# Presentation: 120349

## The Exploratory IND Guidance

**“****Phase 0” Trials in Oncologic Drug Development**
**September 5, 2007**
**David Jacobson-Kram, Ph.D. DABT**
**Office of New Drugs**
**Center for Drug Evaluation and Research**
**Food and Drug Administration**

## Challenges in Improving Efficiency of Drug Development

- NME development = _**high**_ risk and cost
- Extremely high failure rate before IND
- NME IND = NDA <20% of time
- Reported >50% failure rate in Phase 3
- Decreased NME NDAs _despite_ increased INDs
- Cost per NME approved estimated at >$800M

## Number Approved

- As of 31-Aug-06*Includes the therapeutic biologic products transferred from CBER to CDER effective 10/1/2003.

**Number Approved**

**Number Filed**

## Exploratory INDs: Guidance to Industry, Investigators and Reviewers

**Draft guidance published April 2005, over 350 comments to the docket.  Final published in January 2006.**
**“****For the purposes of this guidance the phrase *****exploratory IND *****is intended to describe a clinical trial that occurs very early in phase 1, involves very limited human exposure (up to 7 days of dosing) and has no therapeutic intent.**
**Existing regulations allow flexibility of the amount of data that need to be submitted with an IND—depending on the goals of the investigation, the testing being proposed the expected risks.**
**Viewed as pavestone on the critical path.**

## Use of exploratory INDs (ExpINDs) in improving efficiency of drug development

- ExpINDs allow sponsors to evaluate up to five chemical entities or formulations simultaneously.
- When a lead compound has been selected, the ExpIND is closed and drug development proceeds along the traditional pathway.
- ExpINDs provide opportunity to study PK and target interaction early in drug development.

## Goals of expINDs

- Gain an understanding of the relationship between a specific mechanism of action and the treatment of a disease.
- Provide information on PK
- Select the most promising lead product from a group of candidates designed to interact with a particular therapeutic target.
- Explore a product’s biodistribution characteristics using various imaging technologies.

## Types of studies: microdose

- Microdose studies are designed to evaluate pharmacokinetics or imaging of specific targets and are designed **not** to induce pharmacological effects.
- A microdose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect and ≤100 micrograms.

## Microdose studies

**Potential risks to subjects very limited**
**Enabling study:**
**Single mammalian species**
**Clinical route of administration**
**Single dose, 14-day observation**
**Routine endpoints:**
**Clinical observations**
**Body weights**
**Hematology and clinical chemistries**
**Histopathology**
**Identification of minimally toxic dose or demonstration of large margin of safety (e.g. 100X)**
**Genetox not necessary**.

## Position Paper on Non-clinical Safety Studies to Support Clinical Trials with a Single MicrodoseEMEA, June 2004

- Enabling preclinical safety studies:
- General toxicology studies using two routes of administration, IV plus clinical route
- In vitro genotoxicity studies performed according to ICH guidance
- EMEA requires more data: two routes of administration and genetox studies

## Types of studies: Clinical Trials Designed to have Pharmacological Effects

- Paradigm first proposed by PhRMA in May of 2004
- Up to 5 compounds with a common biological target, not necessarily structurally related
- Up to 7 repeated doses in clinic in healthy subjects or minimally ill patients
- Goal is to achieve a pharmacological response but not an MTD
- PhRMA collected a data base on 106 drugs tested in two species and in phase 1 clinical trial to support preclinical safety paradigm

## Safety Requirements for Exploratory IND designed to produce pharmacological effects

- 14-day repeated dose tox study in rodent, full clinical and histopathology
- Safety pharmacology (cv, cns, resp) as in ICH S7A
- Bacterial mutation assay and micronucleus from 14-day study
- Repeated dose study in second species (dog) at rat NOAEL. Administrations equivalent to number of dosing days in clinical trial

## Clinical starting and stopping doses

- Start dose would be 1/50 the rat NOAEL (mg/m2). If dog shows toxicity at rat NOAEL, compound not included in exploratory IND
- Stopping dose would be whichever is lowest:
- Dose that induces pharmacological effect or target modulation
- 1⁄4 of rat NOAEL
- Dose giving 1⁄2 of AUC in rat 14 day study or dog AUC if lower than rat

## Evaluation of Pharma Dataset*

**Would starting clinical trials at a dose equivalent on a body surface area basis to 1/50 the NOAEL dose in rodents be safe?**
*Conclusion:*** Based on evaluation of 106 compounds, all trials would have been conducted safely under the expIND paradigm**
**Would it be safe to stop trials on the basis of criteria detailed in the guidance (i.e. dose, exposure, clinical effects)?**
*Conclusion:*** Based on evaluation of 100 compounds, all trials would ****	****have been conducted safely under the expIND paradigm**

- *from PhRMA presentation Jan, 2004

## expIND paradigm for a situation where both dose and AUC criteria met*

_**Experimental Data**_

**2 week rodent toxicity study**
**NOAEL dose 30 mg/kg ******** 177 mg/m****2**
**NOAEL AUC = 1970 ug.h/mL**

**Nonrodent qualification**
**177 mg/m****2**
***No findings***

**NR NOAEL Dose = 360 mg/m****2**
**                   ****AUC = 3450 ug.h/mL**

**CNS, CV, respiratory, genotoxicity**
***No findings***

**FIH Parameters**
**Starting Dose (1/50 rodent NOAEL dose) = ****	****  3.5 mg/m****2**
**Stop Dose (1/4 rodent NOAEL dose) = ****	****44 mg/m****2**
**Stop Exposure (1/2 rodent NOAEL AUC) = 985 ug.h/mL**

