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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

                                                    1
               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



                                                      2
                        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
                                                                       3
                                  SNM Assessment Efforts

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

Results:
•   Multiple IND Design Solutions
    —   Regulatory
    —   CMC
    —   Imaging Standardization

                                                      4
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




                                                   5
                      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

                                                          6
International PET imaging sites & PET manufacturers




                                                      7
                        Topic 2: Centralized IND Selection

     Areas                                 Hypoxia
       of                                 Apoptosis
    Interest                          Amyloid Receptors

                                            Lipids

                                    Dopaminergic Receptors

                                        Angiogenesis

                                     Estrogen Receptors




Selection: [F-18] FLT (Oct. 2008)
                                                             8
                              Selection Criteria for [F-18] FLT

•   Investigational PET imaging biomarker
•   Literature reports of “potential” for
    demonstrating tumor proliferation             PRE-TX

•   Potential as a surrogate marker for
    evaluating investigational oncology
    therapeutics as well as existing              22 days

    therapeutics
•   Broadly applicable for lung, breast,
    esophageal, GI, brain, lymphoma               113 days
                                                             9
     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


                                                              10
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”



                                                                          11
                                  Drug Master File (DMF)

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

                                                          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
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




                                                          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
                           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




                                                                       16
                             SNM Imaging Phantom Program

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




                                                     17
                       Plans for Future Centralized IND
•   FDG
•   FLT
•   FDOPA
•   FAZA
•   FMISO
•   Ga-68 octreotide
•   FES
•   FHDT
•   C-11 acetate

                                                     18
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




                                                   19
                          Thank You
                    George Mills, MD, MBA
         Vice President, Medical & Regulatory Relations
                     Perceptive Informatics
                 george.mills@perceptive.com




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


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posted:4/29/2013
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