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THE UNIVERSITY OF NEW MEXICO ▪ HEALTH SCIENCES CENTER
Exploratory IND Studies
Michael Briggs, Operations Director
Human Research Protections
[email protected]
272-1147
August 2006
Topics
• General Overview of IND Types & Components
• Focus on “Exploratory IND”
– Description
– Uses
– Content
– GLP & GMP Guidance for ExpIND
IND Applications
1. Investigator IND (Traditional)
2. Exploratory IND (‘Phase Zero’)
–
–
Conducted early in Phase 1
No therapeutic or diagnostic intent
3. Emergency Use
–
Use of experimental drug in emergency situation – no
time for IND
4. Treatment IND
–
For use in serious/life threatening cases pending final
clinical work
IND Components
1. Pre-Clinical Data
2. Chemistry, Manufacturing, and Controls
(CMC)
3. Clinical Development Plan
1. Pre-Clinical Data
· Pharmacological Profile Developed
· Acute Toxicity Determined in Animal Models
· Short Term toxicity studies conducted
Existing
Non-clinical Data
In-vitro or Animal
Studies
Data from previous
clincial testing/
Marketing of drug
New Pre-Clinical
Studies
2. Chemistry, Manufacturing, & Controls (CMC)
·
Active Pharmaceutical Ingredients (API)
·
Description and characterization
·
Manufacturer
·
Synthesis/method of manufacture
·
Process controls
·
Specifications (list of tests, methods and acceptance criteria)
·
Purity profiles
·
Container/closure system for drug substance (DS) storage
·
Container/closure system for drug product (DP) shelf life
·
Stability
3. Clinical Development Plan
·
Study Protocol
·
Investigator Information/Qualifications
·
IRB Data
·
Facilities Data
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.
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
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).
ExpIND Content
•
Pharmacology & Toxicology Information
Depending on type of study (3 examples)
1. Pharmacokinetic or imaging studies (“Microdose”)
2. Pharmacological Studies
3. Mechanism of action related to efficacy
•
CMC Information
•
Clinical Development Plan Information
Pharmacology & Toxicology Information
1. 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
2.
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.
3.
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.
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.
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.
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.
Questions…