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Transitioning from Microdose Exploratory IND to Traditional IND:

Division of Medical Imaging Products Perspectives

Siham Biade, PharmD., Ph.D.Pharmacology/Toxicology Reviewer

Division of Medical Imaging ProductsCDER/FDA

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Presentation Outline

• Definition of exploratory IND study

• Exploratory IND Guidance

• Scope of eINDs

• eIND: Preclinical Requirements

• Closure/withdrawal of eIND

• Commonly Asked Questions

• Conclusions

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Definition of eIND studyGuidance for Industry, Investigators, and Reviewers—

Exploratory IND Studies (Jan 2006)The phrase exploratory IND study is intended to describe a

clinical trial that

•

is conducted early in phase 1•

involves very limited human exposure

•

has no therapeutic or diagnostic intent (e.g., screening studies, microdose studies)

•

is not designed to establish maximally tolerated doses.

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Objectives of eIND Studies•

Evaluate mechanism of action

•

Explore product characteristics through imaging technologies

•

Obtain PK information

•

Identify lead candidate

•

Characterize new therapeutic targets

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Intent of eIND

•

Accelerate timeline to first in human•

Reduce cost and time to approval

•

Facilitate basic research programs•

However,–

Potential to protract the process especially if a candidate was already selected

–

eIND

works best in weeding out candidates destined to fail

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Microdose ApproachesTwo different microdose approachesICH M3 Guidance for Industry Microdose Trials (7.1)

• ≤

a total dose of 100 ug

administered as a

single dose or divided doses –

No inter-dose interval limitations

• ≤

5 administrations of a maximum of 100 ug

per administration (total of 500 ug

per subject)–

Washout between doses (≥

actual or predicted

half lives)

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eIND Microdose Study Preclinical Requirements

Reduced risk Reduced preclinical requirements

•

Extended single dose toxicity study in 1 species when ≤

100 ug

as a single dose or divided doses

OR•

One 7-day repeated-dose toxicity study in 1 species

when ≤

5 administrations of a maximum of 100 ug per administration (total of 500 ug

per subject)

•

Genetic toxicology testing not needed•

Safety pharmacology studies not recommended

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Closure/Withdrawal of eIND•

eIND objective(s) met

•

eIND Guidance for Industry–

“The eIND is intended to be withdrawn after completion of the outlined study or studies. The withdrawn or inactive IND can be referenced in any subsequent traditional IND”

–

“The closure of eIND is to be followed by opening of traditional IND”

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Commonly Asked Questions (1)Q: What constitutes “Very limited human

exposure” ?

A: The Guidances are silent on this point.

–

For Division of Medical Imaging Products, very limited human exposure refers to approximately 40 subjects

–

Some objectives have been completed with fewer than 10 subjects

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Commonly Asked Questions (2)

Q: I want to increase the number of subjects in my current eIND study; do I need to close the eIND and open a traditional IND?

A: It depends.•

A sponsor may be allowed to increase the number of subjects in the current eIND

•

Request should be submitted/discussed with DMIP•

Determination made on a case by case basis

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Commonly Asked Questions (3)Q: I want to close my eIND and open a

traditional IND; do I need to conduct new animal studies and follow the Medical Imaging Guidance with respect to preclinical requirements?

A: It depends.–

Flexibility in interpretation (eIND, full IND)

–

Available information must be adequate to support further human studies.

–

Case-by-case science-driven decisions–

Nonclinical studies may be waived per justified request [21 CFR 312.10]

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Commonly Asked Questions (4)Q: I want to close my eIND and open a

traditional IND; do I need to conduct genetic toxicology studies for microdose trials?

A: No.–

“Because microdose studies involve only single exposures to microgram quantities of test materials and because such exposures are comparable to routine environmental exposures, routine genetic toxicology testing is not needed”.

–

Consider the presence of a radioactive isotope in genetic risk evaluation

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Commonly Asked Questions (5)

Q: I want to close my eIND and open a traditional IND; do I need to conduct safety pharmacology studies?

A: It depends.–

“For similar reasons, safety pharmacology studies are also not recommended.”

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Commonly Asked Questions (6)

Q: Do I need to conduct reproductive toxicology for radiopharmaceuticals?

A: It depends.–

These studies can be and are often waived.

–

Population studied, indication sought, etc..–

Consider the presence of a radioactive isotope in benefit/risk evaluation

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Commonly Asked Questions (7)

Q: Are carcinogenicity studies required for medical imaging agents?

A: No.–

Duration, dosing frequency.

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Commonly Asked Questions (8)

Q: I want to close my eIND. Can I continue collecting (safety) data in subjects enrolled in the eIND study after I close it?

A: No.–

Once the IND is closed, the clinical study is considered closed as well.

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Conclusions

•

Several developmental pathways available–

eINDs (screening of several compounds), full INDs

•

Regulations allow a great deal of flexibility•

Case by case approach

•

FDA committed to facilitating the preclinical development of new radiopharmaceuticals

•

Early interaction sponsor/FDA for better planning

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Adebayo A. Laniyonu

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Division of Medical Imaging Products

Project Management Staff(1) 301-796-2050