#106 
 
The Use of Published Literature in 
Support of New Animal Drug 
Approvals 
 
Guidance for Industry 
 
This version of the guidance replaces the version made available in August 2000, which 
specifically addressed the use of a single article to support drug approval.  This revision of the 
guidance document considers multiple uses of the scientific literature, including narrative 
reviews, systematic reviews, and meta-analysis to support approval of a new animal drug. 
 
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-2021-D-1155. 
 
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) 
March 2023
 
  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  CONSIDERATIONS FOR USING PUBLISHED LITERATURE ............................. 2 
A.  Submission of a Single Published Study as the Only Supporting Documentation 
for a Safety, Effectiveness, or Product Quality Decision ......................................... 3 
B.  Multiple Publications .................................................................................................. 4 
1. Narrative Review .................................................................................................... 5 
2. Scoping Review ....................................................................................................... 6 
3. Regulatory Systematic Review (SR) ................................................................... 10 
4. Meta-analysis ........................................................................................................ 19 
5. Submitting the Systematic Review and Meta-analysis to CVM ....................... 21 
6. Labeling ................................................................................................................. 21 
IV.  SPECIFIC PROCESSES AND APPROVAL REQUIREMENTS ............................. 22 
A.  Early Information ..................................................................................................... 22 
1. Using Literature in the Early Stages of Drug Development ............................. 22 
2. To Support Elements of a Protocol ..................................................................... 23 
B.  Generic Animal Drugs .............................................................................................. 24 
1. ANADA/and Generic INAD (JINAD) Files ....................................................... 24 
2. Suitability Petitions .............................................................................................. 25 
C.  Chemistry, Manufacturing, and Controls .............................................................. 25 
D.  Effectiveness .............................................................................................................. 26 
1. Scope of Use .......................................................................................................... 26 
2. Dosage Characterization ...................................................................................... 26 
3. Substantial Evidence of Effectiveness ................................................................. 27 
4. Reasonable Expectation of Effectiveness ........................................................... 30 
E.  Target Animal Safety ................................................................................................ 31 
1. Scope of Use .......................................................................................................... 31 
2. Preliminary Information ..................................................................................... 31 
3. Literature to Satisfy Target Animal Safety Requirements .............................. 32 
4. Other Laboratory Safety Studies ........................................................................ 34 
F.  Human Food Safety .................................................................................................. 35 
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  Contains Nonbinding Recommendations 
1. Microbial Food Safety (Antimicrobial Resistance) ........................................... 35 
2. Toxicology and Residue Chemistry .................................................................... 35 
V.  GLOSSARY..................................................................................................................... 36 
VI.  Appendix .......................................................................................................................... 40
ii 
  Contains Nonbinding Recommendations 
The Use of Published Literature in Support of New Animal Drug 
Approvals 
 
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 
The purpose of this document is to provide guidance to animal drug sponsors on specific areas of 
the approval process where the available scientific literature may be useful to support the 
approval of a new animal drug application (NADA), an abbreviated new animal drug application 
(ANADA), or a conditionally approved new animal drug application (CNADA), as well as 
methodologies to ensure the validity of conclusions drawn by animal drug sponsors from the 
scientific literature to support an approval. 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and 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. 
 
Definitions of key terms may be found in section V. Glossary.  The Appendix to this guidance 
provides example tables for organizing published studies and the data they provide to assist with 
screening and eligibility for analysis and data extraction. 
II.  BACKGROUND 
The original GFI #106 was published in 2000.  Since its publication, animal drug sponsors have 
used literature to support various aspects of animal drug development and approval, including 
early stages of drug development, dosage characterization, microbial food safety, design of the 
target animal safety evaluation, prediction of potential adverse effects, and substantial evidence 
of effectiveness. 
Animal drug sponsors have expressed interest in further leveraging information published in the 
scientific literature to support new animal drug approvals.  Use of published scientific literature 
is of interest because it makes use of existing knowledge and may reduce the number of animals 
needed for studies to support approval, and in some cases may provide greater inferential value 
compared to individual studies conducted for the purpose of supporting an approval.  Scientific 
literature may also be used to respond to specific regulatory questions, identify data gaps, and 
1  Contains Nonbinding Recommendations 
inform protocol design. 
However, use of scientific literature to support drug approval has its limitations.  Although there 
may be a wealth of published data on a drug or drug class, underlying study protocols and 
original study data and records generally are not available, making it difficult to determine the 
quality of studies and confirm aspects of study conduct or design necessary to make a safety or 
effectiveness determination.  Implementation of systematic methods to screen and analyze 
information across multiple publications may reduce the uncertainty resulting from analyzing 
limited information in individual studies. 
III.  CONSIDERATIONS FOR USING PUBLISHED LITERATURE 
The Center for Veterinary Medicine (CVM) considers the quality of journals used in literature 
reviews when determining the validity of the review.  CVM needs high-quality data to have 
confidence in its regulatory decisions. 
Changes in the publishing industry have brought more opportunities to publish research and 
greater access to such research.  Because of the vast number of research journals that publish on 
topics relevant to many aspects of new animal drug approvals, sponsors should consider the 
quality and integrity of sources of published literature.  For published studies conducted outside 
the United States, sponsors should consider factors that could affect the generalizability of study 
results to the U.S. target population and conditions of use.1 
 
New reporting guidelines, such as described by the REFLECT statement,2 CONSORT,3 
STROBE,4 and ARRIVE,5 which are designed to improve the reporting of animal research 
studies, may increase the utility of such literature for regulatory purposes. 
Some journals and scientific publications may be found in or as part of mainstream scientific 
databases.  Certain journals may not scrutinize the studies and data they publish.  CVM 
recommends consultation with subject matter experts to assess journal or publisher practices 
(e.g., robustness of the editorial or peer-review process and standards).  Prior to submitting any 
published literature to support regulatory decisions, sponsors should confirm they have identified 
any retractions for literature included in their submission. 
 
1 See CVM GFI #265, Use of Data from Foreign Investigational Studies to Support Effectiveness of New Animal 
Drugs, (October 2021). 
2 REFLECT stands for Reporting guidElines For randomized controLled trials for livEstoCk and food safeTy. 
(https://meridian.cvm.iastate.edu/reflect/ - Accessed on March 2, 2023). 
3 CONSORT stands for Consolidated Standards Of Reporting Trials (http://www.consort-statement.org/ and as 
reported in https://www.bmj.com/content/355/bmj.i5239 - Accessed on March 13, 2023). 
4 STROBE stands for STrengthening the Reporting of OBservational studies in Epidemiology (https://www.strobe-
statement.org/index.php?id=strobe-home - Accessed on March 2, 2023). 
5 ARRIVE stands for Animal Research: Reporting of In Vivo Experiments (https://www.nc3rs.org.uk/arrive-
guidelines - Accessed on March 2, 2023) 
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A.  Submission of a Single Published Study as the Only Supporting Documentation 
for a Safety, Effectiveness, or Product Quality6 Decision 
Studies to support new animal drug approvals are ordinarily conducted in accordance 
with Good Laboratory Practices (GLP) (21 CFR part 58) or Good Clinical Practices 
(GCP) (GFI #85 (VICH7 GL9), Good Clinical Practice8 (May 2001)).  Sponsors are 
required to follow GLP regulations that establish requirements for non-clinical studies 
including safety and bioequivalence studies.  Substantial evidence of effectiveness 
requirements consists of one or more adequate and well-controlled studies conducted in 
accordance with an appropriate standard of conduct (21 CFR 514.117).  The standard of 
conduct generally used for effectiveness studies is GCP.  Although GCP is a guidance 
rather than a regulation, studies conducted in accordance with the GCP guidance are 
more likely to meet requirements for substantial evidence.  
While publications may describe a drugs safety, effectiveness, and chemical or 
pharmacological characteristics, most published studies are not designed or conducted to 
specifically address regulatory requirements for new animal drugs.  Most studies 
published in the peer-reviewed literature aim to explore whether a drug or treatment may 
have an effect, and the discussion is often focused on the generation of hypotheses for 
further investigation.  Studies conducted to support a new animal drug approval are 
required to demonstrate that the drug is effective, safe, and/or can be manufactured to 
meet quality standards.  Further, guidelines for peer review and editorial decisions are not 
necessarily designed with regulatory review requirements in mind.  An article that 
summarizes a single study may not contain sufficient details about the study plans, study 
conduct, quality assurance measures, clinical end-point descriptions, or methods of data 
analysis.  All of these are needed to assess the reliability of the results and their 
applicability to the target animal population.   
Generally missing from published literature are original study data and records, extensive 
documentation9 of the study design, the study protocol, details of study conduct, data 
handling and storage information, and data analysis and interpretation.  Where present, 
these additional details and documentation may allow a single published study to be 
considered adequate for making population-level inferences and ultimately a regulatory 
decision.  
 