**Start dose = 31 mg/m****2**
**Stop dose = 555 mg/m****2 **
**Stop exposure = 4660 ug.h/mL**

_**Outcome**_
**Trial stops at 44 mg/m****2**** w/o effects. Further escalation only upon consultation with FDA.**

***from PhRMA presentation January, 2004**

## expIND paradigm for a situation where nonrodent was more sensitive*

_**Experimental Data**_

**2 week rodent toxicity study**
**NOAEL dose 2000 mg/kg**
** ******** ****11,800 mg/m****2**
**NOAEL AUC = 40 ug.h/mL**

**Nonrodent qualification 11800 mg/m****2**
***CNS, respiratory, hepatic and GI effects***

**CNS, CV, respiratory, genotoxicity**
***CV effects (QTc and HR)***

**FIH Parameters**
**Starting Dose (1/50 rodent NOAEL dose) = 236 mg/m****2**
**Stop Dose (1/4 rodent NOAEL dose) =****	****2950 mg/m****2**
**Stop Exposure (1/2 rodent NOAEL AUC) =   19.9 ug.h/mL**

***from PhRMA presentation January, 2004**

_**Outcome**_
**Toxicity in the NR at the rodent NOAEL dose either terminates the program or triggers additional studies leading in all likelihood to a conventional IND**

**NR NOAEL Dose = 60 mg/m****2**
**                   ****AUC = 1.2 ug.h/mL**

**Start dose = 0.185 mg/m****2**
**Stop dose = 31 mg/m****2**** **
**Stop exposure = 0.61 ug.h/mL**

## 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

## Viability of PhRMA-proposed paradigm

- OND has assembled results from recent submissions with 2 week or 4 week toxicology studies where the results of clinical studies are known.
- The PhRMA paradigm succeeded in identifying safe starting and stopping doses but in many cases, dog or monkey had lower NOAELs.

## Example from data base

- Drug tested in rat and dog by 14-day IV infusion
- Rat NOAEL 25 mg/kg; HED 4 mg/kg
- Dog NOAEL 5 mg/kg; HED 2.7 mg/kg
- Human start dose was 0.003 mg/kg (lower than 1/50th rat NOAEL.
- Highest dose tested in humans 1 mg/kg (1/4 rat NOAEL)
- Paradigm successful but drug would be eliminated because dog more sensitive

## MTD- Rodent Human Correlation from : Smith and Tomaszewski, Preclinical and Clinical Toxicity Correlations for Cancer  Drugs Developed by NCI. ,  2002.

- Clinical MTD (mg/m2/day)

- Rodent MTD (mg/m2/day)

**MTD- Rodent Human Correlation** from : Smith and Tomaszewski, Preclinical and Clinical Toxicity Correlations for Cancer  Drugs Developed by NCI. ,  2002.

- Non-Rodent MTD (mg/m2/day)

## NCI vision of expIND

## NCI vision for a new path for cancer drug development

- Initial clinical experience not driven by toxicity
- Pharmacological endpoints, e.g. plasma concentrations in humans
- Pharmacodynamic endpoints in surrogate or tumor tissue
- Shift in preclinical studies from toxicity to assessment of PK/PD relationships

## Facilitated IND as proposed by NCI

- Used to select promising drugs for life threatening diseases
- Clinical trial populations are terminally ill patients without therapeutic options
- Up to 3 days of dosing in clinic

## Success (or lack of) expINDs

- Only a handful of expINDs have been received by the FDA.  Those that have been received were not for purposes initially envisioned.

## Why is this tool not being used?

- New paradigm, established industry, slow to adopt.
- Microdose studies may not be predictive of pharmacological dose studies.
- Protracts the time line.
- Design to kill drugs early that are likely to fail.  No development team thinks their drug is a loser.

## New paradigms being considered in maintenance of ICH M3R, “Timing of preclinical studies in relation to clinical trials”

- Microdose: up to 5 doses each not to exceed 1/100th the NOAEL determined in the toxicology study or 1/100th the anticipated pharmacodynamically active dose or a total dose of 100 mcg which ever is lower.

## New paradigms being considered in maintenance of ICH M3R, “Timing of preclinical studies in relation to clinical trials”

- Microdose: up to 5 doses of 100mcg each not to exceed 1/100th the NOAEL determined in the toxicology study or 1/100th the anticipated pharmacodynamically active dose and with a washout of 6 half-lives between doses.

## New paradigms being considered in maintenance of ICH M3R, “Timing of preclinical studies in relation to clinical trials”

- Repeat dose exploratory studies up to    14 days in the therapeutic range but not to an MTD.
- Supported by safety studies using large multiples of clinical exposure but not based on toxicity.

## 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  or different than for conventional INDs.**
**Reduction in safety data requirements will be scaled to the goals, duration and scope of the proposed clinical trials.**

## The Next Speaker is:Dr. Joseph Tomaszewski

- The Next Speaker is:Dr. Joseph Tomaszewski