# Presentation: 875939

## 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

## 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.

## 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?

## 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.

- 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

## 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.

## Typical endpoints in toxicology study: in-life

- Clinical signs, behavior
- Food consumption
- Body weights
- Clinical pathology (in larger species)

## Typical endpoints in toxicology study: post-life

- Macroscopic observation at necropsy
- Organ weights
- Clinical pathology
- Hematology
- Clinical chemistries
- Histopathology, all organs
- Toxicokinetics

## Safety pharmacology

- Cardiovascular (non rodent)
- Blood pressure
- Heart rate
- ECGs
- Rhythm and morphology
- Arrhythmia analysis
- Interval analysis including QT interval calculation

## 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

## 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).

## Exploratory INDs 

- Exploratory IND
- Used to select drug candidate

- Exp IND closed, Traditional IND opened

- NDA or BLA

## 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

## 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.

## 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.“

## The expIND will accelerate discovery and development of new pharmaceutical agents*

|  | Conventional IND | expIND |
| --- | --- | --- |
| API | 1 – 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

## The expIND will accelerate discovery and development of new pharmaceutical agents*

|  | Conventional IND | expIND |
| --- | --- | --- |
|  |  |  |
| Disadvantages | Larger quantity of API
Slower decisions
Late and costly attrition | Potential delayed progression to Phase 2
MTD not established |

- *PhRMA presentation January 2004

## 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.**