Phase 0 Imaging StudiesFrom Regulations to Reality:

Obtaining and Holding an IND at Your Institution

Karen A. Kurdziel, MD

Virginia Commonwealth University, Richmond, VA

National Cancer Institute, Bethesda, MDwww.molecularimaging.vcu.edu

Phase 0 “First-in Human” Clinical Protocols

• 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

“… “proof-of-concept" trials that seek to confirm activity” 1/100th of pharmacologically effective dose; ≤100μg

RDRC or xIND?

X X

X X

X X

X X

X X

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 <1/100th physiological dose and ≤100μg

18F Fluoropaclitaxel (FPAC)

O

O

O OH

OOOH

O

O

OH

NH2

O O

O O

OH

18FO

O

O OH

OOOH

O

O

OH

NHO

O O

18F

O

Trialkyl amineDiethyl cyanophosphonate

18F -

•Radiolabeled chemotherapeutic agent

•Marker of multidrug resistance (MDR)

Where to Begin?

• Compile preclinical data (GLP)

– Research literature

– Preliminary toxicity, mutagenicity, genotoxicity

– Target validation

18F Fluoropaclitaxel (FPAC)

18F 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 http://www.fda.gov/cder/guidance/5742prt3.pdf

FDG vs. FPAC

FDG vs. FPAC

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)

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 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

Guidance Documents

• FDAMEDICAL IMAGING AGENTS

http://www.fda.gov/cder/guidance/5742prt1.pdf Part1http://www.fda.gov/cder/guidance/5742prt2.pdf Part2http://www.fda.gov/cder/guidance/5742prt3.pdf Part 3

RDRChttp://www.fda.gov/Cder/regulatory/RDRC/

PET CGMPhttp://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

• EMEAhttp://www.emea.europa.eu/pdfs/human/swp/259902en.pdf