1. The Radioactive Drug Research Committee Approval Process for Tracer Use Anthony F. Shields, M.D., Ph.D. Karmanos Cancer Institute Wayne State University Detroit, Michigan

2. RDRC Basic research for the purpose of advancing scientific knowledge –The research is intended to obtain basic information regarding the metabolism of radioactive drugs including kinetics, distribution, dosimetry, and localization OR –Obtain basic information regarding human physiology, pathophysiology, and biochemistry of radioactive drugs. The research in NOT intended to determine the safety and efficacy of a radioactive drug in human subjects as a therapy, diagnostic or preventive medical product. The research is NOT intended for the immediate therapeutic, diagnostic or preventive benefit.

3. RDRC Title 21 Code of Federal Regulations (CFR) 361.1 Conditions for RDRC Research –Basic Science Research – “…not intended for immediate therapeutic,diagnostic, or similar purposes or to determine the safety and effectiveness of the drug…” –No pharmacologic effect –Radiation dose limits FDA approves committee members RDRC Responsibilities –Reviews and approve each research protocol per regulations, with IRB concurrence –Submit variety of regulatory reports to FDA

4. RDRC 74 Active RDRCs as of June, 2006. RDRC protocols average 10 subjects each. –RDRC PET protocols average 8 patients –IND PET protocols average 62 patients RDRC research (as of 2003): –77% PET tracer development –5% gamma tracer development –18% beta (in vitro bioassay) Types of RDRC research (2003) –Neuroreceptor – 45% –Cancer – 15% –Diabetes – 12% –Cardiac – 9% –Other – 22 % (Exercise, pain, obesity, acupuncture, prostheses, GI, pulmonary, auditory, bone physiology, etc.)

5. Purpose of Research RDRC The research is intended to obtain basic information regarding: –Metabolism of the radioactively labeled drug kinetics distribution dosimetry localization –Human physiology, pathophysiology, biochemistry The research is not intended for immediate therapeutic, diagnostic, or similar purposes, or to determine the safety and effectiveness of the drug in humans for such purposes (i.e., to carry out a clinical trial) IND Intent of the research is not restricted Can include: –Research involving therapeutic, diagnostic, or preventive benefit to the subject –Study of safety and efficacy (clinical trial) –Basic research that does not meet the requirements of 361.1 –Basic research that meets requirements of 361.1

6. Review, Approval, and Oversight RDRC and IND Both Need: Institutional Review Board (IRB) –21 CFR 56 –Responsibilities include: Review of initial research and subsequent changes –Authority to approve, require modification in, or disapprove research activities. –Authority to suspend or terminate approval of research –Approval must be obtained prior to implementation Continuing review of ongoing research –Criteria for approval: Minimization of risks to subjects; risks are reasonable in relation to anticipated benefits Equitable selection of subjects Compliance with the informed consent requirements of 21 CFR 50, including subpart D if some subjects are children Adequate provision for monitoring data to ensure safety of subjects Protection of rights and welfare of vulnerable subjects Adequate provisions to protect privacy and confidentiality

7. Review, Approval, and Oversight (cont.) RDRC Radioactive Drug Research Committee –Approved, monitored by FDA –Responsible for ensuring that the requirements of 361.1 are met: Qualified study investigators Proper licensure for radioactive materials Appropriate selection and consent of research subjects Appropriate quality of radioactive drug administered Sound research protocol design Reporting of adverse events Approval by IRB Labeling IND FDA –Reviews: Protocols, protocol changes Study investigators CMC, Pharm/tox, PK Information amendments –Primary objectives of review: To assure the safety and rights of subjects To assess the scientific quality of the clinical investigations –Ability of sponsor to proceed: First 30 days Ongoing studies

8. Review, Approval, and Oversight (cont.) Reporting to FDA Monitoring by FDA FDA enforcement actions RDRC Annual report Study Summary Membership Summary Special Summary Adverse events If requested: Minutes Full protocols FDA monitors the activities of the approved RDRCs Notification of deficiencies On-site inspections Withdrawal of approval of RDRC IND Annual report New protocols Protocol changes New investigators Information amendment Adverse events FDA monitors the research On-site inspections Full or partial clinical hold, termination of IND

9. Dosing

10. Study Subjects RDRCIND Informed Consent (21 CFR 50) Number of subjects Required, incl. Subpart D Sufficient but no greater than necessary for the purpose of the study Should reflect that the study is intended to obtain basic research information (usually <30) Required, incl. Subpart D No limit Subjects < 18 years of age Permitted only in special situations described in 361.1(d)(5) Permitted Women of child bearing potential Must state in writing that she is not pregnant, or be confirmed as not pregnant Permitted

11. Adverse Event (AE) Reporting RDRC Investigator must immediately report to RDRC all AEs associated with use of the radioactive drug in the research study –Serious- FDA recommends 2 business days –All others- FDA recommends 5 business days RDRC must immediately report to FDA all adverse events probably attributable to use of the radioactive drug in the research study –Serious- FDA recommends 7 business days –All others- FDA recommends 15 business days IND Sponsor must review all info relevant to the safety of the drug from any source, foreign or domestic –clinical trials –literature –animal studies –commercial marketing –unpublished papers –reports from foreign regulatory authorities Safety reports –Serious/unexpected within 15 days of receipt –Unexpected fatal or life- threatening within 7 days of receipt Annual reports

12. Information Needed for RDRC With any tracer one needs to know: Toxicity data Can be obtained on tracer from –previous unlabeled drug studies –knowledge that it is a natural compound in the body –knowledge that it is a metabolite of a drug that has been given to patients Dosimetry –From animal studies –Studies of related compounds Purity and specific activity of with the tracer. Sterility

13. Personal RDRC Examples: Studies of Labeled Thymidine and Analogs 11 C-Thymidine: – 11 C-Thymidine had been used at other centers in patients (dosimetry). –Unlabeled drug had previously used in cancer patients at high doses (toxicity data). –Natural body and blood constituent (toxicity data). 11 C-Thymine: –Natural body and blood constituent (toxicity data). –Unlabeled thymidine is metabolized to thymine, so we used thymidine toxicity data. –Used 11 C-thymidine dosimetry data, since thymidine converted to thymine and cleared more rapidly. –We did not need direct toxicity or dosimetry data with thymine.

14. 18 F-FLT (3'-deoxy-3'-fluorothymidine): –Unlabeled FLT had previously been in AIDS patients at high doses (it was too toxic). –Dosimetry from dog studies. 18 F-FMAU (1-(2’-deoxy-2'-fluoro-ß-D-arabinofuranosyl)thymine) –Unlabeled FMAU had previously been in AIDS patients at high doses (it was too toxic). –Dosimetry from dog studies. 18 F-FAU (1-(2’-deoxy-2'-fluoro-ß-D-arabinofuranosyl)uracil). –FAU had NEVER been injected into patients. Toxicity data used from FIAU which is metabolized to FAU. –Dosimetry from dog studies. Personal RDRC Examples: Studies of Labeled Thymidine Analogs

15. Conclusions The RDRC mechanism complements the IND process for pilot studies of radioactive tracers. It generally allows for testing up to about 30 patients on a given study. One needs toxicity and dosimetry data, but this can sometimes be inferred from data and natural compounds, unlabeled drugs, and metabolites. Radiochemical purity and specific activity are needed. Since RDRC committees are run by individuals at different institutions, the rulings can sometimes vary. Proposals to allow testing of very small quantities of tracer without toxicity data would help to speed imaging development.