Reporting: NAD for Investigational Use

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.
IX.
X.
XI.
XII.
I.

Purpose ...........................................................................................................................1
Definition of an NCIE .......................................................................................................1
Studies for which an NICE is required .............................................................................2
Studies and shipments for which an NICE is not required................................................3
Importing an investigational drug for conducting clinical investigations ............................3
Timing for submission of an NCIE ...................................................................................4
How we use an NCIE ......................................................................................................4
How we review an NCIE ..................................................................................................4
Final actions ....................................................................................................................5
Correcting NICE omissions and errors.............................................................................6
References ......................................................................................................................6
Version history.................................................................................................................6
PURPOSE
This document describes:

II.

•

an NCIE;

•

the types of studies that require sponsors to submit NCIEs, and when NCIEs are not
required;

•

how to correct errors or omissions in an NCIE;

•

when we should receive an NCIE relative to the shipment of a new animal drug;

•

the notification process if a sponsor is importing a new animal drug for use in clinical
studies; and

•

how we review and use the information in an NCIE.

DEFINITION OF AN NCIE
An NCIE, also known as a drug shipment notice, is a written notification to FDA under
their investigational new animal drug (INAD) file of a sponsor’s intent to ship an
investigational new animal drug, including animal feed containing or bearing a new
animal drug, and animal biotechnology products1 (including animals containing intentional
genomic alterations (IGAs), and animal cell- and tissue-based products (ACTPs)) for use
in clinical investigations intended to support approval of a new animal drug. The INAD
regulations for clinical studies (21 CFR 511.1(b)) describe the information that must be
submitted in an NCIE. An NCIE is coded as a B submission in the Submission Tracking
and Reporting System (STARS).

1

For additional information about reviewing shipping information for animal biotechnology products, see DABCT SOP
1243.106.001 or the appropriate DABCT Team Leader (TL).
Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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III.

STUDIES FOR WHICH AN NICE IS REQUIRED
Studies that fall under 21 CFR 511.1(b), new animal drugs for clinical investigation in
animals, require the submission of an NCIE. If a study meets any criteria below, then the
study is considered a clinical investigation and an NCIE is required. This requirement
pertains to domestic and international shipments, including shipment from one foreign
site to another, and both the importation and exportation of investigational drugs for use
in clinical studies intended to support approval in the United States. This requirement also
applies to shipment of approved products being used as the investigational drug.
An NCIE may be needed before the collection of real-world data or evidence from
approved drugs, depending on the specific situation. Consult with ONADE's Policy Team,
as needed, to address questions about NCIE requirements in these cases.
A. Animal Studies Conducted for the Effectiveness Technical Section under an
INAD or in a New Animal Drug Application (NADA). 2
NCIEs are required for effectiveness studies conducted to support dosage
characterization, or to establish substantial evidence of effectiveness or reasonable
expectation of effectiveness if pursuing conditional approval. These studies may
include, but are not limited to:
•

field studies;

•

laboratory studies;

•

bioequivalence studies (excluding dissolution studies); and

•

in vitro studies.

B. Other Studies in Client-Owned Companion Animals
NCIEs are required for any study(ies) conducted in client-owned companion animals
under an INAD file (e.g., pilot study in pet dogs). While pets are generally considered
client-owned animals, not all client-owned animals are pets. Working and racing
horses and dogs are generally considered client-owned animals. For the purpose of
NCIEs, the incorporation of shelter-housed animals or purpose-bought animals into
field effectiveness studies generally follow the same recommendations as clientowned animals.
C. Other Studies in Animals Whose Products Will Enter the Food Supply
NCIEs are required for all studies under any investigational file (including generic
investigational new animal drug (JINAD) files) in food-producing animals when the
products from these animals are intended for human food use.3

2

All pivotal effectiveness studies require NCIEs. NCIEs may also be required for pilot effectiveness studies. Some pilot
effectiveness studies are covered by Sections III-B, III-C and III-D of this P&P. The target animal division determines when NCIEs
are needed for other pilot studies.

3

An investigational food-use authorization must be granted before edible products from treated food-producing animals may be
used as human food (21 CFR 511.1(b)(5)).

Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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D. Other Studies Conducted with an IGA or ACTP
NCIEs are required for all shipments under an INAD of an IGA or ACTP.
IV.

STUDIES AND SHIPMENTS FOR WHICH AN NICE IS NOT REQUIRED
Below are examples of when NCIEs are not required:

V.

