CVM GFI #265 Use of Data from Foreign Investigational Studies to Support Effectiveness of New Animal Drugs

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

#265
Use of Data from Foreign
Investigational Studies to Support
Effectiveness of New Animal Drugs
Guidance for Industry
Submit comments on this guidance at any time. Submit electronic comments to
https://www.regulations.gov. Submit written comments to the Dockets Management Staff
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD
20852. All comments should be identified with the docket number FDA-2020-D-1396.
For further information regarding this document, contact AskCVM@fda.hhs.gov.
Additional copies of this guidance document may be requested from the Policy and Regulations
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish
Place, Rockville MD 20855, and may be viewed on the Internet at https://www.fda.gov/animal-
veterinary, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or
https://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine (CVM)
October 2021

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Table of Contents
I. 	Introduction ....................................................................................................................... 3
II. 	Background ....................................................................................................................... 3
III. 	Scope................................................................................................................................... 4
IV. 	Acceptance of Foreign Investigational Studies............................................................... 5
A. Substantial Evidence of Effectiveness ....................................................................... 5
B. Adequacy of Foreign Data for Regulatory Use ........................................................ 5
C. Field Effectiveness Studies ......................................................................................... 6
D. Laboratory Effectiveness Studies .............................................................................. 7
E. Foreign Data Applicable to the U.S. Population ...................................................... 7
F. 	Foreign BioResearch Monitoring (BIMO) ............................................................... 8
V. 	The Use of Data to Support Effectiveness of New Animal Drugs................................. 8
VI. 	International Cooperation................................................................................................ 9
A. Parallel Scientific Advice ............................................................................................ 9
B. Simultaneous Review with Health Canada’s Veterinary Drug Directorate
(VDD) ........................................................................................................................... 9
VII. 	Special Considerations...................................................................................................... 9
A. Translations ................................................................................................................. 9
B. Units of Measurements ............................................................................................. 10
C. Regulatory Requirements ........................................................................................ 10
VIII. 	Obtaining CVM Feedback on Use of Data from Foreign Investigational Studies.... 11
A. When to submit information regarding the use of data from foreign
investigational studies ............................................................................................... 11
B. How to submit information regarding the use of data from foreign
investigational studies ............................................................................................... 12
IX. 	Glossary ........................................................................................................................... 13

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Use of Data from Foreign Investigational Studies to Support
Effectiveness of New Animal Drugs
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	Introduction
FDA is issuing this Guidance for Industry (GFI), as required under section 305 of the Animal
Drug and Animal Generic Drug User Fee Amendments of 2018 (Pub. L. 115-234), to assist
sponsors in incorporating data from foreign countries into proposed clinical investigation
protocols and applications for new animal drugs under the Federal Food, Drug, and Cosmetic
Act (FD&C Act). Section 305 of Pub. L. 115-234, among other things, directed FDA to hold a
public meeting for interested parties to discuss innovative animal drug investigation designs and
to issue guidance addressing the incorporation of the use of such elements of investigations as
complex adaptive and other novel investigation designs, data from foreign countries, real-world
evidence (including ongoing surveillance activities, observational studies, and registry data),
biomarkers, and surrogate endpoints into clinical investigation protocols and applications to
support the effectiveness of new animal drugs.
The contents of this document do not have the force and effect of law and are not meant to bind
the public in any way, unless specifically incorporated into a contract. This document is intended
only to provide clarity to the public regarding existing requirements under the law. FDA
guidance documents, including this guidance, should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use of the word should in Agency
guidances means that something is suggested or recommended, but not required.
II. 	Background
In the Federal Register of July 9, 2019 (84 FR 32749), FDA’s Center for Veterinary Medicine
published a notice of a public meeting entitled “Incorporating Alternative Approaches in Clinical
Investigations for New Animal Drugs” giving interested persons until August 17, 2019, to
comment on the topics discussed at the public meeting and the questions published in the
meeting notice (84 FR at 32750-32751).1 On August 13, 2019, we published a notice
announcing the extension of the comment period to September 16, 2019 (84 FR 40071). CVM
received numerous comments on the topics discussed at the public meeting and the questions
1 https://www.fda.gov/animal-veterinary/workshops-conferences-meetings/public-meeting-incorporating-alternative-
approaches-clinical-investigations-new-animal-drugs

