1. Paula M. Jacobs, Ph.D. SAIC Frederick Cancer Imaging Program/DCTD/NCI/NIH September 5, 2006 Phase 0 Trials in Oncologic Drug Development DCTD Phase 0 Workshop Nuts and Bolts: You Too Can Prepare an IND

2. Overview of Early Development   Synthesize a number of new imaging drugs   Evaluate them in pre-clinical settings   Pick the best ones to test in humans   Learn to prepare them consistently   Perform in vivo pharmacology and toxicology in appropriate animal models   Chose initial dose for human studies: least risk   Assemble the data and submit to FDA or to your RDRC   Obtain IRB approval   Test in human subjects

3. Approach to Regulatory Requirements   Regulations are the same for ¬ ¬Labeled therapeutic agents ¬ ¬Functional imaging agents ¬ ¬General imaging agents   Development strategy may differ with goal ¬ ¬Basic information about a therapeutic ¬ ¬Basic information about a tumor ¬ ¬Imaging for evaluating response to therapy

4. Investigational Clinical Trials   The sponsor must apply for permission to study drugs in humans ¬ ¬From FDA for IND – traditional or exploratory ¬ ¬From the Radioactive Drugs Research Committee (RDRC) at your institution ¬ ¬From an IRB for either   “Sponsor” ¬ ¬Individual physician ¬ ¬Institution ¬ ¬Industry

5. RDRC vs. IND   RDRC: for basic research only ¬ ¬E.g., kinetics, distribution, dosimetry ¬ ¬NOT safety or efficacy ¬ ¬Pediatric studies restricted ¬ ¬Only small doses and few patients ¬ ¬Drug must have been in humans before   IND: not restricted to basic research ¬ ¬Can study safety and efficacy (i.e., clinical trials) ¬ ¬Can do basic research ¬ ¬Pediatric studies less restricted

6. Types of IND   Three types of traditional INDs: ¬ ¬An investigator initiated IND ¬ ¬Emergency use IND (E-IND) ¬ ¬Treatment IND   And a new type: ¬ ¬Exploratory (“phase 0”, x-IND)

7. What’s the difference?   Traditional ¬ ¬Single agent ¬ ¬Plans for Phase 1, 2, 3 trials and NDA ¬ ¬Extensive pre-clinical data needed to begin ¬ ¬Dose escalation, therapeutic evaluation   Exploratory ¬ ¬Multiple agents under one IND, go/no go ¬ ¬Microdose, first in man studies ¬ ¬No therapeutic intent ¬ ¬Biodistribution, pharmacokinetics, safety ¬ ¬Less pre-clinical data required ¬ ¬Resubmit as Traditional IND if successful

8.   FDA Guidance on the IND process with multiple links to other documentation: ¬ ¬http://www.fda.gov/cder/regulatory/applications/ind _page_1.htmhttp://www.fda.gov/cder/regulatory/applications/ind _page_1.htm   Comprehensive FDA Guidance Page ¬ ¬http://www.fda.gov/cder/guidance/ guidance.htm   An “how-to” guide from the Biological Development Program at NCI-Frederick with multiple links ¬ ¬http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdfhttp://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf   Schedule a pre-IND meeting Where to get information Talk to the FDA!

9. Nuts and Bolts of an IND   What data are needed   What supporting information is needed   How is the application put together   What happens when it is submitted

10. Information Required in INDs   Pharmacology/toxicology in animals   Dosimetry for radiopharmaceuticals   CMC: Chemistry, Manufacturing and Controls   Some of these data may be referenced from existing INDs or the literature   Clinical Information

11. Clinical Protocols and Investigator Information   Detailed protocol for clinical study   Qualifications of clinical investigators   Commitments ¬ ¬To obtain informed consent ¬ ¬To obtain review of the study by an institutional review board (IRB) ¬ ¬To adhere to the investigational new drug regulations

12. IND Application 1. Form 1571 (Application) 2. Table of Contents of Application 3. Introductory Statement 4. General Investigational Plan 5. Investigators’ Brochure (multi-site) 6. Protocol ¬ ¬ Study Protocol ¬ ¬ Investigator Data – Form 1572, CV

13. IND Application 7. Chemistry, Manufacturing, and Control Data 8. Pharmacology and Toxicology Data 9. Previous Human Experience 10. Additional Information. ¬ ¬Dosimetry ¬ ¬Letter from IND or DMF-holder allowing cross- reference to their files ¬ ¬Site/NCI Data and Safety Monitoring Plan ¬ ¬Cited literature

14. Practical Issues   Make it easy for multiple reviewers to find and understand the information – repeat information in different sections   Include all sections, even if empty   Comprehensive Table of Contents and TOC for any section more than a few pages   Consecutive page numbers for entire IND (can be numbered by section )   Include copies of all cited literature   Don’t assume the reviewers will be expert in your subject area

15. What happens next?   Submit 5-15 copies (ask FDA Division)   Wait 30 calendar days before beginning the first study on IND   The document goes to several reviewers   FDA reviews the IND first and foremost for risk to subjects – NOT for scientific interest   FDA may request changes ¬ ¬Safety related in protocol ¬ ¬Purity/safety related in CMC   FDA will call/fax with questions

16. Begin your investigational study in human subjects jacobsp@mail.nih.gov

17. The Next Speaker is: Dr. Anthony Shields