#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  Contains Nonbinding Recommendations 
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 Canadas 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 
   
  2  Contains Nonbinding Recommendations 
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), FDAs 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 
  3  Contains Nonbinding Recommendations 
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 CVMs 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). 
  4  Contains Nonbinding Recommendations 
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 
FDAs 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 
Canadas 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) 
  5  Contains Nonbinding Recommendations 
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.  CVMs 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 drugs 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) 
  6  Contains Nonbinding Recommendations 
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/ 
  7  Contains Nonbinding Recommendations 
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 animals 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 
  8  Contains Nonbinding Recommendations 
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 Canadas Veterinary Drug Directorate (VDD) 
CVM and Health Canadas 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 
  9  Contains Nonbinding Recommendations 
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) 
  10  Contains Nonbinding Recommendations 
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 sponsors 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 ONADEs 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 
  11  Contains Nonbinding Recommendations 
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).  
CVMs 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) 
  12  Contains Nonbinding Recommendations 
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.   
  13  Contains Nonbinding Recommendations 
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 (), 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 
.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 
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