Phase 0 Imaging Studies From Regulations to Reality: Obtaining and Holding an IND at Your Institution

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Phase 0 Imaging StudiesFrom Regulations to
Reality Obtaining and Holding an IND at Your
Institution
Karen A. Kurdziel, MD Virginia Commonwealth
University, Richmond, VANational Cancer
Institute, Bethesda, MD
www.molecularimaging.vcu.edu
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Phase 0 First-in Human Clinical Protocols
proof-of-concept" trials that seek to confirm
activity
1/100th of pharmacologically effective dose
100µg

• Microdose studies14C radiolabeling of drug for
  accelerator mass spectrometry (AMS)
• PET/SPECT tracer radiolabeling of drug
• Biodistribution, pharmacokinetics, routes of
  elimination
• Pilot imaging studies
• PET/SPECT radiotracers
• Imaging feasibility, dosimetry

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RDRC or xIND?
xIND
RDRC
X X
X X
X X
X X
X X
X
X
No therapeutic intent
Biodistribution, dosimetry, binding
Pharmacokinetics
Limited human subject exposure
Preclinical data
5/15 rads organ limit
Previous human experience
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Where to Begin?

• Chemistry (USP CGMP?)
• Validate synthesis
• Verify purity
• Establish expected specific activity/yield
• Drug concentration must be lt1/100th physiological
  dose and 100µg

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18F Fluoropaclitaxel (FPAC)

• Radiolabeled chemotherapeutic agent
• Marker of multidrug resistance (MDR)

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Where to Begin?

• Compile preclinical data (GLP)
• Research literature
• Preliminary toxicity, mutagenicity, genotoxicity
• Target validation

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18F Fluoropaclitaxel (FPAC)
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18F Fluoropaclitaxel (FPAC)
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Write Clinical Protocol

• 10 subjects
• Specify data analysis methods
• DosimetryOLINDA software (Stabin et al., JNM
  2005)
• MBq/mL can be converted to µg/g tissue if the
  specific activity of injected tracer is known
• FDA Guidance for Industry Medical Imaging Drug
  and Biological Products Part 3?
  http//www.fda.gov/cder/guidance/5742prt3.pdf

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FDG vs. FPAC
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FDG vs. FPAC
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As an Investigator you must

• Obtain IRB review (21 CFR 312.66)
• Control administration of investigational drug
  (21 CFR 312.61)
• Ensure the protocol is followed (all individuals
  with clinical responsibilities must file Form
  1572
• Reporting (21 CFR 312.64)
• submit progress reports for IND annual report
• report safety concerns
• submit final report after study completion
• Provide FDA with records upon request (21 CFR
  312.68)

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Who are you?

• Sponsor pays for study, reports to FDA, recruits
  investigators
• Investigator performs study, reports to sponsor
• Co-investigator reports to investigator
• Investigator/Sponsor (i.e., physician-sponsored
  IND) performs study and reports to FDA (i.e.,
  R01 funding)

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As an Investigator you must

• Maintain records (21 CFR 312.62)
• Drug disposition
• Subject data
• Case report forms (CRF)
• Informed consent documents (ICF)
• Record must be kept for 2 years post drug
  approval or study discontinuation

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Guidance Documents

• FDA
• MEDICAL IMAGING AGENTS
• http//www.fda.gov/cder/guidance/5742prt1.pdf
  Part1
• http//www.fda.gov/cder/guidance/5742prt2.pdf
  Part2
• http//www.fda.gov/cder/guidance/5742prt3.pdf
  Part 3
• RDRC
• http//www.fda.gov/Cder/regulatory/RDRC/
• PET CGMP
• http//www.fda.gov/Cder/guidance/5425dft2.pdf
• Approaches to Complying with CGMP During Phase
  1
• http//www.fda.gov/cder/guidance/6164dft.htm
• Exploratory IND Studies
• http//www.fda.gov/cder/guidance/7086fnl.htm
• Imaging.cancer.gov
• EMEA
• http//www.emea.europa.eu/pdfs/human/swp/259902en.
  pdf