6 Section 512(d)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360b(d)(1)). 
7 VICH is the acronym for International Cooperation on Harmonisation of Technical Requirements for 
Registration of Veterinary Medicinal Products.  The VICH is a trilateral program (United States, Japan, and the 
European Union) aimed at harmonizing the technical requirements for veterinary product registration. 
8 All FDA guidances for industry mentioned in this document are available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
9 Study documentation includes all records in any form (including documents, magnetic and optical records) 
describing methods and conduct of the study, factors affecting the study, and any actions taken.  These records 
include, but are not limited to: protocol, raw data, reports, standard operating procedures, reference materials, and 
specimens. 
3  Contains Nonbinding Recommendations 
Although information provided in a single published article may be insufficient, on its 
own, for CVM to make inferences and regulatory decisions, it may be used in a 
supportive fashion to fill critical data gaps.  However, studies using inappropriate study 
animal populations, inclusion/exclusion criteria, dosages, routes of administration, design 
features (e.g., lack of masking or randomization, inappropriate statistical methods), or 
different formulations may not allow CVM to make any meaningful inferences.  
If a single published study is intended to demonstrate safety or substantial evidence of 
effectiveness of a proposed new animal drug product, the following items, either included 
within the publication or included with the submission of a published study, will provide 
information on the value of the study.  This is not intended to be an exhaustive list. 
  The protocol used for the study, as well as any important protocol amendments 
that were implemented during the study and their relationship to study animal 
acquisition or randomization. 
  Details on the masking procedures or impact on the study if masking was not 
performed. 
  The prospective statistical analysis plan and any changes from the original plan 
that occurred during or after the study. 
  Randomization codes and documented study entry dates for the animals. 
  Individual animal or herd source data for critical variables and pertinent baseline 
characteristics. 
  Full accounting of all study animals, including identification of any animals with 
treatment data that have been omitted from analysis and the reasons for 
omissions. 
  Complete information for all deaths and removals and details of any adverse 
event(s) regardless of whether the adverse event resulted in a death or removal. 
  Documentation of the characterization of the test substance. 
  Documentation of proper operating procedures and quality controls. 
  Evidence that the study was conducted by investigators with properly documented 
training and expertise and a history of implementing such procedures effectively. 
  Discussion of potential limitations and biases in the study in light of FDA 
requirements. 
  Access to copies of the original recordings of observations. 
B.  Multiple Publications 
There are several types of review methods that may be used to synthesize information 
from multiple publications (Grant and Booth 200910).  Review methods commonly used 
 
10 Grant, M. J., and A. Booth. 2009. A typology of reviews: an analysis of 14 review types and associated 
methodologies. Health Info Libr J no. 26 (2):91-108. doi: 10.1111/j.1471-1842.2009.00848.x. 
4  Contains Nonbinding Recommendations 
to support new animal drug approvals include narrative review, scoping review, 
systematic review, and meta-analysis.  The choice of method(s) used depends on how the 
literature is intended to support the new animal drug application. 
The literature review methods are presented below in an order of increasing levels of 
evidence.  Evidence from systematic reviews of all relevant and appropriately designed 
studies are considered a higher level of evidence and are more likely to satisfy safety 
and/or effectiveness requirements than other literature review methods.  However, other 
literature review methods are still integral to supporting portions of the new animal drug 
application, including identifying and/or filling gaps, and provide a foundation for the 
other methods. 
1.  Narrative Review 
Narrative reviews are probably the most common type of reviews found in the 
scientific literature.  They are often used to provide broad overviews, discussions, 
assessments of previous work, or to identify current knowledge gaps.  Generally, they 
describe and evaluate a general question or range of topics.  Sponsors often use 
narrative reviews for dosage characterization or to support some aspect of a protocol.  
They typically do not use or state the explicit processes used to compile, evaluate, 
synthesize, or report the evidence included in the review.  They may not encompass 
all relevant published sources of evidence, and search strategies are generally not 
specified.  These omissions limit the ability of others to reproduce the review 
independently.  Sources of bias may be introduced into the review and may not be 
easily identified by the reader.  Quantitative summaries (e.g., meta-analysis) of the 
body of evidence are typically absent.    
 
For regulatory purposes, a narrative review should be comprehensive.  Although not 
intended to be a systematic review (described in section III.B.3. Regulatory 
Systematic Review below), narrative reviews in new animal drug applications should 
incorporate some of the principles of a systematic review, such as transparency, 
balance, and limiting bias. 
The scope of the literature search for a narrative review will depend on the topic or 
question(s) the sponsor is trying to address.  
To improve the quality of the review, CVM recommends including information on 
the database(s) searched, the keywords or search string(s), and any limitations, such 
as date range(s) imposed.  To ensure that bias was minimized, the sponsor should also 
provide the rationale for inclusion and exclusion of papers from the review 
discussion.  Primary research articles are preferred, as review articles may introduce 
author bias.  
In developing the narrative review, the following principles should be considered: 
  Indicate the specific issues/questions the literature is intended to address. 
  Discussion should be focused. 
5  Contains Nonbinding Recommendations 
  Articles selected should be relevant to the current application (e.g., 
population, management practices, assay methods). 
  Critically evaluate the available literature on the subject. 
  Build the argument logically and present available evidence that both supports 
and refutes the desired position.  It is important to include studies with 
unfavorable, as well as favorable results, and explain why unfavorable results 
may not be applicable or could be mitigated.  The sponsor should draw 
conclusions based on their determination of what the literature supports. 
  If there are major differences among studies, discuss possible reasons for 
disparate results. 
  Identify where data gaps exist and recommend additional research that might 
help fill those gaps. 
It may be helpful to group similar articles together and discuss whether or not a 
scientific consensus has formed around the topic, using the corroborating literature to 
support the thesis.  If there are contradicting viewpoints or theories, supportive 
literature should be compared and contrasted to the common view and discussed 
critically.  Some authors recommend structuring the literature review as an inverted 
triangle, by starting with the broad, overarching issue(s), then becoming more 
specific.  Finally, the sponsor should draw overall conclusions and refer to the 
literature that supports such conclusions. 
To expedite review, CVM recommends providing full copies of the papers used in the 
literature review (rather than abstracts) and a reference list.  Complete and accurate 
English translations of foreign language papers used in the review must also be 
included (21 CFR 514.1(a)). 
2.  Scoping Review 
A consensus definition of a scoping review is not currently available; however, for 
the purpose of this guidance, scoping reviews are defined as the process of 
systematically, but broadly and qualitatively, mapping the available literature on a 
topic, rather than answering a narrow research question.  Because scoping reviews are 
high-level overviews and only qualitatively synthesize available evidence, they are 
not expected to be a labor-intensive or costly process.  Scoping reviews should be 
used by sponsors when a repeatable and objective review of available evidence (both 
published and grey literature (see section V. Glossary for definition), and including 
proprietary reports available to a drug sponsor where appropriate) would improve the 
quality and efficiency of the drug development process, or allow a sponsor to evaluate 
the feasibility of a particular approach to generating the information necessary to 
satisfy the requirements of a technical section.  
 
Sponsors should consider the use of scoping reviews in a variety of situations.  For 
example, CVM generally recommends conducting a scoping review prior to the 
conduct and submission of a systematic review.  A scoping review may allow a 
6  Contains Nonbinding Recommendations 
sponsor to map available evidence related to the effectiveness of a new animal drug in 
an unbiased and qualitative manner to determine if a systematic review would be a 
feasible approach to demonstrate the substantial evidence of effectiveness.  Potential 
topics to explore include dose, formulation, endpoints, conditions of clinical use, and 
inferential value for the target population.  The results of the scoping review may also 
provide information necessary to develop the protocol for the systematic review, 
including the definition of appropriate inclusion or exclusion criteria, identification of 
reliable endpoints, and/or establishment of an appropriate control group.  CVM 
anticipates that formal scoping reviews may also be useful to summarize 
pharmacologic and toxicologic properties of an active ingredient for use in the 
justification of target animal safety study designs (dose selection, overdose levels, 
treatment duration, and/or endpoints), or to justify innovative effectiveness study 
designs.  
 
When a scoping review is desired, a protocol should be developed and followed.  
CVM encourages sponsors to discuss their scoping review plans and protocols before 
performing the review.  The methods of the scoping review should be described in a 
protocol.  A variety of published methods (Armstrong et al. 2011,11 OBrien et al. 
2016,12 and The Joanna Briggs Institute (Peters et al. 202013)) provide useful 
summaries of methods for developing a protocol for a scoping review.  A scoping 
review should be performed in a way that minimizes bias for future systematic 
reviews and meta-analyses.  Because of the importance of limiting bias, consider 
whether it is appropriate for those involved in the review to also participate in 
developing the protocol for the planned systematic review.  Also, consider how 
concepts and presence or absence of certain inclusion criteria might impact 
objectivity of the reviewers.  For example, if the scoping review is focused on 
concepts rather than results, objectivity may be maintained, so that the same group 
may work on both the scoping review and the protocol for the planned systematic 
review. 
 
The scoping review protocol should include the following components: 
 
a.  Defined research question 
The research question for a scoping review should be consistent with the 
objectives of the scoping review.  The research question should include the 
population (e.g., species and class, if needed), the primary topic, and the context.  
Sub-questions may be necessary if the evidence needs to be divided by 
 
11 Armstrong, R., B. J. Hall, J. Doyle, and E. Waters. 2011. Cochrane Update. Scoping the scope of a cochrane 
review. J Public Health (Oxf) no. 33 (1):147-50. doi: 10.1093/pubmed/fdr015. 
12 OBrien, K, D. Levac, A Tricco, W Zarin, E. Lillie, and S. Straus. Current best practices for the conduct of 
scoping reviews. Available at: http://www.equator-network.org/wp-content/uploads/2016/06/Gerstein-Library-
scoping-reviews_May-12.pdf. University of Ontario 2016. 
13 Peters, M. D. J., C. Marnie, A. C. Tricco, D. Pollock, Z. Munn, L. Alexander, P. McInerney, C. M. Godfrey, and 
H. Khalil. 2020. Updated methodological guidance for the conduct of scoping reviews. JBI Evid Synth no. 18 
(10):2119-2126. doi: 10.11124/jbies-20-00167. 
7  Contains Nonbinding Recommendations 
populations or there are multiple topics being evaluated.  Unlike systematic 
reviews, research questions for scoping reviews do not restrict the evidence to 
certain dosages, single outcomes, or study types. 
Examples of appropriate research questions include: 
  What effectiveness outcomes are reported following the use of [drug or 
drug class] in [population of interest]? 
  What formulations of [new animal drug/drug class] are reported for use 
[list of broad indications] in [species/class]?  
  What comparative interventions (control group(s)) are reported in the 
evaluation of the effectiveness of [new animal drug/drug class]? 
  What adverse effects are reported following the use of [drug or drug class] 
in [species or range of species]? 
b.  Literature search strategy 
The search strategy including the terms and databases or other sources of 
information (proprietary reports, conference proceedings, etc.) should be clearly 
defined in the protocol.  When searching a database, the search terms and strategy 
should be chosen with a consideration for the standard terms or dictionaries used 
for that database.  The search terms and strategy should allow for sufficient 
breadth of coverage (published and unpublished, including proprietary research 
reports; reviews and primary research) while also balancing the feasibility of the 
review.  Broad scoping review questions have the potential to lead to searches that 
yield a tremendous amount of literature, and limitations (e.g., language, date 
published) should be carefully considered to allow for a comprehensive, yet 
feasible review in terms of time and resources. 
 
