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George Q. Mills, MD, MBA

Vice President, Medical & Regulatory RelationsPerceptive Informatics

Workings of the SNM Clinical Trials Network Centralized IND for FLT

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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

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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

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Multiple Discussions:

• Therapeutic Developers• Participating PET Imaging Centers• FDA: Pre-IND Process

Results:

• Multiple IND Design Solutions

— Regulatory — CMC — Imaging Standardization

SNM Assessment Efforts

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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

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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

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International PET imaging sites & PET manufacturers

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Topic 2: Centralized IND Selection

Areas of

Interest

Selection: [F-18] FLT (Oct. 2008)

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• 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

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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

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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”

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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)

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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

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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

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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

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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

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[F-18] FLT fillable phantoms• Qualitative & Quantitative (SUV)

• VA system

— Torso: Oncology

— Head/Brain: CNS

— Cardiac

SNM Imaging Phantom Program

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Plans for Future Centralized IND

• FDG• FLT• FDOPA• FAZA• FMISO• Ga-68 octreotide• FES• FHDT• C-11 acetate

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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

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Disclosures:

• Consultant to SNM (Society of Nuclear Medicine)

• Employee: PAREXEL/Perceptive Informatics - CRO

Thank You

George Mills, MD, MBAVice President, Medical & Regulatory Relations

Perceptive Informaticsgeorge.mills@perceptive.com