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published in the meeting notice and those comments were considered as the draft guidances were
developed.
This document describes principles for designing, conducting, and reporting the results for
investigations or studies including data from foreign countries to demonstrate substantial
evidence of effectiveness or a reasonable expectation of effectiveness of drugs intended for use
in animals and to support the approval of a new animal drug application (NADA) or an
application for conditional approval of a new animal drug (CNADA). This guidance also
provides information about obtaining feedback from FDA with respect to incorporating data
from foreign countries in investigations and study protocols for new animal drugs. Other centers
within FDA, including the Center for Drug Evaluation and Research (CDER), the Center for
Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health
(CDRH), have released draft and final guidance documents on the topic of data from foreign
countries.
CVM will consider all foreign data in submissions to investigational new animal drug (INAD)
files, NADAs, and CNADAs to demonstrate substantial evidence of effectiveness or a reasonable
expectation of effectiveness. This guidance document provides CVM’s recommendations
specific to investigations for animal drugs.
Some concepts and language in the recommendations for animal drugs are intended to be similar
to or the same as those in other guidance documents issued by FDA on the same or similar
topics. Because these recommendations are specific to investigations for animal drugs, they
have been tailored to the unique aspects of and considerations for animal drug development.
III. 	Scope
The purpose of this guidance is to provide guidance to animal drug sponsors on specific areas of
the approval process where the use of data from foreign investigational studies may be
considered acceptable to support the effectiveness requirement of a new animal drug application.
In this context, a new animal drug application may be an NADA or an CNADA.2 In addition,
this guidance describes how sponsors may obtain feedback from CVM on the use of data from
foreign investigational studies before the submission of an application.
The use of data from foreign investigational studies intended to support effectiveness of the drug
may be acceptable to support NADAs submitted to CVM if certain conditions are met. This
guidance outlines what CVM would expect to see in the documentation provided in support of
any application that uses foreign investigational studies to demonstrate effectiveness. This
guidance does not address the use of data from foreign investigational studies to support
technical sections other than Effectiveness or Reasonable Expectation of Effectiveness. For the
purpose of this guidance, CVM considers foreign data to be data generated outside of the United
States both by entities based within or outside of the United States.
CVM encourages sponsors to explore a variety of design options in the planning of clinical
effectiveness study designs, and to proactively discuss their considerations with CVM. Some
2 See CVM GFI #261, “Eligibility Criteria for Expanded Conditional Approval of New Animal Drugs,” (July 2021).

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recommendations in this guidance may be technically involved and we recommend you consult
with the appropriate CVM experts to help facilitate use of these recommendations.
FDA is committed to supporting data that may be recognized globally in order to enhance animal
drug development, facilitate the use of foreign data and minimize the need to conduct duplicative
studies. The Food and Drug Administration Safety and Innovation Act (FDASIA) reaffirms
FDA’s longstanding practice of accepting data from foreign investigational studies provided that
the data are adequate under applicable standards to support approval (see section 1123
Optimizing Global Clinical Trials).3
FDA also supports international harmonization activities that help leverage work and expertise
from other expert authorities. Pathways exist for international collaboration on the use of data
from foreign investigational studies to support regulatory decisions. For example, Health
Canada’s Veterinary Drugs Directorate (VDD) and CVM coordinate their respective submission
and review processes to enable simultaneous reviews of veterinary drug applications though the
US-Canada Regulatory Cooperation Council (RCC). The International Cooperation on
Harmonization of Technical Requirements for Registration of Veterinary Medical Products
(VICH) is a joint effort between the U.S., the European Union, and Japan whose aim is
harmonizing technical requirements for veterinary product registration.
IV. 	Acceptance of Foreign Investigational Studies
A. Substantial Evidence of Effectiveness
To establish substantial evidence of effectiveness, one or more adequate and well-
controlled studies must be conducted in accordance with an appropriate standard of
conduct (21 CFR 514.117) and include all the information required by 21 CFR
514.1(b)(8). The standard of conduct generally used for effectiveness field studies is
Good Clinical Practice (GCP),4 although some laboratory effectiveness studies are
conducted according to Good Laboratory Practice (GLP, 21 CFR part 58). GCP is
intended to be an international scientific quality standard for designing, conducting,
monitoring, recording, auditing, analyzing, and reporting effectiveness studies evaluating
veterinary products. GCP provides public assurance about the integrity of the study data,
and that due regard has been given to animal welfare and protection of the personnel
involved in the study, the environment, and the human and animal food chains. Although
GCP is a guidance rather than a regulation, studies conducted to this standard are more
likely to meet the requirements for substantial evidence of effectiveness; therefore, CVM
recommends that sponsors adhere to GCP.
Foreign data may be used to support a reasonable expectation of effectiveness for
conditional approval as defined in section 571 of the FD&C Act.
B. Adequacy of Foreign Data for Regulatory Use
3 https://www.govinfo.gov/content/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf
4 See CVM GFI #85 (VICH GL9), “Good Clinical Practice,” (May 2001)