In order to refine search terms, an initial search of one database followed by a 
review of words in the title, abstract, and keywords may assist sponsors in the 
development of final search strategies for multiple databases.  Revisions to the 
search terms and methods may be needed during the search process if additional 
keywords are identified or new sources are discovered.  Protocol amendments that 
include a discussion of the changes and justification are expected.   
  
The choice of databases should be clearly stated in the protocol and be made 
based on the review question with an aim of obtaining the most relevant literature. 
 
The use of a librarian or other information specialist is recommended in the 
search term/strategy development and refinement.  Reviewing the reference list of 
literature obtained in the initial search and/or contact with authors to request 
access to other publications may be appropriate depending on the topic, objective, 
and breadth of the literature.  In some cases, these procedures are not feasible for 
scoping reviews and should be reserved for the systematic review. 
 
8  Contains Nonbinding Recommendations 
c.  Selection of studies 
The protocol should describe the process and personnel (logistical details) used to 
select studies for inclusion in the scoping review.  This process should result in 
study selection in a consistent manner that minimizes introduction of bias.  At 
least two reviewers are recommended for screening the literature or other 
information sources.  A process for comparing results and resolving 
disagreements should be described in the protocol for the scoping review.  
Consistency should be assessed after screening a limited number of publications 
and protocol amendments created as needed to simplify and/or clarify the 
screening and eligibility process and improve the consistency between reviewers.  
 
A two-step process is recommended for efficiently selecting studies from which 
to extract information.  In the screening phase, study titles, abstracts, and, in some 
cases, keywords are examined to eliminate irrelevant publications retrieved by the 
search.  The protocol should state how results without abstracts should be 
screened as these reports have limited information on which to base screening 
decisions.  The full text of publications that pass the screening phase should be 
reviewed during an eligibility phase to determine whether they meet the inclusion 
criteria; publications meeting inclusion criteria should have pre-specified 
information extracted, including data for potential inclusion in a meta-analysis if 
appropriate. 
  
d.  Extracting information from eligible studies   
A detailed process for extracting data from eligible studies should be included in 
the scoping review protocol.  At a minimum, the following data should be 
extracted from each publication or other reference: author(s), date of publication, 
country in which the study was conducted, objective(s) of the study, description 
of study population (numbers, species, class), methods, intervention, control 
comparator, outcomes, and a brief list of key findings.  Similar to the study 
selection process, the protocol should specify that the review team will meet and 
discuss the data extraction process after the extraction from a limited number of 
studies to determine if revisions to the process are needed and to ensure all 
necessary data to address the review question(s) are extracted.  Protocol 
amendments should be written as necessary.  
 
e.  Summarizing and reporting results 
The protocol should describe how the results will be presented and described. 
Scoping reviews generally do not include a statistical analysis or a summary of 
quantitative safety or effectiveness results.  In fact, such quantitative summaries 
are discouraged when scoping reviews are being used to develop the protocol for 
a systematic review because they are not supported by the broad objectives and 
associated methodology of the scoping review.  However, a qualitative summary 
which addresses the objective(s) of the scoping review should be provided.  The 
number of records identified, duplicates removed, number of 
9  Contains Nonbinding Recommendations 
publications/references that met screening and/or eligibility criteria, and the final 
number of studies selected for data extraction should be included in the summary. 
3.  Regulatory Systematic Review (SR)14 
The purpose of a regulatory systematic review is to answer a specific question or to 
reach a specific, evidence-based regulatory decision or recommendation.  Systematic 
reviews aim to minimize bias by using explicit, systematic methods.  In a regulatory 
systematic review, studies should be critically evaluated to ensure that they are 
relevant to the regulatory question and that the decision-making procedure or 
statistical analysis is appropriate for the intended purpose.  In most systematic 
reviews used to inform healthcare decisions or make evidence-based 
recommendations, many publications/references may be eliminated, but the review 
may still be useful as supportive information.  However, in a regulatory SR, 
eliminating many publications/references may lead to an inability to move forward 
with a regulatory decision or recommendation. 
The results of a regulatory SR are specific to the particular animal drug product under 
consideration for the stated indication and condition(s) of use; conclusions cannot be 
transferred to another similar product or to a product from the same drug class. 
a.  Critical factors 
Two issues that should be considered by sponsors early in the SR development 
process are the drug product formulation and the endpoints to establish safety or 
effectiveness, because they often affect the feasibility of using a regulatory SR 
approach to satisfy technical section15 requirements for a new animal drug.  These 
issues should be well-defined in the protocol. 
i.  New animal drug product formulation 
The formulation includes the active drug ingredient as well as the inactive 
ingredients.  The SR should evaluate the formulation of the new animal drug 
for which approval is sought and which is produced in accordance with 
appropriate manufacturing practices (i.e., final formulation).  The final 
formulation and any acceptable deviations from the final formulation should 
be defined in the protocol.  Depending on the purpose of the SR (e.g., 
effectiveness, target animal safety), the decision to include or exclude an 
individual study based on the formulation may differ, as other formulations 
may also include information useful for safety evaluations (e.g., differences in 
exposure).  Formulation should be taken into consideration in the selection of 
 
14 For the purposes of this guidance, the term systematic review is used synonymously with regulatory systematic 
review. 
15 Information to support the approval of an NADA are contained in seven technical sections: Effectiveness, Target 
Animal Safety, Human Food Safety, CMC, Environmental Impact, Labeling, and All Other Information.  See GFI 
#132, Administrative Applications and the Phased Review Process, (May 2018). 
10  Contains Nonbinding Recommendations 
studies that are appropriate for inclusion.  All individual studies included in 
the SR should have sufficient detail to confirm the identity of the drug 
included in the study for comparison to the new animal drug.  
Literature using the proposed final formulation manufactured by or for the 
sponsor provides the best, most relevant evaluation and the highest 
evidentiary weight.  Unless appropriate justification is provided, literature that 
does not use the final formulation of the proposed new animal drug product 
provides less weight in the evidentiary support scheme.  Formulation changes 
to a drug product may occur over time and will be evaluated on a case-by-case 
basis to determine their significance.  Such formulation changes may alter the 
identity, strength, quality, purity, or potency of the drug.  If there are 
differences in the formulations of the drug(s) reported in the published 
literature and the proposed new animal drug product, the sponsor should 
carefully evaluate the formulation differences and the impact of those 
differences on the safety or effectiveness evaluation.  Sponsors should justify 
how information from references that do not use the proposed final 
formulation supports the approval of the specific proposed product.  
References that are not relevant to the evaluation should be eliminated.  If a 
sufficient number of studies using an acceptable formulation are not available 
and/or a connection to information found in the Chemistry, Manufacturing, 
and Controls (CMC) technical section cannot be made, the SR approach may 
not be appropriate. 
ii.  Choose appropriate endpoints 
As discussed above, studies should be critically evaluated to ensure that they 
are relevant to the regulatory question.  SRs should assess the scientific 
outcome(s) associated with the use of the drug, whether negative or positive.  
Sponsors should consider whether there are a sufficient number of studies that 
report the appropriate finding(s) in a consistent manner so as to allow for an 
evaluation of the safety or effectiveness of the new animal drug product.  A 
scoping review, as described in section III.B.2. Scoping Review, may be 
instrumental in selecting endpoints of interest supported by the literature as 
well as determining whether a sufficient number of studies are available to 
support safety or effectiveness. 
b.  Development of a protocol for an SR 
Before conducting an SR, sponsors should define an appropriate review question 
and write a protocol.  In many cases, a scoping review of relevant literature will 
also assist in the development of the protocol.  Sponsors should consider the 
resources necessary to conduct an SR, including the need for an information 
specialist, software programs to document the study selection process and to carry 
out the SR, and the time necessary for the review team to implement the SR 
process. 
11  Contains Nonbinding Recommendations 
i.  Developing the review question: 
Various sources16,17,18 describe SRs as a means to collate all evidence that fits 
pre-specified eligibility criteria in order to address a specific question.  An 
organized and well-conducted systematic review begins with the formulation 
of a focused problem or question.  The problem or question states the 
objective of the review.  The question usually takes the form of Population + 
Intervention (or Exposure) + Control + Outcome (PI(E)CO).  The WHO 
Handbook19 describes the key components and provides examples of a well-
formulated question for SRs.  Although most of these sources are focused on 
questions related to human medicine, many elements are equally applicable to 
veterinary medicine.  In addition to the general framework for question 
formulation, regulatory SRs should be designed to answer a specific 
regulatory question. 
Following the PI(E)CO format, a review question for a regulatory 
systematic review will usually include the following components: the study 
animal population/intended species and class (P); the new animal drug product 
and in some cases the specific indication (I); the type of control, such as 
untreated concurrent controls and/or active concurrent controls (C); and 
endpoints (outcome measures) (O).  For example, the review question for an 
SR to demonstrate effectiveness of a new animal drug may be described as 
follows: To evaluate the effectiveness of [new animal drug product name] for 
[specific indication] as compared to [control group identification] in [animal 
species/class] based on [endpoint/outcome measures]. 
ii.  Scope of relevant literature: 
Once the review question has been formulated, and before developing the 
protocol for the SR, the sponsor should perform a scoping review of available 
literature for the purpose of developing the review question and/or evaluating 
the feasibility of a regulatory SR (see section III.B.2. Scoping Review).  
Many factors influence the number of studies that may be included in the 
regulatory SR to address the question of interest (e.g., intended population, 
 
