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

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

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

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

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

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

18 F Fluoropaclitaxel (FPAC)

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 

FDG vs. FPAC

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

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)

As an Investigator you must… Maintain records (21 CFR ) –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

Guidance Documents FDA MEDICAL IMAGING AGENTS Part1 Part2 Part 3 RDRC PET CGMP Approaches to Complying with CGMP During Phase 1 Exploratory IND Studies Imaging.cancer.gov EMEA