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To demonstrate that a study supporting an effectiveness claim is adequate and well-
controlled, sponsors typically submit extensive documentation of study planning,
protocol, conduct, and data handling to FDA, and study documentation is made available
at the study sites. CVM’s ability to review the copies of raw data for information critical
to a study, whether submitted to CVM or maintained at the study site, has proven to be
important in regulatory decisions; however, FDA recognizes that the extent of
documentation necessary depends on the specific study, the types of data involved, and
the other evidence available to support the claim. Therefore, CVM may accept different
levels of documentation to support data quality and integrity, as long as the adequacy of
the scientific evidence can be assured.5 Sponsors are encouraged to consult with CVM
prior to submitting the specific study.
C. Field Effectiveness Studies
The field effectiveness study should use a design that permits a valid comparison with a
control to provide an appropriate evaluation of the drug’s effect. Within the broad range
of studies conducted to support a determination of the effectiveness of a new animal
drug, certain controls would be appropriate depending on the study conducted (e.g.,
placebo concurrent control, untreated concurrent control, active treatment concurrent
control, or historical control). The choice of an active treatment concurrent control may
have implications on the interpretability of the results.
1. 	Use of an active control
An “active treatment concurrent control” (active control) is defined as a known
effective therapy (see 21 CFR 514.117(b)(4)(iii)). Typically, effectiveness of the
investigational new animal drug may be demonstrated through non-inferiority to an
active control if the active control is a U.S. approved new animal drug in the target
species for the same indication as the investigational new animal drug.6 Under
certain conditions (see next section), a non-inferiority study using an active control
that is not approved in the U.S. may be used to support substantial evidence of
effectiveness. The sponsor should contact CVM to discuss specific details regarding
the design of a study that uses an active control.
2. 	Use of an active control not approved in the United States
For CVM to accept the use of a non-inferiority study utilizing an active control that is
not approved for use in the U.S. (unapproved active control), the sponsor should
provide sufficient data or information to substantiate effectiveness. A compelling
justification of effectiveness can include literature, laboratory work, clinical work, or
other information to show that the unapproved active control is effective for the
proposed indication. Specifically, the information should support a clinically relevant
effect size to allow the determination of an acceptable noninferiority margin. Section
5 See CVM GFI #106, “The Use of Published Literature in Support of New Animal Drug Approval,” (August 2000)
6 See CVM GFI #204, “Active Controls in Studies to Demonstrate Effectiveness of a New Animal Drug for Use in
Companion Animals,” (December 2015)

