1. Phase 0 Imaging Studies From Regulations to Reality: Obtaining and Holding an IND at Your Institution Karen A. Kurdziel, MD Virginia Commonwealth University, Richmond, VA National Cancer Institute, Bethesda, MD www.molecularimaging.vcu.edu

2. Phase 0 “First-in Human” Clinical Protocols Microdose studies 14 C 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 “… “proof-of-concept" trials that seek to confirm activity” 1/100th of pharmacologically effective dose; ≤100μg

3. RDRC or xIND? XX XX XX XX XX X X xINDRDRC No therapeutic intent Biodistribution, dosimetry, binding Pharmacokinetics Limited human subject exposure Preclinical data 5/15 rads organ limit Previous human experience

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

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

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

7. 18 F Fluoropaclitaxel (FPAC)

9. Write Clinical Protocol ~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

12. FDG vs. FPAC

14. 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)

15. 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)

16. 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

17. 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