal or regulatory requirement to file a DMF (submission by Holder, … ref by applicant or authorized party) – Applicant submits a Letter of Authorization (LOA) from the Holder with their IND submission

11. Page 11 Letter of Authorization (LOA) – Enabling review of DMF The DMF will be reviewed ONLY when it is referenced in a submission or another DMF (initially receives an administrative review) The Holder MUST submit an LOA (2 copies) to the DMF and send a copy to the Applicant The Applicant submits LOA in their submission … the mechanism to trigger review of the DMF by FDA In Europe, the LOA is called a Letter of Access

12. Page 12 DMF Advantages Maintains proprietary information/trade secrets (e.g. manufacturing procedure) belonging to the Holder, from being revealed to the Applicant while permitting review by FDA Permit review of information referenced by a number of applicants & will be used to support submissions from many sponsors Time efficient – cost effective

13. Page 13 Imaging standardization 1. Pre-clinical Imaging Standardization - Imaging Phantom Program Oncology – CNS - Cardiovascular 2. Clinical imaging - Standardized protocol 3. International imaging clinical site registry (217 sites) documentation of equipment & demonstrated capabilities 4. Clinical Trials Educational programs – Multicenter Trials

14. Page 14 F-18 fillable phantoms – Qualitative & Quantitative (SUV) – VA system Torso – Oncology  Head – CNS Cardiac SNM Imaging Phantom Program

15. Page 15 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

16. Page 16 Topics Overview – Key Elements – Centralized IND Clinical Trials Network – Resources – Sites Registry – Phantom Program – Education & Training Program F-18 FLT selection

17. Page 17 Thank you George Mills, MD, MBA Vice President, Medical & Regulatory Relations Perceptive Informatics george.mills@perceptive.com

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