16 Centre for Reviews and Dissemination. Systematic Reviews CRDs guidance for undertaking reviews in health 
care (2009).  Available at: https://www.york.ac.uk/media/crd/Systematic_Reviews.pdf - Accessed on March 2, 
2023. 
17 European Food Safety Authority. Guidance of EFSA: Application of systematic review methodology to food and 
feed safety assessments to support decision making (2010).  Available at: 
https://efsa.onlinelibrary.wiley.com/doi/abs/10.2903/j.efsa.2010.1637 - Accessed on March 2, 2023. 
18 P. T. Higgins et.al. Cochrane Collaboration (2011). Cochrane Handbook for Systematic Reviews of Interventions 
version 6.0 (updated February 2021).  Available at: https://training.cochrane.org/handbook - Accessed on March 2, 
2023. 
19 WHO Handbook for Guideline Development Geneva, World Health Organization.  Available at: 
https://www.who.int/publications/i/item/9789241548960  - Accessed on March 2, 2023. 
12  Contains Nonbinding Recommendations 
breadth of indication, quality of studies, assessment of bias of studies, the 
inferential value of the available studies, and independent substantiation 
across the studies).  Although there is no standard or minimum number of 
studies which should be included, the number of studies should be sufficient 
to support a regulatory decision commensurate with the regulatory standards 
currently in place for prospective studies.  If a meta-analysis is proposed, the 
number of studies included should provide adequate statistical power. 
iii. Writing the protocol: 
All regulatory SRs should be conducted in accordance with a protocol. 
 
Protocol review by CVM is not required, but it is strongly recommended for 
any study intended to support an application.  Protocol concurrence helps to 
prevent expenditure of resources on a study that CVM is less likely to accept.  
Sponsors are encouraged to discuss specific questions about protocol design in 
early communications with CVMs Office of New Animal Drug Evaluation 
(ONADE).  
 
At a minimum, the protocol should include the following components: 
 
  Study objective:  
The protocol should include a clear statement of the study objectives (e.g., 
the objective of the study will be to evaluate the effectiveness of a specific 
formulation of drug, given at a defined dosage, for specific indications 
(and conditions of use) in specific species/classes).  The objectives of the 
study are generally synonymous with the review question. 
  Standard of conduct for SRs: 
The SR should be conducted in accordance with an appropriate standard 
of conduct.  Systematic reviews are, by nature, retrospective, and do not 
meet the definition of either a clinical study or nonclinical laboratory 
study.  Elements of standards of conduct that apply to systematic reviews 
include: protocol development; organizational structure to ensure 
appropriate control of the study (e.g., investigator responsibilities, 
oversight (monitoring), quality assurance, quality control, and 
qualifications of personnel); procedures to ensure appropriate study 
documentation and archiving; and the documentation of the study conduct 
and results in a final study report.  Standard expectations for data quality 
9attributable, legible, contemporaneously recorded, original or a true copy, 
and accurate (ALCOA)) and integrity (credible, consistent, corroborative 
(CCC)) apply. 
  Control type:  
13  Contains Nonbinding Recommendations 
The systematic review protocol should include a design which permits a 
valid comparison to an appropriate control group and should evaluate the 
drug in the appropriate study population (species/class(es)).  It should use 
methods to minimize bias on the part of observers and analysts of the data 
that are adequate to prevent undue influences on the results and 
interpretation of the study data.  The systematic review should include 
procedures to identify, evaluate, and minimize bias both within an 
individual study and across the studies included in the systematic review. 
The type of control chosen should appropriately reflect the review 
question and endpoints of interest and should adequately characterize the 
effect and variability in outcome in the population of interest in the 
absence of the new animal drug.  Generally speaking, there are four types 
of control groups: untreated concurrent control, placebo control, active 
controls, or historical controls (21 CFR 514.117(b)(4) and the 2015 Joanna 
Briggs Institute Reviewers Manual). 
In general, the most suitable control group data source is one that can be 
generated from the eligible studies included in the SR that also had 
treatment groups included in the meta-analysis (concurrent control).  
However, even if the studies selected for the SR are 
randomized/controlled studies, there may not be a sufficient number of 
included studies with the selected control group (negative control vs. 
active, etc.).  In many cases, a mixture of study designs may be available 
for potential inclusion in the SR, including, in some cases, studies which 
do not have a concurrent control group.  Studies that do not have the 
control group of interest should not be automatically excluded from the 
SR.  In situations where not all eligible studies include the control group 
of interest, mathematical procedures may be employed to adjust the 
estimated control group effect size to account for unknown extraneous 
influences (Hunter, Jensen, and Rodgers 2014).20 
If a control group cannot be compiled from the studies that also had 
treatment groups included in the meta-analysis, use of a historical control 
group may be appropriate for the regulatory decision in certain situations 
(e.g., studies in which the effect of the new animal drug is self-evident or 
studies of diseases with high and predictable mortality, or signs and 
symptoms of predictable duration or severity, or, in the case of 
prophylaxis, predictable morbidity) (see 21 CFR 514.117(b)(4)(iv)). 
  Literature search strategy: 
A literature search strategy should be described which has a high 
likelihood that articles relevant to the review question will be retrieved.  
 
20 Hunter, J.E., J.L. Jensen, and R. Rodgers. 2014. The control group and meta-analysis. Journal of Methods and 
Measurements in the Social Sciences no. 5 (1):3-21. 
14  Contains Nonbinding Recommendations 
The protocol should include a description of the databases, search terms 
(keywords and Boolean operators), date and language restrictions, plans 
for hand-searching of certain publications (e.g., review articles) or 
personal contact of scientists, and a search of other sources of information 
such as conference proceedings, unpublished studies, theses, or 
dissertations. 
Sponsors should include relevant pilot work or otherwise non-publicly 
available, proprietary studies in the regulatory SR.  By not restricting the 
studies to those that are published, publication bias may be reduced. 
The methodology of indexing within a database (e.g., the use of controlled 
vocabulary) should be considered in the design of the search strategy.  As 
with scoping reviews, the inclusion of an information specialist in the 
design and implementation of the literature search is recommended.  
Overall, the description should be sufficient to allow the search to be 
repeated with the same results. 
  Study selection (screening and eligibility assessment):  
A highly sensitive literature search may retrieve many studies which are 
not relevant to the SR.  Therefore, the protocol should describe methods 
for choosing the studies including first screening the full list of literature 
(based on title, abstract, and keywords) and then reviewing full reports to 
determine the eligibility for inclusion in the SR.  Appropriately designed 
screening inclusion and exclusion criteria are important for identifying 
literature that will contribute to a comprehensive database in an efficient 
manner without excluding relevant literature.  The criteria should ensure 
the selection of studies which are designed to answer the review question 
for the particular drug formulation for the indication and conditions of use.  
The protocol should describe the use of more than one reviewer for 
conducting the screening and eligibility assessments to minimize the risk 
of error and/or bias.  In addition, the protocol should describe the process 
for resolving disagreements between reviewers, if they occur (e.g., use of 
a third independent reviewer).  The final study report should describe the 
numbers of reports that were screened, as well as the number that passed 
screening and eligibility phases and were ultimately included in the 
qualitative or quantitative (meta-analysis) assessment. 
 
Examples of screening criteria: 
 
Type of study: The types of studies utilized for the review will depend 
on the objectives of the study.  Examples include prospective 
randomized studies, cluster randomized control trials (RCTs), some 
types of non-randomized controlled studies, cohort studies, and case 
control studies.  Review articles are generally excluded but are used 
for hand-searching of additional references. 
15  Contains Nonbinding Recommendations 
Study animals: The studies are usually limited to the species (and class 
if necessary) for which the new animal drug is intended. 
Treatment: In the screening phase, criteria are usually specific only to 
the active ingredient because the title, abstract, and/or key words do 
not always provide enough information to identify specific drug 
products.  At this phase, citations that are specific to alternate dosage 
forms or formulations which would not be used in the SR are 
excluded. 
Outcome measure: Whether or not a study includes a particular 
outcome measure is not always evident from the title, abstract, or 
keywords.  Broad criteria are necessary to avoid excluding relevant 
studies.  For example, if the outcome of interest is specific to a disease, 
it would be appropriate to include citations for studies in which a drug 
is used for the treatment of that disease.  The evaluation of the full text 
of the study report may be necessary to determine if the outcomes of 
interest were used in the study. 
For those citations with insufficient information to enable a screening 
evaluation using the inclusion/exclusion criteria, the protocol should allow 
for an evaluation of the full report in the eligibility phase of the study.  For 
example, some citations (particularly those in foreign languages and/or 
without abstracts) do not have a sufficiently detailed title to allow for an 
appropriate screening assessment.  If, after reviewing the full text, the 
reviewer determines that the report does not meet the screening criteria, it 
should be included in the counts of reports that did not pass the screening 
phase of the SR.  
Generally, the eligibility criteria build upon screening criteria and require 
more specific information that is found in the full text of the study report. 
 
