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

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 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 FDA / IOM Meeting – October 2007

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

5 Solution Topics 1.Clinical Trials Network (CTN) Sites Registry 2.Selection of IND biomarker – [F-18] FLT 3.Distributed Manufacturing of PET agents – CMC 4.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

Hypoxia Apoptosis Amyloid Receptors Lipids Dopaminergic Receptors Angiogenesis Estrogen Receptors 8 Topic 2: Centralized IND Selection Areas of Interest Selection: [F-18] FLT (Oct. 2008)

9 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 Selection Criteria for [F-18] FLT PRE-TX 22 days 113 days

10 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 Topic 3: Distributed Manufacturing of PET Agents

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 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)

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 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 Key Point

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 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 Topic 4: Imaging Standardization

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

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

19 Review: Solution Topics 1.Clinical Trials Network (CTN) Sites Registry 2.Selection of IND biomarker – [F-18] FLT 3.Distributed Manufacturing of PET agents – CMC 4.Imaging Standardization

20 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