511.1(b)(4) NCIE for clinical investigations

CENTER FOR VETERINARY MEDICINE
PROGRAM POLICY AND PROCEDURES MANUAL

1243.4066

OFFICE OF NEW ANIMAL DRUG EVALUATION REVIEWER’S CHAPTER

NOTICE OF CLAIMED INVESTIGATIONAL EXEMPTION (NCIE)
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
I.

Purpose ............................................................................ 1
What is an NCIE and for what studies are they appropriate? .... 1
How we use NCIEs ............................................................. 2
Timing for Submission of an NCIE ........................................ 3
How do we review an NCIE? ................................................ 3
Final Actions ...................................................................... 4
References ........................................................................ 4
Version history................................................................... 5

Purpose
This document:

II.

·

Describes an NCIE

·

Describes the types of studies that require sponsors to submit NCIEs

·

Specifies what information should be included in the NCIE

·

Identifies when we should receive an NCIE relative to the shipment of a new
animal drug for investigational use

·

Describes how we use the information in an NCIE

·

Describes how we review an NCIE submission

What is an NCIE and for what studies are they appropriate?
An NCIE, also known as a drug shipment notice, is a written notification to FDA
of a sponsor’s intent to ship an investigational new animal drug (INAD), including
animal feed containing or bearing a new animal drug, for use in clinical
investigations intended to support approval of a new animal drug. The INAD
regulations (21 CFR 511.1(b)(4) for clinical studies describe the requirements for
submitting an NCIE. An NCIE is coded as a “B” submission in STARS
(Submission Tracking and Reporting System).

Responsible Office: Office Of New Animal Drug Evaluation
Date: October 9, 2014

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We require NCIEs for clinical (i.e., effectiveness) studies intended to support
substantial evidence of effectiveness, including but not limited to studies in the
target species, laboratory studies, field studies, bioequivalence studies
(excluding dissolution studies) and in vitro studies.1 This requirement includes;
·

the importation of investigational new animal drugs shipped directly to
researchers responsible for clinical investigational use in animals.2

·

exportation of investigational new animal drugs for use in clinical studies
intended to support approval of a new animal drug in United States

·

nonclinical laboratory study(ies) under any investigational file (including
generic investigational new animal drug (JINAD) file) for the purpose of
evaluating safety in food-producing animals when the edible products from
these animals are intended for human food or animal feed use3

·

studies conducted in client-owned companion animals

Sponsors are not required to submit NCIEs for non-clinical studies. Sometimes
we receive NCIEs for drug shipment for studies such as in vitro trials where
animals are not used and in other non-clinical studies. See section V for
information on reviewing such NCIEs. Refer to the Appendix for information that
should be submitted by the sponsor in the NCIE when submitted in paper.
III.

How we use NCIEs
The NCIE provides us with information primarily about studies conducted to
support substantial evidence of effectiveness. NCIEs are used by the target
animal review divisions for a variety of purposes including to:
·
·
·
·

·
·
·
·

keep track of how much drug is shipped, where and when,
be informed when studies start,
initiate Bioresearch Monitoring (BIMO) requests,
monitor whether the sponsor unduly prolongs investigation or distribution,
or engages in commercial distribution, or test marketing of the
investigational new animal drug
monitor activity under the investigational exemption
monitor food use authorizations,
monitor movement of genetically engineered animals or products derived
from them, and
be aware of studies conducted in client-owned animals.

1

21 CFR 514.4(a)
See 21 CFR 511.1(b)(9) and P&P 1243.4065, Requirements for Investigational New Animal Drug
Exemptions
3
In such cases, a food-use authorization is required (P&P 1243.4040).
Responsible Office: Office Of New Animal Drug Evaluation
Date: October 9, 2014
2

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IV.

Timing for Submission of an NCIE
As stated in 21 CFR 511.1(b)(4), the INAD regulations require that sponsors
submit the NCIE prior to shipment of the investigational new animal drug. The
regulations require submission of the NCIE prior to and not concurrent with or
after shipment.

V.