Examples of eligibility inclusion/exclusion criteria: 
 
Treatment: For many SRs, eligible studies include a specific drug 
product (including the intended formulation).  Criteria should be 
established to allow for confirmation of formulation and other 
information as needed and consistent with the purpose of the SR.  
Animal information: If certain animal characteristics (e.g., disease 
state) are critical to the objectives of the study, these should be defined 
in the eligibility criteria. 
Outcome measure(s): Outcome measures should be defined with the 
specificity necessary for the objectives of the study.  Typically, these 
outcome measures are described with the same level of detail as 
required for a prospective study to demonstrate the safety or 
16  Contains Nonbinding Recommendations 
effectiveness of the new animal drug.  
Confounding factors: If certain confounding factors would invalidate 
the interpretation of the study in accordance with the review question, 
these should be described in the eligibility criteria.  For example, if the 
SR is designed to evaluate the effectiveness of an antiparasitic drug 
against a certain parasite, the administration of an additional 
concurrent antiparasitic drug with known activity against that parasite 
in a study would not allow the inclusion of that study in the SR. 
  Data extraction plan:  
The protocol should describe the methods for data extraction from studies 
that meet the screening and eligibility criteria.  The data extracted from the 
study should include qualitative and/or quantitative information 
(depending on the objectives of the SR), information related to the 
screening and eligibility determination, characteristics that relate to the 
quality of the study, and data necessary for the synthesis and analysis of 
the data (if applicable). 
Examples of the information that may be extracted from each study 
include, but are not limited to: authors, year of publication, study animal 
identifying information (class, breed, age, physiological condition, etc.), 
case definition, location of study, identification of treatment or control 
arm, number of animals treated, number of animals used in the statistical 
analysis, product specific information (formulation, dose, route of 
administration, etc.), endpoint identification, use of a concurrent control 
group, experimental unit, randomization information, use of masking, 
quality standard to which the study was conducted (GCP, GLP, unknown), 
identification of any quality assurance or monitoring procedures, 
qualifications of study personnel, availability of raw data, how endpoint 
variability is reported (error mean square, standard error of the mean, etc.), 
and identification of any field safety assessments (e.g., clinical exams, 
clinical pathology, necropsy, and/or histopathology).  Contact with authors 
or access to raw data may be helpful in addressing gaps in data availability 
or quality assessment that exist in the publications (e.g., for verification of 
masking, exclusion of publications due to lack of information, connecting 
the formulation in the publication to the formulation to be evaluated in the 
CMC technical section). 
The extracted data should be entered into an appropriate database which 
can be used for quantitative or qualitative evaluation. 
  Study quality assessment  
The protocol should describe the assessment criteria for individual studies 
in order to identify study limitations such as lack of allocation 
17  Contains Nonbinding Recommendations 
concealment, lack of masking, completeness of data, and incomplete or 
selective accounting of outcomes.  The criteria and methods for the 
assessment should be defined in the protocol to ensure consistent 
application for each study. 
The protocol should select the most likely types of bias to evaluate based 
on the types of studies (e.g., RCTs, observational).21  At a minimum, the 
protocol should describe the assessment of bias in individual studies; 
define the criteria for the determination that the risk of bias is high, 
low, or uncertain for each bias type; and state that the support for the 
assessment will be documented as part of the data extraction process. 
The protocol should state how the SR will be assessed for the overall 
quality of evidence, including, but not limited to, assessment of individual 
study limitations, research group bias (e.g., if the bulk of data comes from 
one group and how that is weighted), reporting biases (e.g., publication 
bias, time lag bias, location bias, citation bias, language bias, outcome 
reporting bias), magnitude of effect, dose response, precision of estimates, 
consistency of results, and directness of evidence. 
  Statistical analysis methodology:  
The protocol for each study should describe the plan for the qualitative or 
quantitative assessment, depending on the objectives of the study, 
including any statistical analysis or risk assessment approach.  If the intent 
of the SR is to conduct a meta-analysis, the protocol should include 
appropriate methods for statistical analysis and assessment of bias which 
are adequate to assess the effects of the new animal drug. For additional 
information on meta-analysis, see section III.B.4. Meta-analysis below.  
  Results presentation: 
The protocol should describe the methods that will be used to present the 
findings of the study (forest plots, summary of findings tables, etc.).  In 
addition to the findings presented, complete references including complete 
and accurate English translations of foreign language references must be 
provided (21 CFR 514.1(a)) and any raw data available for the studies 
included in the assessment should be provided. 
  Basis of study conclusion:  
The protocol should describe the methods that will be used to evaluate the 
quality of the evidence and interpretation of the results of any statistical 
analyses.  The discussion should identify remaining gaps and characterize 
 
21 Suggested risk of bias criteria for EPOC reviews.  EPOC Resources for review authors.  Available at: 
https://epoc.cochrane.org/resources/epoc-resources-review-authors - Accessed on March 2, 2023. 
18  Contains Nonbinding Recommendations 
any limitations to the conclusions that may be drawn from the literature or 
caveats which exist.  Sponsors should formulate proposals addressing any 
gaps by means of a field study, protocol-controlled retrospective study, or 
other acceptable method. 
4.  Meta-analysis 
Depending on the objective and endpoints of the systematic review, CVM may 
recommend a meta-analysis within an SR.  The term meta-analysis, as used in this 
document, refers to the combining of evidence from relevant studies using 
appropriate statistical methods to allow inference to be made to the population of 
interest.22  Results from the meta-analysis provide a more general estimate of the 
effect than those derived from individual studies.  A meta-analysis includes an 
estimate of effect size (the strength or the magnitude of the effect of an independent 
variable [treatment] on a dependent variable [outcome] in an experiment) and an 
evaluation of statistical significance of effect size (this includes an evaluation of 
variation of effect size between and within studies, and an assessment of bias).  
Subject level data is not required to conduct a meta-analysis.  A meta-analysis may be 
conducted with data aggregated to the level of each treatment group, combined 
treatment groups, or study.  For example, the mean, variance, proportion, effect size, 
number of successes, number of failures, and sample size from each treatment group, 
combined treatment group, or study, may be used as data values or may be used in 
combination to calculate data values for the outcome of interest.  
a.  Meta-analysis protocol: 
Procedures for the meta-analysis should be provided in the SR protocol which should 
include a complete statistical analysis plan with sufficient details to address the type 
of outcome to be analyzed (e.g., mean, proportion, score), the model or statistical 
method (e.g., generalized linear mixed model, Kaplan-Meier curves), and any factors 
to be included in the analysis (fixed effects, random effects, etc.).  The statistical 
analysis plan should also include details and criteria to address the following 
elements: the power of the meta-analysis, investigation of heterogeneity, investigation 
of sensitivity of the findings, publication bias, and decision rule. 
i.  The power of the meta-analysis 
The protocol should include a justification for a sample size sufficient to 
achieve the desired statistical power (typically this is 80 percent).  The ability 
of the meta-analysis to provide evidence of effectiveness is a function of the 
number and types of studies that are included in the analysis, as well as the 
number of relevant treatment arms (i.e., groups in a clinical study delineated 
 
22 From draft GFI, Meta-Analyses of Randomized Controlled Clinical Trials to Evaluate the Safety of Human 
Drugs or Biological Products (November 2018).  When final, this guidance will represent FDAs current thinking 
on this topic. 
19  Contains Nonbinding Recommendations 
by intervention received) (Cafri, Kromrey, and Brannick 2010,23 Hedges and 
Pigott 2001).24  The sample size justification should also consider the variance 
and effect size of the intervention.  
  Investigation of heterogeneity 
Heterogeneity (statistical heterogeneity) is evident if observed 
intervention effects are more different from each other than expected 
due to random error alone.  Heterogeneity may exist if there is 
variability among the studies included in the SR.  Variability in 
intervention effects may be due to clinical diversity (i.e., variability in 
the subjects, intervention types, and outcomes studied), 
methodological diversity (i.e., variability in study design, analysis 
method, and risk of bias), or both. 
Investigation of heterogeneity (within- and between-paper 
heterogeneity) may be based on Cochrans Q-statistic and Higgins I-
squared value as described in the Cochrane Handbook (Higgins and 
Green 2011).25  If these values indicate heterogeneity, then an 
investigation of the most appropriate mixed effects model is needed.  
If heterogeneity is not found, then a statistical analysis using a fixed 
effects model may be most appropriate. 
  Investigate the sensitivity of the findings 
Study conclusions should be based on a primary statistical analysis 
described in the protocol.  However, an SR with a meta-analysis often 
involves a sensitivity analysis which is an investigation of the impact 
decisions made during the study design process (i.e., study inclusion 
criteria, outcome metrics, and analysis methods) may have on study 
conclusions.   
A discussion of the results of a sensitivity analysis should also provide 
information to enhance the conduct and decision-making process of 
future related studies. 
  Publication bias 
Publication bias occurs when the decision to publish or not publish the 
 