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II.H. of GFI #204 discusses how the noninferiority margin should be determined.7
Additionally, the information provided for effectiveness should be inferred to the
intended target animal population in the U.S. The sponsor should contact CVM to
discuss details regarding information to support the use of an unapproved active
control.
If the unapproved active control drug is approved outside of the U.S., then ideally the
unapproved active control drug indication(s) should be the same as the indication(s)
proposed for the investigational new animal drug. If the proposed investigational
new animal drug indication(s) deviate from the indication(s) for the unapproved
active control drug, then more robust information may be needed to support the use of
the unapproved drug as an active control to demonstrate substantial evidence of
effectiveness (NADA). If the unapproved active control is recognized as standard of
care, the use should be similar to the proposed indication for the investigational new
animal drug.
The information the investigational drug sponsor submits to support the effectiveness
of the unapproved active control that is contained within their INAD or NADA
belongs to the sponsor of the investigational drug8 and is considered proprietary
information. For example, all information related to the unapproved active control
would be submitted to the INAD file for the investigational drug including Notice of
Claimed Investigational Exemptions (NCIEs) and Investigational Food Use
Authorizations.
D. Laboratory Effectiveness Studies
Many laboratory dose confirmation effectiveness studies are conducted in other countries
to support approval of various investigational new animal drugs, such as anthelmintics.
Data generated from studies that comply with the existing VICH anthelmintic GFIs are
acceptable for submission to CVM. For other types of laboratory dose confirmation
studies conducted outside of the U.S., please refer to components of this GFI for
acceptability of the data. Generally, the principles of GCP should be followed. The
standard used to conduct the study (e.g., Organisation for Economic Co-operation and
Development [OECD], GLP or GCP) should be stated in the Final Study Report (FSR).9
Any departures from these standards should be documented and the impact on the study
conduct and results should be discussed in the FSR.
E. Foreign Data Applicable to the U.S. Population
Because of differences in animal breeds, nutrition, husbandry practices, and disease,
sponsors of foreign studies should show that the study conditions are representative of the
7 See footnote 6 on p. 6
8 See 21 CFR 514.11 and 514.12 for the general proposition that information contained in INADs/NADAs is
confidential. 21 CFR 514.1(a) states, “Any reference to information furnished by a person other than the applicant
may not be considered unless its use is authorized in a written statement signed by the person who submitted it.”
9 http://www.oecd.org/

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U.S. For CVM to accept data from a study conducted outside of the U.S., the sponsor
should include a justification, as applicable, for using the foreign sites and discuss
similarities and differences in the following areas between the U.S. and the country
where the study was conducted:
• 	Conditions of use of the investigational drug product, as defined in section 21 CFR
514.4(a) Definition of substantial evidence;
• 	The practice of veterinary medicine with respect to any differences that may impact
the study;
• 	Management and husbandry practices;
• 	Species, breeds, or classes used in the study;
• 	Bacterial strains, including target pathogen virulence, and target pathogen
susceptibility to the investigational antimicrobial;
• 	Parasitic strains, including source, age, and susceptibility (if applicable); and
• 	Any other practices or conditions (if applicable) that could impact the study conduct
or results.
If there are differences, the sponsor should document them and state the impact of those
differences on the study conduct or on an animal’s response to the drug. For
anthelmintics, see CVM GFI #90 (VICH GL7), “Effectiveness of Anthelmintics: General
Recommendations” (October 2001).10
Management, husbandry, and other practices, as well as bacterial pathogen virulence and
sensitivity, may be similar across the U.S., Canada, and Mexico. Therefore, the
information needed to accept use of data from Canada and Mexico may be minimal.
FDA encourages sponsors to talk with us early in development when these issues can be
discussed.
F. 	Foreign BioResearch Monitoring (BIMO)
FDA may conduct inspections of clinical investigations in support of a U.S. drug
approval. For more information on the compliance program, refer to Compliance
Program Guidance Manual (CPGM) 7348.811, Chapter 48-Bioresearch Monitoring
Clinical Investigators and Sponsor-Investigators (December 2008).11
V. 	The Use of Data to Support Effectiveness of New Animal Drugs
For CVM to consider the use of foreign investigational studies to support the
effectiveness of a new animal drug, the studies should have the same data qualities and
study integrity standards as expected from domestic studies. As with any study submitted
10 https://www.fda.gov/media/70349/download
11 https://www.fda.gov/media/75927/download