How do we review an NCIE?
NCIEs are submitted to CVM electronically using FDA’s e-submitter tool or under
a cover letter in paper. An NCIE is coded as a “B” submission in STARS. Upon
receipt of the NCIE, determine if the sponsor has submitted either a claim for a
categorical exclusion or an environmental assessment (X submission) for the
INAD or JINAD file. If neither one is found in our STARS, contact the sponsor
and remind them that under 21 CFR 511.1(b)(10) they must submit one of these
in order to maintain an investigational exemption.4 Review any NCIE that you
receive from the sponsor, regardless of whether it was required to be submitted.
Check the submission and shipment dates to determine if the sponsor submitted
the NCIE prior to shipment. When we find that sponsors have not submitted the
required NCIEs, or if they submitted NCIEs after the initiation of investigations,
contact the sponsor via telephone or email to remind them of their
responsibilities under the 21 CFR 511.1(b)(4) for submitting NCIEs prior to
shipment of new animal drugs for investigational use. Record these
communications in either the review summary field in STARS or the review
documentation you prepare for the NCIE. For subsequent occurrences (either in
the same (J)INAD file or across multiple (J)INAD files for that sponsor), discuss
with your team leader the need to send an acknowledgment letter to the sponsor
that they must submit their NCIEs prior to shipment of investigational new
animal drugs.5
In your review of an NCIE, check for completeness and accuracy and compare it
to the regulations (21 CFR 511.1(b)). Confirm that the use of the drug outlined
in the NCIE is consistent with the proposed indications of use and target animals
and any other limitations of the (J)INAD file. It may be appropriate to compare
the NCIE with other information in the (J)INAD file, such as:

4
5

·

A-0000 submission

·

Food use authorizations

·

Protocols

P&P 1243.4065, Requirements for Investigational New Animal Drug Exemptions
See P&P 1243.4065.

Responsible Office: Office Of New Animal Drug Evaluation
Date: October 9, 2014

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·

Other submissions to the (J)INAD file

·

Our reviews of these submissions

Apply other division or team specific procedures for review of NCIEs as required.
For example, the division or team may use an NCIE as a prompt to request an
inspection under our BIMO program.
If you detect errors in a sponsor’s NCIE (i.e., information required by 21 CFR
511.1(b)(4) is missing, or information in the NCIE contradicts information
contained in the (J)INAD file), contact the sponsor via telephone or email to
request the corrections, and record these communications in the review
documentation. If necessary, request a revised NCIE (a new B submission) to
correct significant errors. For subsequent incorrect submissions (either in the
same (J)INAD file or across multiple (J)INAD files for that sponsor), discuss with
your team leader the need to send an acknowledgment letter to the sponsor
requesting corrective action.
VI.

Final Actions
Appropriate final actions for NCIEs include:6
·

submission filed with NO review documentation; no letter sent (FNR)

·

submission filed with review documentation; no letter sent (FNR w/memo)

·

submission reviewed; letter sent (acknowledgment letter)

In most instances, you may use the FNR final action for NCIEs. Use the FNR
w/memo final action where your division or team procedures dictate, or to
document communications between you and sponsors for correction of errors
detected in NCIEs. Though used infrequently, issuing an acknowledgment letter
to sponsors who repeatedly submit incorrect NCIEs may be warranted.
VII.

References
CVM Program Policy and Procedures Manual
1243.3030 – Completing Final Action Packages for STARS Submissions
1243.4040 – Investigational Food-Use Authorization: The Role of the Primary
(AA) Review Divisions
1243.4065 – Requirements for Investigational New Animal Drug Exemptions

6
P&P 1243.3030, Completing Final Action Packages for STARS Submissions
Responsible Office: Office Of New Animal Drug Evaluation
Date: October 9, 2014

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VIII. Version history
March 31, 2009 – Original version
April 3, 2009 – Revised to clarify that when nonclinical laboratory safety studies
use food-producing animals and the sponsor intends to use the edible products
for human food or animal feed a food-use authorization is required.
May 28, 2010 – The document has been rearranged and the information has
been updated to reflect current ONADE processes.
October 9, 2014 – The document has been updated to reflect the electronic
process.