•

approved drug used as a control in a clinical study;

•

an exploratory or early effectiveness study, conducted in laboratory animals and in a
laboratory setting, that is not intended to support dosage characterization or any label
statement. In general, if an INAD is not established or needed to conduct the study
(e.g., laboratory studies in early product development, laboratory studies where the
sponsor has not determined the final molecule) and the study is not intended to
support approval of a specific product (e.g., dosing, labeling, etc.), then NCIEs are not
required. These studies may be considered under 21 CFR 511.1(a) - tests in vitro and
in laboratory research animals;

•

shipment of the investigational drug to an intermediary site, such as a Contract
Research Organization (CRO) (an NCIE will be required for the shipment from the
intermediary site to the site conducting the study);

•

shipment of the active pharmaceutical ingredient (API) to the site where the
investigational drug will be manufactured; and

•

studies to support generic drugs (JINAD), with one exception. CVM has updated the
policy on NCIEs regarding bioequivalence studies to support generic new animal drug
approvals. Generic drug sponsors are no longer required to submit NCIEs for
bioequivalence or any other studies intended to support approval, except when an
investigational food-use authorization is requested, as outlined in Section III.C.

IMPORTING AN INVESTIGATIONAL DRUG FOR CONDUCTING CLINICAL
INVESTIGATIONS
If a sponsor is importing the investigational drug directly to the site conducting the clinical
investigations, they only need to submit an NCIE.
If a sponsor is importing an investigational drug to an intermediary, then the sponsor must
notify us of the shipment in a notification of import (G submission) under the INAD file,
followed by an NCIE (B submission) for shipment to the site conducting the clinical
investigations. A notification of import should include the following:
•

name and proposed use of drug;

•

destination of the shipment (name and address);

•

name and address of distributor, broker, or agent through whom the drug or drug
substance is to be imported;

•

port of entry;

•

approximate date of drug or drug substance entry;

Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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•

name and address of foreign manufacturer;

•

amount of drug or drug substance to be imported; and

•

which investigational labeling statement under 21 CFR 511.1 will be affixed to the
investigational drug (see P&P 1243.4065 for the appropriate labeling statement).

If you receive a notification of import, then review the information following the principles
described in Section VIII to determine whether a response to the sponsor is needed; if
not, then file the submission with no reply (FNR).
Note: If it is a drug in a bulk package intended for processing, repacking or use in the
manufacture of another drug, we should NOT be receiving a notification of import OR an
NCIE. Once the drug is repacked or used in the manufacture of a new animal drug that
will be used in a clinical investigation, an NCIE must be provided when that
investigational new animal drug is shipped to the clinical investigation location/site.
VI.

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 drug, not concurrent with or after shipment.

VII.

HOW WE USE AN NCIE
The NCIE provides us with information primarily about clinical investigation studies in
animals. NCIEs are used by the target animal divisions for a variety of purposes,
including to:

VIII.

•

keep track of how much drug is shipped, where, and when;

•

receive timely information on when studies start;

•

initiate Bioresearch Monitoring (BIMO) requests;

•

monitor activity under the investigational exemption;

•

monitor investigational food-use authorizations;

•

know what obligations the sponsor has transferred to a CRO;

•

monitor movement of investigational animals with IGAs or products derived from
animals with IGAs; and

•

maintain current, accurate knowledge of studies conducted in client-owned animals.

HOW WE REVIEW AN NCIE
NCIEs are submitted to CVM electronically using eSubmitter or, rarely, under a cover
letter in paper. NCIEs are coded as B submissions in STARS. Review any NCIE received
from the sponsor, regardless of whether it was required as described above.
Upon NCIE receipt, determine whether the sponsor has submitted either a claim for a
categorical exclusion (CE) or an environmental assessment (EA) for the intended
investigational use (X submission). If the sponsor has not submitted either a CE or an EA,

Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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then discuss with your TL and/or an Environmental Team TL and contact the sponsor to
remind them that, under 21 CFR 511.1(b)(10), they must submit one of these to maintain
an INAD exemption (see P&P 1243.4065). Proposed boilerplate language to request a
CE or EA from a sponsor for investigational use is in P&P 1243.7220, Section III.A.2.
Check the submission and shipment dates to determine whether the sponsor submitted
the NCIE prior to shipment. If sponsors have not submitted the required NCIEs or if they
submitted NCIEs after the initiation of investigations, then discuss with your TL whether to
contact the sponsor to remind them of their responsibilities under 21 CFR 511.1(b)(4) for
submitting NCIEs prior to shipment of new animal drugs for investigational use. Record
any communications with the sponsor in the review summary field in STARS and/or
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
TL whether to send an acknowledgment letter to the sponsor reminding them that they
must submit their NCIEs prior to shipment of investigational drug.
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 previous
information and reviews in the (J)INAD file, such as:
•

A-0000 submission;

•

investigational food-use authorizations;

•

protocols; or

•

other submissions to the (J)INAD file.