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to FDA, data is generally assessed by evaluating several factors including, but not limited
to, those outlined below:
• 	Adherence to applicable FDA regulations;
• 	Adherence to protocols, standard operating procedures, and previous agreements with
CVM;
• 	Maintenance of data and study integrity; and
• 	Construct of the FSR and access to the copies of raw data for information critical to a
study.
VI. 	International Cooperation
A. Parallel Scientific Advice
Parallel Scientific Advice (PSA) is an opportunity to receive feedback on a set of
questions from CVM and the European Medicines Agency (EMA) in parallel. To
participate, a PSA request should be simultaneously submitted to CVM and EMA with a
set of scientific and regulatory questions. A request could also include a protocol with
specific questions, but PSA is not intended for granting protocol concurrence. After
CVM receives the request, CVM and EMA will meet to discuss the questions and the
respective responses with the goal of harmonizing responses where possible. The
sponsor would then receive separate responses from CVM and EMA.
CVM recommends using PSA at the point when a sponsor would be seeking a
presubmission conference with CVM. Before making a Parallel Scientific Advice
request to CVM, the sponsor should contact CVM and EMA so that each Agency can
prepare for receipt of the request.
B. Simultaneous Review with Health Canada’s Veterinary Drug Directorate (VDD)
CVM and Health Canada’s VDD simultaneously review new animal drug applications on
a case-by-case basis though the US-Canada RCC. If a sponsor is interested in including a
new animal drug in simultaneous review, they should contact both CVM and VDD. If
both Agencies agree that the project is acceptable for simultaneous review, they will send
the sponsor a letter requesting a commitment to provide both agencies with identical
submissions simultaneously and authorization to discuss the full content of the
submissions between Agencies. CVM and VDD reviewers will meet to discuss the
submissions under review and both Agencies will be invited to participate in meetings
with the sponsor. Simultaneous review does not guarantee the same conclusions from
both Agencies, as CVM and VDD have different regulations and requirements. A benefit
of simultaneous review is that the process can lead to simultaneous approval of the
animal drug product in two countries.
VII. 	Special Considerations
A. Translations

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Requirements for Data, Reports, and Published Literature – As required by 21 CFR
514.1(a), “if any part of the application is in a foreign language, an accurate and complete
English translation of each part that is not in English shall be appended[.]” 21 CFR
514.1(a) also requires the sponsor to submit translations of literature printed in a foreign
language in addition to copies of the original publication.
• 	For data, study reports, and published literature that are in a foreign language, a
certified translation is not required. The sponsor should verify the information and
that it is accurately translated into English. By signing the eSubmitter Administrative
Cover Form, the sponsor is attesting to that accuracy.12
• 	For paper submissions, the sponsor attests that the translations are accurate using
FORM FDA 356v.13 In accordance with the reauthorization of the Animal Drug User
Fee Act (ADUFA), effective October 1, 2018, all applications and submissions
should be submitted electronically using the eSubmitter tool.14 Therefore, paper
submissions are not typically accepted by CVM; however, there are rare exceptions to
this requirement, and these should be discussed with CVM prior to submission.
B. Units of Measurements
• 	All units of measurements should be consistent with the Imperial system of
measurement (e.g., inches, pounds, and ounces/gallon), with the International System
of units (SI Units) or acceptable SI derivatives (e.g., centimeters, kilograms, and
milligrams per milliliter), or a combination of both as appropriate (e.g., milligrams
per pound.).
• 	Raw data should be submitted as recorded (e.g., in kilograms, grams, pounds, etc.);
however, all data for a specific variable should be converted to the same unit of
measure for evaluation and documentation in the FSR.
• 	Unit conversion details should be provided in the FSR.
C. Regulatory Requirements
Sponsors should be aware that the requirements for the conduct of studies may differ
between regulatory authorities. CVM will evaluate submitted information and determine
whether the information is sufficient to satisfy the regulatory requirements for the
approval of a new animal drug. CVM recommends that sponsors consider potential
differences to FDA regulatory requirements prior to completing FSRs containing data
12 See CVM Program Policy and Procedures (P&P) Manual 1243.2180 Certifications for New Animal Drug
Submissions and Applications (July 2019)
13 See additional information regarding the FDA eSubmitter tool at https://www.fda.gov/industry/fda-esubmitter
14 See section 301 of the Animal Drug and Animal Generic Drug User Fee Amendments of 2018 (Pub. L. No. 115-
234)