23 Cafri, G., J. D. Kromrey, and M. T. Brannick. 2010. A Meta-Meta-Analysis: Empirical Review of Statistical 
Power, Type I Error Rates, Effect Sizes, and Model Selection of Meta-Analyses Published in Psychology. 
Multivariate Behav Res no. 45 (2):239-70. doi: 10.1080/00273171003680187. 
24 Hedges, L. V., and T. D. Pigott. 2001. The power of statistical tests in meta-analysis. Psychol Methods no. 6 
(3):203-17. 
25 Higgins, P.T., and S. Green. 2011. Cochrane Handbook for Systematic Reviews of Interventions.  Available at: 
http://handbook.cochrane.org.  In: Cochrane Collaboration. 
20  Contains Nonbinding Recommendations 
results of an individual study is influenced by the outcome of the 
study; for example, studies that report a large effect size or beneficial 
therapeutic effect may be published, while studies that show no effect 
or a very small effect size may not be published.  Funnel plots and 
Eggers regression are examples of analyses which may be performed 
to detect and evaluate publication bias.  The criteria for interpreting 
publication bias should be defined in the protocol.  
  Decision rule 
Criteria on which a study conclusion (for safety and/or effectiveness) 
will be based should be included in a meta-analysis.  Data analysis 
results, safety information, and the results of any bias investigation 
should be considered. 
5.  Submitting the SR and meta-analysis to CVM 
The SR (and its accompanying meta-analysis, if applicable, referred to as an SRMA) 
should be submitted as a technical section data submission (STARS code P).  
Similar to other data submissions, sponsors should submit a final study report which 
provides a description of the materials and methods, results, statistical analysis (if 
applicable), and conclusions of the study.  The final study report should include: a 
summary of the literature search, including the search criteria; numbers of 
publications/reports retrieved; a full accounting of the process of inclusion/exclusion 
during the screening and eligibility phases of the study; and a summary of all protocol 
deviations.  In addition, a copy of the protocol with all amendments and the full 
statistical analysis should be attached to the final study report.  Copies of raw data 
should be provided and should include the electronic databases identifying all studies 
retrieved from the literature search, identification of studies meeting screening and/or 
eligibility criteria, identification of excluded studies and reason for exclusion, data 
extracted from the studies included in the final literature review and meta-analysis, 
documentation of any protocol deviations including their impact on the study, and the 
qualifications of the investigator and any other key personnel involved in the study.  
The full text of study reports and publications included in the final literature review or 
meta-analysis should also be provided. All non-English publications must be 
submitted with complete and accurate English translations (21 CFR 514.1(a)).  
In some cases, it may be appropriate and more efficient to submit the SR in two 
phases.  The first phase could include information related to the conduct of the study 
through the eligibility phase.  This will allow CVM and the sponsor to agree on the 
database that is used for data extraction and statistical analysis.  The second 
submission could include the final study report and copies of all raw data as described 
above.  
6.  Labeling 
Draft labeling (for example, a products package insert) is submitted during review of 
21  Contains Nonbinding Recommendations 
target animal safety and effectiveness technical sections and should be submitted with 
literature-based technical sections as well.  Draft labeling language should adequately 
summarize the safety and effectiveness findings (for example, target organ toxicity, 
observed adverse events, percent effectiveness) as supported by systematic literature 
reviews and meta-analyses included in the submission.  However, full accounting or 
listing of individual publications as presented in SRs and meta-analyses is not 
necessary in draft labeling. 
IV.  SPECIFIC PROCESSES AND APPROVAL REQUIREMENTS 
A.  Early Information 
In the early stages of drug evaluation, scientific literature can help guide the discussion of 
the feasibility of a drugs development for a particular indication and identify potential 
issues that may be addressed as part of safety or effectiveness studies.  Information to 
support these early stages of development may be presented in various ways, such as 
material included in an initial Investigational New Animal Drug (INAD) file submission, 
a presubmission conference request, or to support a protocol. 
At this early stage in development, CVM does not expect literature reviews to be 
exhaustive.  A quantitative synthesis (e.g., SRMA) is not necessary.  Rather, a literature 
review at this stage should be of sufficient scope to provide an understanding of the novel 
issues the sponsor wishes to introduce and appropriately targeted to the goal of the 
submission.  Each review will be different, depending on the issues the sponsor wishes to 
discuss with CVM.  These issues may include: the drugs characteristics (metabolism, 
receptors, mode of action); the suitability of the indication; the reliability of endpoints for 
establishing effectiveness; highlighted data gaps that would be filled by a proposed study; 
and/or support for innovative study designs to demonstrate safety or effectiveness.26 
1.  Using Literature in the Early Stages of Drug Development 
Literature may be used as part of the initial submissions to an INAD file to address 
considerations such as: 
  Discuss the suitability of a novel indication:  
-  Is it reasonable to believe the drug may have the proposed effect? 
-  Is the effect measurable? 
-  Is the effect observable to the end user? 
-  Does the indication have utility to the end user? 
-  Could the indication be considered false or misleading? (FD&C Act 
 
26 A more comprehensive discussion of the goals and types of information for these early development discussions is 
presented in the CVM Program Policy and Procedures Manual 1243.2200 Submission and Review of Early 
Information (EI) Prior to Presubmission Conferences and Protocol Review. 
22  Contains Nonbinding Recommendations 
section 502(a))27  
  Provide information on metabolism or mode of action: this information may 
be useful to support a novel indication or highlight potential safety issues or 
systems at risk. 
  Discuss similarities to and differences from other approved products. 
  Identify gaps in existing data. 
  Characterize the target population: a particular class, age, or physiologic state 
(e.g., lactating dairy cows, growing calves). 
  Support the choice of the dosage for the development of safety and 
effectiveness studies: literature may be used to characterize the critical aspects 
of the dose-response relationship for those parameters relevant to the proposed 
indication. 
  If considering pursuing a systematic review/meta-analysis approach to support 
approval, a scoping review of the literature during the early development 
phase generally will be useful to assess the feasibility of that approach.  Refer 
to section III.B.2. Scoping Review for additional information on scoping 
reviews.  Scoping reviews are useful to: 
-  Determine availability of literature 
-  Refine the research question(s) 
-  Develop inclusion/exclusion criteria 
-  Identify gaps in existing knowledge 
-  Define appropriate comparators (control groups) 
2.  To Support Elements of a Protocol 
  Define and support the use of an endpoint as a well-defined and reliable 
means to evaluate effectiveness.  
  Narrow the scope of a study. 
  Define/justify the enrollment population for a study (i.e., inclusion and 
exclusion criteria). 
  Establish the adequacy of infection or infestation for dose confirmation 
studies for antiparasitic drugs (see GFI #90 (VICH GL7), Effectiveness of 
Anthelmintics: General Recommendations (October 2011)).  Published 
literature may provide some or all of the necessary information to enable a 
sponsor to justify a particular level of infection and distribution of infection 
among control animals as part of the development of a study protocol. 
 
