George Q. Mills, MD, MBA

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

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• SNM Assessment Efforts

• Multiple Discussions
• Therapeutic Developers
• Participating PET Imaging Centers
• FDA Pre-IND Process
• Results
• Multiple IND Design Solutions
• Regulatory
• CMC
• Imaging Standardization

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• Solution Topics
• Clinical Trials Network (CTN) Sites Registry
• Selection of IND biomarker F-18 FLT
• Distributed Manufacturing of PET agents CMC
• 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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• 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

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• 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

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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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• Drug Master File (DMF)

• DMF Efficient CMC submission tool for
  manufacturers
• Drug Manufacturers 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

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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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• 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

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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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• 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

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• SNM Imaging Phantom Program

• F-18 FLT fillable phantoms
• Qualitative Quantitative (SUV)
• VA system
• Torso Oncology
• Head/Brain CNS
• Cardiac

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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
• Clinical Trials Network (CTN) Sites Registry
• Selection of IND biomarker F-18 FLT
• Distributed Manufacturing of PET agents CMC
• Imaging Standardization

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• Thank You
• George Mills, MD, MBA
• Vice President, Medical Regulatory Relations
• Perceptive Informatics
• george.mills_at_perceptive.com

• Disclosures
• Consultant to SNM (Society of Nuclear Medicine)
• Employee PAREXEL/Perceptive Informatics - CRO