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from foreign investigational studies and discuss the impact of those differences with
CVM prior to the submission.
CVM recognizes that foreign privacy laws may pose challenges in the submission of data
to CVM; therefore, we recommend sponsors consult with experts of their locality to
determine how to navigate their local laws while still meeting the requirements for
approval of new animal drugs in the U.S.
VIII. 	Obtaining CVM Feedback on Use of Data from Foreign Investigational Studies
There are various approaches that sponsors may take to open a discussion with CVM on the use
of data from foreign investigational studies as part of their development program to demonstrate
effectiveness or a reasonable expectation of effectiveness. The sponsor’s decision regarding
which approach to select may be affected by where the project is in the development process.
Communication about data from foreign investigational studies may occur at any point in the
development process.
The Office of New Animal Drug Evaluation (ONADE) project managers (PMs) serve as a
central point of contact for drug sponsors and can provide information about the new animal
drug review process and ONADE’s regulatory procedures. If you have questions about the
approval process and do not have an ONADE PM assigned to your company, you can contact the
PMs through the CVM mailbox AskCVM@fda.hhs.gov.
A. When to submit information regarding the use of data from foreign
investigational studies
There are a variety of points in the development process and a variety of submission
types that can be used to obtain feedback. CVM encourages sponsors interested in
using data from foreign investigational studies as part of their development program
for a new animal drug to inform CVM as early in the product development process as
possible.
Sponsors planning to incorporate data from foreign investigational studies to
demonstrate effectiveness or reasonable expectation of effectiveness are encouraged
to inform CVM of their intent either as part of their initial request to open a General
Correspondence (GC) file or an INAD file (A-0000), or as part of their initial
presubmission conference with CVM to discuss the drug product development plan
(Z-submission product development meeting). If one or more studies incorporating
data from foreign investigational studies are already complete, CVM recommends
sponsors submit information described in section VIII.B. How to submit information
regarding the use of data from foreign investigational studies prior to the initial
presubmission conference. While CVM cannot make a determination if existing data
would satisfy technical section requirements outside of a data submission, if the
sponsor submits sufficient information about the existing data early, we can provide

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feedback to help inform the development plan.15 Sponsors are also encouraged to
contact their assigned PM for assistance in determining the most appropriate method
for obtaining feedback from CVM.
B. How to submit information regarding the use of data from foreign
investigational studies
There are several ways that sponsors may submit detailed information about plans for
incorporating data from foreign investigational studies into their development program to
demonstrate substantial evidence of effectiveness or reasonable expectation of
effectiveness. The regulatory pathway selected (CNADA versus NADA), the stage of
development, the information available, and the feedback being sought from CVM,
among other factors, may influence the submission type selected.
Sponsors may seek general assistance on the use of data from foreign investigational
studies in a GC file prior to opening an INAD file. Sponsors may submit information to
support use of data from foreign investigational studies as part of their initial request to
open an INAD file; as part of a meeting request for a presubmission conference (Z-
submission) to discuss the Effectiveness technical section requirements; or as part of an
information submission (H-submission) or meeting request (Z-submission) to discuss
study protocol design.
Sponsors considering incorporating data from foreign investigational studies or site(s)
into future studies to demonstrate effectiveness or reasonable expectation of effectiveness
should, prior to conducting a study, submit a study protocol for review (E-submission).
CVM’s review of a study protocol that includes a foreign investigational site(s) will
consider the points outlined in section IV.E. Foreign Data Applicable to the U.S.
Population. Obtaining CVM input regarding study design will make reaching protocol
concurrence more efficient.
Sponsors may also open a Veterinary Master File (VMF) to hold detailed information
regarding a specific study design, including that regarding pre-investigational discussions
about the use of foreign data from foreign investigational studies or site(s), or if the
information will be used in the development of multiple applications.16 The VMF is
confidential and is typically used when a holder wishes the material in the VMF to
remain proprietary, although the material may be referenced by multiple third-party
products or files (INAD, NADA, or CNADA). Alternatively, if multiple sponsors are
cooperating on product development, sponsors may establish a Public Master File (PMF)
to allow all cooperators to reference the information. As suggested by the name, the
information in a PMF is publicly available.
15 See CVM P&P Manual 1243.2200 Submission and Review of Early Information (EI) Prior to Presubmission
Conferences and Protocol Review (June 2020) and CVM P&P Manual 1243.3050 Determining Technical Section
Requirements for New Animal Drug Product Approval (May 2019)
16 See CVM P&P Manual 1243.2400 Veterinary Master Files with Manufacturing Information (August 2019)