27 Section 502(a) of the FD&C Act provides that a drug is misbranded if its labeling is false or misleading in any 
particular. 
23  Contains Nonbinding Recommendations 
  Establish the prevalence of a disease condition (used to estimate size of test 
population). 
  Define the current standard of care for a condition.  For some drug approvals, 
sponsors intend to demonstrate that a new animal drug provides an increased 
benefit over a current standard of care.  In these cases, the standard of care for 
a particular disease or pathologic condition is based on the scientific literature 
and sound and accepted professional judgment.  Some examples may include 
the use of a pain-relieving drug in addition to standard anesthetic regimens to 
control post-operative pain or the addition of a drug to treat heart failure in 
addition to standard medication(s) to treat the condition. 
  Provide background pharmacology information (receptor interactions, 
concentration/time dependent effects, absorption/distribution/metabolism/ 
elimination (ADME), formulation release characteristics, and prandial 
considerations may be useful for understanding how the drug achieves its 
effect and to identify potential hazards). 
  Identify properties of the formulation that may affect its safety or 
effectiveness, such as a modified release profile or the use of nano-materials. 
B.  Generic Animal Drugs 
1.  ANADA/and Generic INAD (JINAD) Files: 
Approval of an ANADA requires submitting data to satisfy six technical sections. 
Systematic review and meta-analysis (SRMA) would not be appropriate for 
addressing the majority of these technical sections.  A more limited set of references 
from the literature may be acceptable to supplement part of the requirements for these 
technical sections.  Appropriate use of the literature, or SRMA, in addressing the 
requirements of the applicable technical sections may be as follows: 
  Human Food Safety/Withdrawal period information: refer to section IV.F. 
Human Food Safety of this GFI pertaining to Human Food Safety decisions 
  Labeling: the generic sponsor will copy the currently approved label of the 
reference listed new animal drug (RLNAD) 
  CMC: refer to section IV.C. Chemistry, Manufacturing, and Controls of this 
GFI pertaining to CMC review 
  Environmental Impact: refer to GFI #89 (VICH GL6), Environmental Impact 
Assessments (EIAs) for Veterinary Medicinal Products (VMPs)  Phase I 
(March 2001) and GFI #166 (VICH GL38), Environmental Impact 
Assessments (EIAs) for Veterinary Medicinal Products (VMPs)  Phase II 
(January 2006) pertaining to environmental assessments 
  Bioequivalence:  because of the uniqueness of formulations attributable to 
manufacturing processes and formulation, etc., each generic sponsor will have 
to submit formulation and/or active pharmaceutical ingredient (API) specific 
data to address the bioequivalence of their product with respect to that of the 
24  Contains Nonbinding Recommendations 
RLNAD.  CVM considers it highly unlikely that there would be literature 
regarding the exact formulation using the same manufacturing process for a 
specific generic drug product.  Therefore, an SR and meta-analysis would not 
be appropriate or acceptable for demonstrating bioequivalence without 
confirmation that the formulation of the proposed generic drug product is the 
same as the RLNAD.  However, literature may be used to justify decisions 
made in a determination of bioequivalence, or to confirm that an unexpected 
result is appropriate for that API or product. 
2.  Suitability Petitions: 
  Suitability petitions allow prospective applicants to request permission to submit 
an application for a generic new animal drug product that differs from an RLNAD 
in certain specified ways (FD&C Act section 512(n)(3)).  Sponsors may use 
information from literature to support a suitability petition.  As a general matter, 
literature submitted in support of a suitability petition does not need to meet the 
requirements for an SRMA.  
C.  Chemistry, Manufacturing, and Controls 
In order to approve new animal drug products, including those where safety and 
effectiveness is established by reference to publications in the scientific literature, all 
relevant information as described in 21 CFR 514.1(b)(4) and (b)(5) must be submitted to 
support the CMC technical section.  Release and stability specifications are a critical 
aspect of the CMC technical section and verify the identity, strength, quality, purity, and 
potency of the drug product.  Typically, the drug product used in the safety and 
effectiveness studies and the marketed drug products are tested using the same set of 
release and stability specifications.  This establishes a link between the clinical studies 
and the marketed product and provides assurance that the marketed product will have the 
same product performance as the drug product used in the clinical studies.  If publications 
in the scientific literature are used to support the safety and effectiveness technical 
sections, the following information should be considered to determine if a link between 
the proposed CMC specifications and the published studies can be supported: 
  Was the specific proposed commercial formulation used in the literature? 
  Were the lots used in the published study tested according to the proposed release 
testing and are the results of the release testing published or available for review? 
  Does the sponsor have experience with manufacturing the product under current 
good manufacturing practices (CGMP) (FD&C Act section 501(a)(2)(B)) 
conditions and can historical data be provided to support the proposed release and 
stability specifications? 
If a direct connection cannot be made between the proposed commercial formulation and 
the published literature (e.g., a different drug product was used in the studies described in 
the published literature), the sponsor should consider: 
  If the literature indicates that a specific safety (e.g., byproduct of manufacturing 
25  Contains Nonbinding Recommendations 
process or stability that could lead to toxicity) or effectiveness (e.g., narrow 
therapeutic range) issue exists that should be controlled in the manufacturing 
process. 
  If bridging studies (e.g., bioequivalence) have been performed to demonstrate the 
relevance of the information in the literature to the proposed drug product. 
  Depending on the complexity of the drug product and the manufacturing process, 
if general specifications (e.g., assay 90-110 percent), based on appropriate VICH 
or CVM guidance documents or United States Pharmacopeia (USP) chapters or 
monographs, can be utilized. 
If there are any critical quality attributes of the drug product where a link to clinical 
safety and effectiveness data is needed (e.g., release characteristics, new dosage form, 
bioassay, viability), reference to published scientific literature alone may not be sufficient 
to support the approval of the new animal drug product. 
D.  Effectiveness 
1.  Scope of Use 
Literature may be used to fulfill all or part of the requirements for the effectiveness 
technical section for new animal drug product approvals or the reasonable expectation 
of effectiveness (RXE) technical section for conditional new animal drug product 
approvals.  For example, SRs and meta-analyses may provide substantial evidence of 
effectiveness for either all or a portion of the indication.  Individual literature reports 
may provide information to satisfy a particular data gap, lead to the identification of a 
data gap, or satisfy RXE. 
The degree of support that literature submissions may provide toward fulfilling 
requirements for substantial evidence of effectiveness or reasonable expectation of 
effectiveness cannot fully be determined until after review of the submission and 
review of other technical information such as chemistry and pharmacokinetic data.  
CVM encourages sponsors to request meetings early in the approval process to 
discuss options for presenting the available information, designing protocols, and 
determining viability of a path forward. 
2.  Dosage Characterization 
Dosage characterization is the justification of the dosage (dose or dose range, dosing 
frequency, and the dosing duration) and a characterization of the critical aspects of 
the dose-response relationship related to each intended use and associated conditions 
of use.  Dosage characterization is part of the effectiveness technical section of an 
INAD file and may be derived from dose titration studies, pilot studies, foreign 
studies, scientific literature, or other sources.  Scientific literature, including 
individual or multiple sources, may be used to support a portion or all of the 
justification of the dosage and may significantly assist protocol development.  For 
example, literature may provide information integral for the selection of optimal 
26  Contains Nonbinding Recommendations 
study time points or specify study design parameters for protocols for novel drugs and 
drugs with modified-release characteristics or extended duration of action.  In 
general, sufficient scientific literature to reasonably support the basis for the dose 
characterization is acceptable; for example, a narrative review.  Full scoping or 
systematic literature reviews are not routinely expected.  If the use of literature to 
fulfill a portion or all other technical sections is contemplated, any literature used to 
characterize the dosage should be identified and evaluated in an independent manner 
to avoid biasing a future systematic review. 
3.  Substantial Evidence of Effectiveness 
a.  Regulatory standards: 
Effectiveness must be demonstrated by substantial evidence consisting of one or 
more adequate and well-controlled studies (FD&C Act sections 512(d)(1)(E) and 
(d)(3); 21 CFR 514.1(b)(8)(ii); 21 CFR 514.4(a); and 21 CFR 514.117).  
Substantial evidence is defined in 21 CFR 514.4(a) as evidence consisting of one 
or more adequate and well-controlled studies ... 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.  
An SR intended to demonstrate substantial evidence of effectiveness of a new 
animal drug for an original or supplemental NADA must be adequate and well-
controlled (21 CFR 514.4(a)).  The protocol for an SR should provide details 
relative to the study design, conduct, and analysis in accordance with the 
characteristics of an adequate and well-controlled study (21 CFR 514.117(a)-(b)).  
When using an SR to demonstrate substantial evidence of effectiveness, the 
review objective is generally the same as a traditional clinical study (e.g., the 
objective of the study will be to evaluate the effectiveness of a specific 
formulation of drug, given at a specific dosage, for specific indications (and 
conditions of use) in specific species/classes). 
Things to consider when developing a proposal for an SR to demonstrate 
substantial evidence of effectiveness: 
  The regulations (21 CFR 514.4) require a demonstration of substantial 
evidence of effectiveness for the new animal drug, and 21 CFR 
514.117(b)(3) requires that adequate and well-controlled studies be 
conducted with ...a new animal drug that is produced in accordance with 
appropriate manufacturing practices, which include, but are not 
necessarily limited to, the manufacture, processing, packaging, holding, 
and labeling of the new animal drug such that the critical characteristics of 
27  Contains Nonbinding Recommendations 
identity, strength, quality, purity, and physical form of the new animal 
drug are known, recorded, and reproducible, to permit meaningful 
evaluations of and comparisons with other studies conducted with the new 
animal drug [emphasis added].  Therefore, for SRs, as is the case for 
other types of adequate and well-controlled studies, critical factors in the 
study design are the identity, strength, quality, purity, physical form, and 
critical quality attributes28 of the new animal drug product used in the 
study.  All individual studies included in the SR should have sufficient 
detail to confirm the identity of the drug product.  In some cases, author 
contact may facilitate the retrieval of additional product specific 
information (lot numbers, batch numbers, certificates of analysis) useful 
for the SR and confirmation of appropriate manufacturing practices. 
  Generally, if studies using a proposed new animal drug products final 
formulation are not available for inclusion in the SR (and accompanying 
meta-analysis, if applicable), this will limit the applicability of the 
information.29  The acceptability of published studies will depend on the 
complexity of the formulation, how much control the sponsor had over the 
manufacturing process, etc.  CVM will evaluate the drug product used in 
each published study included in the SR (and accompanying meta-
analysis, if applicable) using information on the identity, strength, quality, 
purity, and physical form.  The level of documentation and known 
information is usually not the same as what is included in a single 
adequate and well-controlled study submitted to CVM with raw data.  
However, the assessment of how much a formulation and other critical 
quality attributes can deviate from the proposed/final formulation is 
generally the same regardless of the type of study (SRMA or single 
prospectively designed study). 
  As noted in section III.B.3. Critical Factors, literature using the proposed 
final formulation manufactured by or for the sponsor provides the best, 
most rigorous evaluation and the highest evidentiary weight.  If a 
sufficient number of studies using an acceptable formulation are not 
available or a connection to information found in the CMC technical 
section cannot be made, the SR approach will be unlikely to demonstrate 
substantial evidence of effectiveness. 
  The sponsor should provide CVM with an assessment of the information, 
a meaningful evaluation of the new animal drug used in the published 
 
28 ICH Q8(R2), Pharmaceutical Development (November 2009). 
29 Formulation changes to a drug product may occur over time and will be evaluated on a case-by-case basis to 
determine their potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug as 
these factors relate to the safety or effectiveness of the drug.  These principles are discussed in more detail in 
Guidance for Industry #83, Chemistry, Manufacturing, and Controls Changes to an Approved NADA or ANADA 
(May 2007).  In some cases, studies will be necessary to establish the equivalence of different formulations (e.g., 
pharmacokinetic studies, and/or clinical studies as appropriate). 
28  Contains Nonbinding Recommendations 
report included in the SR (and accompanying meta-analysis, if applicable) 
and a justification that it is appropriate to use the data generated in the 
study along with other studies in the SR (and accompanying meta-
analysis, if applicable).  The decision about the value of the information 
from the published studies to the SR (and accompanying meta-analysis, if 
applicable) will be made with the collaboration of ONADEs Division of 
Manufacturing Technologies and the target animal review team. 
  Adequate and well-controlled studies, including SRs, include the use of 
methods to assess the animal response to the use of the new animal drug 
that are well defined and reliable (21 CFR 514.117(b)(8)).  Sponsors 
should consider whether there are a sufficient number of studies which 
report the appropriate endpoint(s) in a consistent manner which would 
allow for quantification of the effect of the new animal drug. 
b.  Protocol considerations specific to effectiveness: 
  Review question: The review question should closely match the objectives of 
the study and follow the format described in section III.B.3.b.i. Developing 
the Review Question of this guidance.  In general, effectiveness study review 
questions follow the format: Evaluation of the effectiveness of [drug product 
and dose if appropriate] for [indication] as compared to [control type] in 
[species/class/animal age as appropriate].  
  Definition of the control: Please refer to section III.B.3.b.ii. Writing the 
protocol (Control Type). 
  Inclusion/Exclusion Criteria: 
Examples of screening inclusion/exclusion criteria which may be assessed 
based on the title, abstract, and/or key words include: 
 