Responsible Office: Office Of New Animal Drug Evaluation
Date: October 9, 2014

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Appendix: Information to Include in
Notice of Claimed Investigational Exemption (NCIE)
Submission Information
Date:
Document Type (INAD or JINAD):
Document Number:
Firm Information
Are you a US company? (Yes/No)
Firm Name:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone number:
Fax number:
D&B D-U-N-S Number:
U.S. Agent Information (to be completed if the firm is not a US company)
Contact Name:
Occupation Title:
Email Address:
Firm Name:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone number:
Fax number:
D&B D-U-N-S Number:
Responsible Official Information (to be completed if the firm is a US company)
Contact Name:
Occupation Title:
Email Address:
Firm Name:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone number:
Appendix: Information to Include in
Notice of Claimed Investigational Exemption (NCIE)

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Fax number:
D&B D-U-N-S Number:

Is this an amendment to pending information that was previously submitted to
CVM?(Yes/No)
If Yes, provide the submission number and identify the amended information. If
No, provide the rest of the information requested below.
General Information
Study/ Trial ID:
Drug Shipment Number:
Is this Notice of Claimed Investigational Exemption (NCIE) in relation to:
(Shipment/Receipt)
Is this an IMPORT? (Yes/No)
Is this going directly to an investigator or institution where the research will be
conducted? (Yes/No)
Type of Shipment: (Initial, Supplemental, or Corrected)
If Supplemental, Reason for Supplemental:
If Corrected, Instructions for Corrected:
Product Description
Established Name (list all active pharmaceutical ingredients):
Proprietary Name, if available:
Total Quantity (Weight or Volume) and Concentration of Drug(s) Shipped or Received:
Proposed Use:
Proposed Dose & Duration:
Dosage form:
Route of Administration:
Type and Number of Animals
Common Animal Name:
Production Class (if applicable):
Size and Type of Animals:
Approximate Number of Animals in this study/ trial:
Treated:
Control:
Total:
Shipment or Receipt Information
Date of Drug Shipment or Receipt:
Type of Study/ Trial:
Is this Study or Trial intended to support a technical section or (A)NADA submission?
(Yes/No)
Appendix: Information to Include in
Notice of Claimed Investigational Exemption (NCIE)

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Investigator Information
Investigator Name:
Occupation Title:
Email Address:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone Number:
Study/Trial Information
Approximate date(s) of study/ trial:
Start:
Finish:
Was a Protocol for the study/ trial previously submitted to CVM? (Yes/No)
If Yes, provide CVM Submission Number:
Location of Study/ Trial Information:
Firm Name:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone Number:
Fax Number:
Study Monitor Information
Study Monitor Name:
Occupation Title:
Email address:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone Number:
CRO Information
Was a Contract Research Organization (CRO) used? (Yes/No)
If Yes, enter CRO information below
Appendix: Information to Include in
Notice of Claimed Investigational Exemption (NCIE)

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Firm Name:
Address Line 1:
Address Line 2:
City:
State, Province, or Territory:
Post Office or Zip Code:
Country:
Telephone Number:
Fax Number:
D&B D-U-N-S Number:
Description of obligations transferred to CRO:
Animals Intended for Use in Food
Are animals intended for use as human food? (Yes/No)
Do you have a food use authorization? (Yes/No)
If Yes, provide the CVM Submission Number:
Has a food use authorization request been submitted? (Yes/No)
If Yes, provide the Correspondence Date:
NOTIFICATION WAIVER: A waiver of requirements for notification of the date and place
of slaughter, following the required withdrawal period had been granted by the FDA
(Yes/No)
If Yes, provide the CVM Submission Number:
Investigational New Animal Drug Labeling
Please select the labeling text that will be used on your investigational new animal
drug:
o New animal drugs for tests in vitro and in laboratory research: Caution.
Contains a new animal drug for investigational use only in laboratory research
animals or for tests in vitro. Not for use in humans.
o

New animal drugs for clinical investigation: Caution. Contains a new animal
drug for use only in investigational animals in clinical trials. Not for use in
humans. Edible products of investigational animals are not to be used for food
unless authorization has been granted by the U.S. Food and Drug
Administration or by the U.S. Department of Agriculture.

o

New animal drugs for EXPORT: Caution. Contains a new animal drug for use
only in investigational clinical trials. Not for use in humans. Edible products from
animals used for investigation are not to be used for food in any manner
contrary to the requirements of the country in which the clinical trials are to be
conducted.

Comments
If you have additional comments that you would like to include in this submission,
please add them below.
Appendix: Information to Include in
Notice of Claimed Investigational Exemption (NCIE)

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