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Regardless of how information is submitted to CVM, sponsors should submit an
organized and focused information package. This will allow CVM the best opportunity
to provide appropriate recommendations in response. Although full information may not
be available in the early stages of the development process, the amount of information
provided and the level of detail of the information provided should be commensurate
with the submission type. The information should address some or all of the following
elements, as appropriate for the submission type:
1. 	Indicate how the study will fit within the overall development plan for the
investigational new animal drug (i.e., support substantial evidence of effectiveness,
reasonable expectation of effectiveness or dosage characterization, or some other
aspect of the effectiveness evaluation);
2. 	Indicate the regulatory standard followed or to be followed;
3. 	Indicate how the data are applicable to the U.S. target animal population, U.S.
veterinary medical practice, and U.S. production/husbandry practice;
4. 	Provide information regarding the use of an active control that is not approved in the
U.S.; and
5. 	Provide information regarding differences in study conduct and impact of those
differences as discussed in section IV. Acceptance of Foreign Investigational Studies.
IX. 	Glossary
The following definitions are supplied to provide the reader with an understanding of the specific
terms used in this guidance as applicable to new animal drugs. These definitions should not be
construed to be new interpretations or clarification of the use of similar words or phrases in the
FD&C Act, related code or regulation, other Federal, State, or local laws, or other guidance
documents.
Active Control: The new animal drug is compared with known effective therapy. The use of
this control is appropriate when the use of a placebo control or of an untreated concurrent control
would unreasonably compromise the welfare of the animals. Similarity of the new animal drug
and the active control drug can mean either that both drugs were effective or that neither was
effective. The study report should assess the ability of the study to have detected a difference
between treatments. The evaluation of the study should explain why the new animal drugs
should be considered effective in the study, for example, by reference to results in previous
placebo-controlled studies of the active control. (21 CFR 514.117(b)(4)(iii)).
Data from Foreign Investigational Studies: Data generated outside of the United States both
by entities based within or outside of the United States.
eSubmitter: A computer-based tool that allows animal drug sponsors to create regulatory
submissions that can then be submitted electronically and securely to CVM.

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Final Study Report: The comprehensive description of the study written after its conclusion.
This report includes a description of the objective(s), experimental materials and methods, and a
presentation and critical scientific evaluation of the results (including statistical analyses where
appropriate).
Non-inferiority Margin: The non-inferiority margin, also called the margin of difference or
delta (Δ), defines the extent to which the investigational new animal drug can be less effective
than the active control and still allow the applicant and CVM to conclude that is the new animal
drug is “non-inferior.” The margin of difference is specified before conducting the study
because it will determine whether a study supports the effectiveness of the investigational new
animal drug. In the active control comparison, the results provide a point estimate of the
difference between treatments and a confidence interval around that difference. In general, the
study seeks to show that the upper bound of that confidence interval is less than the acceptable
Δ.17
Raw Data (for clinical studies): Any original worksheets, calibration data, records,
memoranda, and notes of first-hand observations and activities of a study that are necessary for
the reconstruction and evaluation of the study. Raw data may include, but are not limited to,
photographic materials, magnetic, electronic or optical media, information recorded from
automated instruments, and hand-recorded datasheets. Facsimile transmissions and transcribed
data are not considered raw data.
Substantial Evidence of Effectiveness: Evidence consisting of one or more adequate and well-
controlled studies, such as a study in a target species, study in laboratory animals, field study,
bioequivalence study, or an in vitro study, on the basis of which it could fairly and reasonably be
concluded by experts qualified by scientific training and experience to evaluate the effectiveness
of the new animal drug involved that the new animal drug will have the effect it purports or is
represented to have under the conditions of use prescribed, recommended, or suggested in the
labeling or proposed labeling thereof. Substantial evidence shall include such adequate and well-
controlled studies that are, as a matter of sound scientific judgment, necessary to establish that a
new animal drug will have its intended effect (21 CFR 514.4(a)).
17 See footnote 6 on p. 6