T HE U NIVERSITY OF N EW M EXICO ▪ H EALTH S CIENCES C ENTER
Michael Briggs, Operations Director
Human Research Protections mbriggs@salud.unm.edu
272-1147
August 2006

• General Overview of IND Types & Components
• Focus on “
– Description
– Uses
– Content
– GLP & GMP Guidance for ExpIND

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

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Pharmacological Profile Developed
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Acute Toxicity Determined in Animal Models
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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

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Active Pharmaceutical Ingredients (API)
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Description and characterization
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Manufacturer
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Synthesis/method of manufacture
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Process controls
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Specifications (list of tests, methods and acceptance criteria)
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Purity profiles
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Container/closure system for drug substance (DS) storage
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Container/closure system for drug product (DP) shelf life
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Stability

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Study Protocol
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Investigator Information/Qualifications
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IRB Data
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Facilities Data

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.

• 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

• 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).

• 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

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.

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CMC for ExpIND very similar to Traditional IND
CMC updated in “graded” fashion corresponding to the development phase as IND progresses
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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.

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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.
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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.

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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.