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), then contact the sponsor to request corrections and record these communications in
the review. Request an amendment or a revised NCIE to correct significant errors if
needed (see Section X). For subsequent incorrect submissions (either in the same
(J)INAD file or across multiple files for that sponsor), discuss with your TL whether to
send an acknowledgment letter to the sponsor requesting corrective action.
If the NCIE included information on transferal of obligations to a CRO and you have any
concerns, speak with your team leader. If necessary, contact the sponsor for clarification
or to address the issue(s). It may be appropriate to document the concerns and
discussions in the administrative record. 4
IX.

FINAL ACTIONS
Appropriate final actions for NCIEs include:

4

•

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

•

submission filed with review documentation; no letter sent (FNR/MEMO); and

Note that transferal of obligations can also be submitted by the sponsor as a G submission. Follow the process in section VIII for
discussion and documentation of any concerns.

Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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•

submission reviewed; letter sent (ACK).

In most instances, use the FNR final action. Use the FNR/MEMO final action when
dictated by your division/team procedures or to document communications between you
and the sponsor for correction of errors in NCIEs. Though used infrequently, issuing an
acknowledgment letter to sponsors who repeatedly submit incorrect NCIEs may be
warranted.
X.

CORRECTING NICE OMISSIONS AND ERRORS
If an investigational drug was shipped without an NCIE being submitted, then as soon as
we or the sponsor identify the omission, the sponsor must submit an NCIE reflecting the
actual shipping date.
If we or the sponsor identify an error in an NCIE currently under review, then, depending
on the extent of the error, the sponsor can amend the submission or submit a new NCIE.
If they submit a new NCIE, then we will void the original.
If we or the sponsor identify an error in an NCIE that has been closed out, then the
sponsor must submit the correction in a new NCIE (B submission) referencing the original
B submission number. In that case, the reviewer specifies in the review documentation
that the NCIE is a correction of a previously completed NCIE (e.g., “This NCIE is to
correct XXX of B-0028.”)

XI.

REFERENCES
CVM Program Policies and Procedure Manual – ONADE Reviewer’s Chapter
1243.3030 – Completing Final Action Packages for Submission Tracking and
Reporting System (STARS) Submissions
1243.4040 – Investigational Food-Use Authorizations: The Role of the Target Animal
Division Reviewer
1243.4065 – Requirements for Investigational New Animal Drug Exemptions
1243.7220 – Processing Environmental Impact Submissions for New Animal Drugs

XII.

VERSION HISTORY
March 31, 2009 – Original version
April 3, 2009 – Revised to clarify that when nonclinical laboratory safety studies use foodproducing 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.
October 5, 2016 – Updated categorical exclusion and environmental assessment
information in Section V. and updated the format.

Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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July 18, 2017 – Updated to add clarity to the process and to put document into current
format.
December 20, 2018 – Updated to reflect CVM policy change on NCIEs for abbreviated
(generic) new animal drugs.
May 14, 2021 – Updated language to current terminology and also to reflect the
electronic process.
February 16, 2022 – Revised structure and criteria describing when an NCIE is and is not
required. Moved information for importing investigational drugs for clinical studies from
P&P 1243.4065 to this P&P. Updated language for correcting NCIE errors and omissions.
Removed Appendix containing outdated list of required information for NCIE
submissions. Updated section on corrections to NCIEs to indicate those submissions
should be B submissions.
May 25, 2022 – Revised Sections III and IV to clarify language for which studies do/do
not require NCIEs, including international shipments and pilot work. Second-level
headers were updated to follow the current formatting expectations of A, B, C instead of
1, 2, 3.
July 5, 2022 – Revised Sections III and IV to clarify language for which studies do/do not
require NCIEs. Added information about NCIEs reviewed by DABCT. Minor formatting
updates for consistency with P&P formatting.
August 4, 2022 – Clarified expectations for early studies and international shipping
(Section III)
February 22, 2023 – Updated to fix heading 2 errors and updated the TOC.
January 26, 2024 – Updated to include information that sponsors sometimes include
information on transferring obligations to a CRO in their NCIE to section VII. Also added
information on reviewing that transfer of obligation information to section VIII and noted
that the sponsor may notify us of the transfer of obligations in the NCIE or a G
submission. Updated into the new P&P template. To bring all office quality system
documentation into compliance with the FDA Visual Identity Program approved fonts,
ONADE has adopted Arial 11-point font. The font of this document was changed from
Verdana 10-point font to Arial 11-point font.
March 13, 2024 – Revised section V to remove the citation to 21 CFR 201.122 because it
pertains to bulk drug substances intended for further processing, repacking, or use in the
manufacture of another drug. Also, added a statement to the section that clarifies that for
a drug in a bulk package (as described in 21 CFR 201.122) we should not receive an
NCIE or an import notification.

Responsible Office: Office of New Animal Drug Evaluation
Date: March 13, 2024

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