The RDRC and “first in man” studies

1. The RDRC and “first in man” studies Andrew Taylor, M.D. Emory University School of Medicine Atlanta, GA

2. “Reducing drug costs and expanding access to prescription drugs for all Americans have been the cornerstones of my domestic policy agenda.” George W. Bush “At the center of my strategy for addressing the health care crisis is a plan to control spiraling health care costs.” John F. Kerry

3. The RDRC can play an important role in facilitating translational research and minimizing the growth of health care costs.

4. In the 1980s, the FDA allowed RDRCs to approve “first in man” studies. • Tracer doses – too low to have a toxic or pharmacological effect • Tracer was chemically similar to a drug or class of drugs shown to be safe in man

5. University of Utah RDRC: 1981-1985 1. 1.Tc-99m-OH-DADS 2. Tc-99m asym-CO2DADS 3. Tc-99m CH2-CO2-DADS 4. Tc-99m MAG3

6. It is impossible to perform toxicity studies for technetium based tracers. • Tc-99m has too short a half life • Tc-99 cannot be obtained in sufficient quantities for toxicity studies. • Even if enough Tc-99 could be obtained, animal studies would be prohibited because it is a beta emitter with a 210,000 half life.

7. Toxicity Studies: Ligand vs Complex • Ligand: MAG3 (mercaptoacetyltriglycine) • Complex: Tc-99m MAG3 • Complex and ligand differ in: • Structure • Charge • Biodistribution

8. Kit formulation vs HPLC purification • Kit formulation • Ligand • Complex • Kit components/solvent • HPLC purification • Complex • Solvent

9. Comparative toxicity data Bacterial protein toxins resemble enzymes and have evolved to act catalytically and exhibit specificity of action. If research tracers were to be toxic, they are most appropriately compared to plant toxins. Ricin 7,000 ng/kg Aflatoxin 500,000 ng/kg Strychnine 2,000,000 ng/kg Tc-99m MAG3: 10 mCi = 0.1 ng/kg

10. Conclusions • RDRCs should be permitted to allow “first in man” studies with Tc-99m complexes since: • These complexes can only be administered in tracer doses because of physical constraints. • Even if the complex is toxic (thallium is a rat poison) there is a safety factor of 1000-100,000 compared to known plant toxins. • This approach will facilitate translational research and reduce the cost of drug development.

11. Conclusions 2. For reasons cited on the previous slide, RDRCs should also be given authority to approve “first in man” studies when: • The radiopharmaceutical will be given in tracer quantities (<100 ng/kg) • The radiopharmaceutical has a structure similar to drugs which have been shown to be safe in man