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Phase 0 Imaging Studies: Obtaining and Holding an IND at Your Institution

This article provides guidance on conducting Phase 0 imaging studies, including microdose studies, radiolabeling of drugs, biodistribution and pharmacokinetics, and pilot imaging studies. Topics covered include regulatory requirements, chemistry validation, synthesis verification, and expected specific activity/yield. Case examples and resources are provided.

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Phase 0 Imaging Studies: Obtaining and Holding an IND at Your Institution

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  1. 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

  2. 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 Phase 0 “First-in Human” Clinical Protocols “… “proof-of-concept" trials that seek to confirm activity” 1/100th of pharmacologically effective dose; ≤100μg

  3. RDRC or xIND? RDRC xIND

  4. Chemistry (USP; CGMP?) Validate synthesis Verify purity Establish expected specific activity/yield Drug concentration must be <1/100th physiological dose and ≤100μg Where to Begin?

  5. 18F Fluoropaclitaxel (FPAC) • Radiolabeled chemotherapeutic agent • Marker of multidrug resistance (MDR)

  6. Compile preclinical data (GLP) Research literature Preliminary toxicity, mutagenicity, genotoxicity Target validation Where to Begin?

  7. 18F Fluoropaclitaxel (FPAC)

  8. 18F Fluoropaclitaxel (FPAC)

  9. ~10 subjects Specify data analysis methods Dosimetry—OLINDA 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 Write Clinical Protocol

  10. FDG vs. FPAC

  11. FDG vs. FPAC

  12. 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) As an Investigator you must…

  13. 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) Who are you?

  14. 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 As an Investigator you must…

  15. 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 Guidance Documents

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