1. Exploratory IND Studies
THE UNIVERSITY OF NEW MEXICO ▪ HEALTH SCIENCES CENTER
Exploratory IND Studies
Michael Briggs, Operations Director
Human Research Protections
August 2006

2. Topics General Overview of IND Types & Components
Focus on “Exploratory IND”
Description
Uses
Content
GLP & GMP Guidance for ExpIND

3. IND Applications Investigator IND (Traditional)
Exploratory IND (‘Phase Zero’)
Conducted early in Phase 1
No therapeutic or diagnostic intent
Emergency Use
Use of experimental drug in emergency situation – no time for IND
Treatment IND
For use in serious/life threatening cases pending final clinical work

4. IND Components Pre-Clinical Data
Chemistry, Manufacturing, and Controls (CMC)
Clinical Development Plan

5. 1. Pre-Clinical Data

6. 2. Chemistry, Manufacturing, & Controls (CMC)

7. 3. Clinical Development Plan

8. Exploratory IND
Clinical exploratory approach to enable sponsors to more efficiently identify and develop promising compounds under an IND, based on a more limited preclinical data set than that required for a traditional Phase 1 study.

9. Exploratory IND Study…
is conducted very early in Phase 1 (often referred to as “Phase Zero”)
is conducted prior to the traditional dose escalation, safety, and tolerance studies
involves very limited human exposure (7 days)
has no therapeutic intent

10. Uses for ExpIND
Obtaining information on pharmacokinetics, including biodistribution
Exploring a product’s biodistribution characteristics using imaging technologies
Selecting the most promising lead product from a group of candidates designed to interact with a particular therapeutic target
Understanding the relationship between a MOA and the treatment of a disease. (e.g., binding to target or enzyme inhibition).

11. ExpIND Content Pharmacology & Toxicology Information CMC Information
Depending on type of study (3 examples)
Pharmacokinetic or imaging studies (“Microdose”)
Pharmacological Studies
Mechanism of action related to efficacy
CMC Information
Clinical Development Plan Information

12. Pharmacology & Toxicology Information
Pharmacokinetic or imaging studies (“Microdose”)
Most drug candidates are dropped during development due to PK properties or ADME characteristics. Consequently, attrition rates can be increased by evaluating the PK properties of the compounds at the earliest possible stage.
In-vitro
Animals
Human
In silco (high-throughput screening emerging for very early prediction of PK properties)
Microdosing allows the evaluation of PK properties in humans, prior to setting up the standard Phase 1 single and repeated escalating dose studies.
Abbreviated pre-clinical:
NOAEL/Dose-Response
Single Dose Toxicity (14 d, single species)
Repeat Dose Toxicity (repeat dosing “ok” if separated by 1 week)
Safety Pharmacology
Genotoxitiy
Carcinogenicity
Local Tolerance
Not required for ExpIND

13. Pharmacological Studies
Require more extensive pre-clinical safety data, because they are intended to select a safe starting dose (and maximum dose) for a clinical study.
May include data from a “2-week repeat dose toxicology study in a sensitive species accompanied by toxicokinetic evaluations”
Candidates should be evaluated for safety pharmacology and genotoxicity.

14. Mechanism of action related to efficacy
Alternate or modified pharmacological and toxicology studies to select clinical starting doses and dose escalation schemes are acceptable.
Short-term, modified toxicology or safety studies in two animal species based on a dosing strategy to achieve a clinical pharmacodynamic endpoint can serve as the basis for selecting the safe clinical starting dose for a new candidate drug.
E.g., If the degree of saturation of a receptor or the inhibition of an enzyme were considered possibly related to effectiveness, this parameter would be characterized and determined in the animal study and then used as an endpoint in subsequent clinical investigation.

15. CMC Information CMC for ExpIND very similar to Traditional IND
CMC updated in “graded” fashion corresponding to the development phase as IND progresses
Include a summary report of the specific compound or group of compounds to be studied that includes, for example, a physical and chemical description of the compound, the grade, and quality of manufacturing excipients and product components, and stability data.
If drug from a particular batch that was used in nonclinical toxicology studies is to be used in the clinical setting, FDA will consider the material to be qualified for human use based on the general CMC info included in ExpIND.
However, if the compound used in the nonclinical studies is not the same material that will be used in humans, applicants should provide certain analytical testing data demonstrating that material is representative of drug from batches used in nonclinical toxicology studies.

16. Clinical Development Plan Information
Because studies to be conducted under and ExpIND focus on a limited study or group of studies necessary to identify and further develop a promising compound, applicants must articulate a rationale for selecting the compound rather than providing a more detailed development plan.
Single-and multiple-dose studies are two potentially useful study designs
Single-dose studies could include the administration of a sub-pharmacologic of a compound to a limited number of subjects to collect pharmacokinetic info and/or perform imaging studies, or pharmacologic dose to collect in formation on pharmacological effects.
Dose escalation studies should be designed to investigate a pharmacodynamic endpoint, rather than to determine tolerability limits (typically performed under a traditional IND.

17. GLP & cGMP for ExpIND
FDA expects that all preclinical safety studies supporting an ExpIND will be performed with Good Laboratory Practices (GLP)
FDA final rule on cGMP is intended to streamline and accelerate the drug development process while ensuring the safety and quality of the earliest stage investigational drug products.
The production of investigational new drug products for use in Phase 1 studies conducted under an IND is exempt from cGMP 21 CFR 211.
FDA Guidance provides for the flexibility to allow producers to implement controls appropriate for their specific situation and application… based on a risk assessment for the product and manufacturing process.
FDA will exercise oversight of the production of investigational Phase 1 drugs under the agencies general statutory cGMP authority to ensure that these drugs are produced under conditions sufficient to ensure their safety, identity, strength, quality and purity.
Note: Seek guidance from M.Briggs relating to GMP/GLP issues when planning IND study.

18. Questions…