1. Food and Drug Administration Preclinical safety data for “first in human” (FIH) clinical trials in healthy volunteer subjects Oncology Drug Advisory Committee David Jacobson-Kram, Ph.D. DABT Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration March 13, 2006

2. Food and Drug Administration What preclinical safety data are required prior to giving a new chemical to human beings for the first time – and why  Most phase 1 studies are performed in healthy volunteers. No risk vs. benefit calculation, only risk assessment.

3. Food and Drug Administration Preclinical studies define potential toxicities  What is initial safe starting dose?  What is a safe stopping dose?  What organs/systems are at risk?  Are toxicities monitorable in the clinic?  Are toxicities reversible?  Is the chemical potentially carcinogenic?

4. Food and Drug Administration  Toxicity studies in two species (rat, dog for small molecules, often nonhuman primate for biologics) with the highest dose demonstrating a “maximum tolerated dose” (MTD) and a lower dose demonstrating a “no adverse effect level” (NOAEL).  Single dose clinical study can be supported by single dose animal studies.  Animals dosed once and sacrificed early (24 – 48 hours) and second group after 14 days. Minimal data set to begin a phase 1 clinical trial in healthy volunteers

5. Food and Drug Administration Minimal data set to begin a phase 1 clinical trial in healthy volunteers  Repeat dose toxicity study is more efficient and cost effective (14 – 28 days).  Enables repeat dose clinical trials  Fewer animals are used, but more drug.  Inclusion of recovery group is useful in case toxicities are seen.

6. Food and Drug Administration Typical endpoints in toxicology study: in-life  Clinical signs, behavior  Food consumption  Body weights  Clinical pathology (in larger species)

7. Food and Drug Administration Typical endpoints in toxicology study: post-life  Macroscopic observation at necropsy  Organ weights  Clinical pathology  Hematology  Clinical chemistries  Histopathology, all organs  Toxicokinetics

8. Food and Drug Administration Safety pharmacology  Cardiovascular (non rodent)  Blood pressure  Heart rate  ECGs Rhythm and morphology Arrhythmia analysis Interval analysis including QT interval calculation

9. Food and Drug Administration Safety pharmacology  CNS (rodent functional observation battery, Irwin test)  Spontaneous locomotor activity  Motor coordination  Proconvulsive effects  Analgesic effects  Pulmonary (rodent, plethysmography)  Minute volume  Tidal volume  Respiratory rate

10. Food and Drug Administration Genetic toxicology  Bacterial reverse mutation assay (Ames test, measures induction of point mutations e.g. base substitution, frame shifts)  In vitro assay for chromosomal damage in cultured mammalian cells (metaphase cell analysis or mouse lymphoma gene mutation assay).  In vivo test for chromosomal damage (rodent micronucleus test, not required but often performed).

11. Food and Drug Administration Exploratory INDs Exploratory IND Used to select drug candidate Exp IND closed, Traditional IND opened NDA or BLA

12. Food and Drug Administration Exploratory INDs (expIND)  January 06 FDA published guidance on expIND.  expIND intended to make drug development more efficient by expediting early phase 1 clinical trials  Gain an understanding between a specific mechanism of action and the potential treatment of a disease  Provide information on PK  Select the most promising lead candidate from a group designed to interact with a specific human target, e.g., imaging studies

13. Food and Drug Administration Exploratory INDs (expIND)  Clinical studies have no therapeutic intent, this is simply a method for choosing the most promising drug candidate  When a lead compound is selected, the expIND is closed and the drug development proceeds along the traditional pathway.

14. Food and Drug Administration Use of exploratory INDs (ExpINDs) in improving efficiency of drug development  “The toxicology evaluation recommended for an exploratory IND application is more limited than for a traditional IND application. The basis for the reduced preclinical package lies in the reduced scope of an exploratory IND clinical study.“

15. Food and Drug Administration The expIND will accelerate discovery and development of new pharmaceutical agents* Conventional INDexpIND API1 – 3 Kg 10 - 300 g Preclinical Resources  9 – 12 studies  220 rodent and 38 NR  9 – 18 months  5 – 6 studies  170 rodent and 6 NR  3 – 6 months Benefits  Full toxicology profile  Escalation to MTD in clinical trials  Progression directly to Ph 2  Predictable API requirement  Faster progression to clinical trials  Capability to evaluate candidates based on target activity  Better development decisions made more quickly  Early and less costly attrition *PhRMA presentation January 2004

16. Food and Drug Administration The expIND will accelerate discovery and development of new pharmaceutical agents* Conventional INDexpIND Disadvantages  Larger quantity of API  Slower decisions  Late and costly attrition  Potential delayed progression to Phase 2  MTD not established *PhRMA presentation January 2004

17. Food and Drug Administration Bottom Line  CDER sees implementation of an exploratory IND guidance as an important part of FDA’s commitment to improving the “critical path” to new medical products.  The amount of preclinical safety data required for expINDs will generally be less than for conventional INDs.  Reduction in safety data requirements will be scaled to the goals, duration and scope of the proposed clinical trials.