 
Screening Inclusion  Screening Exclusion 
 
Study types: Complete reports  Incomplete reports (abstracts and 
 
(published or unpublished) on  reviews), or insufficient information 
 
randomized controlled trials (RCTs),  to assess these criteria (incomplete 
 
cluster RCTs, and select non- reports may not be excluded if full 
 
randomized controlled studies  information could be obtained from 
 
the study investigator) 
Study includes intended target animal  Study includes animals that are not 
species and class  representative of the target animal 
species and class 
Use of the drug product of interest (at  Drug product of interest not a part 
screening phase, identification of  of the study 
active ingredient may be sufficient) 
29  Contains Nonbinding Recommendations 
Examples of eligibility inclusion/exclusion criteria based on assessment of the 
full text of the publication: 
Eligibility Inclusion  Eligibility Exclusion 
Drug product as defined in the protocol  Study does not include drug product 
as defined in protocol, or 
publication does not provide 
sufficient information to identify 
the drug product (unable to confirm 
formulation used in the study) 
Study uses intended label dosage (dose,  Dosage used in study inconsistent 
frequency, and route of administration)  with the intended label dosage 
Study includes the use of acceptable  Study includes the use of 
concurrent therapies (e.g., the studies  concurrent therapy that may 
may employ concurrent therapies per  confound the effectiveness 
the current standards of care; however,  evaluation 
these considerations should be 
described clearly within the protocol.) 
Study designed to evaluate endpoint(s)  Study not designed to evaluate 
of interest   endpoint(s) of interest 
Screening and eligibility inclusion and exclusion criteria should only evaluate 
whether the measurement of an effectiveness outcome is present and should 
not specify a particular effectiveness outcome for inclusion in the 
effectiveness database.  For example, studies that do not demonstrate the 
desired level of effect or that report a poor effectiveness outcome should not 
be excluded from the effectiveness database. 
  Basis of study conclusion: 
The protocol should clearly state the criteria on which study conclusions will 
be based.  The study objectives and the statistical analysis results should be 
considered when defining the criteria.  For example, a threshold for an effect 
size or a threshold for the limits of a confidence interval for the effect size 
could be used as criterion.  In addition, the study conclusion should also 
consider bias investigation results.  
4.  Reasonable Expectation of Effectiveness 
Section 571 of the FD&C Act (21 U.S.C. 360ccc) provides for a qualified approval 
pathway, open only to certain qualifying new animal drug products based on 
indication and type, called conditional approval.  Conditional approval allows a 
sponsor to legally market a new animal drug after demonstrating the drug is safe and 
manufactured in accordance with the full approval standards, and that there is a 
reasonable expectation of effectiveness.  To obtain conditional approval, all technical 
sections must be complete except the effectiveness technical section, which is 
30  Contains Nonbinding Recommendations 
replaced with RXE.  The sponsor can market the conditionally approved new animal 
drug product for up to 5 years while gathering the remaining data required to 
demonstrate substantial evidence of effectiveness.  The pathway requires annual 
renewal of the conditional approval to determine whether the sponsor is making 
sufficient progress toward meeting the effectiveness standard for full approval.  
Literature may be used as one of the pathways to support RXE.  Screening and 
eligibility criteria for publications that may be used to support RXE are generally the 
same as for substantial evidence of effectiveness; however, the overall body of 
evidence may be smaller and information gaps may still be present.  Full scoping or 
systematic literature reviews are not routinely expected but may be appropriate. 
 
E.  Target Animal Safety 
1.  Scope of Use 
Section 512 of the FD&C Act (21 U.S.C. 360b) establishes the requirements for new 
animal drug approval, including target animal safety.  See FD&C Act section 
512(d)(1)(A), (B), and (D) (21 U.S.C. 360b(d)(1)(A), (B), and (D)). 
Literature, including narrative reviews, SR, and meta-analysis, may be acceptable to 
fulfill all or part of the requirements for target animal safety for a new animal drug 
application or an application for conditional approval (see FD&C Act section 
571(a)(2)(B)).  Literature is most commonly used to evaluate the extent and quality of 
information available on the safety of a new animal drug for the proposed indication 
or proposed conditions of use, support the design of the target animal safety 
evaluation, and/or provide information to predict potential adverse effects in the 
target species.  In some cases, literature may provide all or a portion of the 
information required to demonstrate whether a new animal drug is safe for the 
intended use and conditions of use.  
CVM encourages sponsors to request meetings early in the development plan to 
discuss options for presenting the available information, designing protocols, and 
determining viability of using literature to fulfill some or all of the target animal 
safety requirements. 
2.  Preliminary Information 
GFI #185 (VICH GL43), Target Animal Safety for Veterinary Pharmaceutical 
Products (April 2009), describes the use of knowledge about the pharmacology and 
toxicology of an investigational veterinary pharmaceutical product (IVPP) to assist in 
the determination of the types of studies necessary in the evaluation of the safety of 
an IVPP in the intended species under the proposed conditions of use; in the design 
(dose, frequency of dosing, overdose levels, durations of treatment, and endpoints) of 
such studies; and in the prediction of potential adverse effects.  GFI #185 
recommends the use of published literature, in addition to preliminary studies from 
target and non-target laboratory animal studies, as potential sources of the 
pharmacology and toxicology data. 
31  Contains Nonbinding Recommendations 
A review of the published literature may provide information about the known 
pharmacologic and toxicological properties in target or non-target species of the drug, 
to include carriers, excipients, inactive ingredients, APIs, or about closely related 
compounds that may be useful in planning the target animal safety evaluation.  
Information that may be useful includes the following:  
  Mechanism of action 
  Mechanism of toxicity 
  Toxicological syndrome/target organs or tissues 
  Clinical signs of toxicity/biomarkers of toxicity 
  Time of onset and duration of clinical signs of toxicity 
  Variability/tolerance among animals (species, breed, class, age, or other 
differences) 
  Severity, chronicity, and likelihood of toxic effects 
  Differences by animal age/life stage/production class/breed 
  Pharmacokinetics/pharmacodynamics 
  Potential for drug-drug interactions 
  Effects of other diseases/conditions on toxicity 
  Endpoints that can be collected from other required studies 
  Effects on reproduction 
  Effects at the site of administration (injection, topical, etc.) 
Generally, a narrative literature review or a scoping review, rather than an SR, is 
appropriate for presenting the pharmacologic and toxicologic information to CVM for 
the purposes of supporting the target animal safety development plan and the design 
of safety studies. 
3.  Literature to Satisfy Target Animal Safety Requirements 
The safety of a new animal drug in the target animal is typically based on one or more 
non-clinical laboratory studies (margin of safety studies) and observations from field 
studies.  As described in GFI #185, other specific studies, such as reproductive safety, 
injection site, or other specifically designed studies, may be needed to address the 
animal safety requirements.  The need for these specific studies depends on the drug 
and the intended conditions of use.   
The literature may provide information from target and non-target species, including 
laboratory animals, which may be used in lieu of the margin of safety study or other 
studies (injection site, reproductive safety, etc.) typically needed to satisfy the target 
animal safety requirements, a justification that typical studies (or certain endpoints 
within these studies) are not needed, an identification of information gaps, or the 
32  Contains Nonbinding Recommendations 
identification of safety observations that could be obtained during the effectiveness 
study(ies). 
a.  Margin of safety study 
Typically, the margin of safety study includes multiples of the highest intended 
drug dosage (daily dose, frequency, and duration) where the study results 
demonstrate the margin of safety above the maximum dosage.  The study must 
adequately demonstrate that the new animal drug is safe for the intended target 
animal/class under the proposed conditions of use, that the chosen endpoints are 
the most appropriate outcomes for the evaluation of safety, and that valid 
inferences can be drawn to the target population.  The number of studies needed 
to assess overall safety, or a particular endpoint will depend on the size and 
number of studies, intended use/conditions of use, breadth of the indication, 
consistency of results, the quality of the studies, and/or the quality of the reporting 
of the studies. 
In some cases, a sufficient amount of information exists in the published literature 
and/or in preliminary studies to either: (1) justify that a margin of safety study is 
not needed (negligible systemic exposure to the API and based on pre-existing 
knowledge in pharmacology and toxicology there is no safety concern30); or (2) 
perform an SR (+/- meta-analysis) which provides adequate information to 
determine the safety of the new animal drug in the target animal.  The literature 
may provide a volume and variety of evidence that far exceeds the data 
traditionally available from a margin of safety study. 
b.  Performing an SR to satisfy target animal safety requirements 
When considering literature to satisfy any or all animal safety requirements, and 
before developing the protocol, the sponsor should perform a high-level initial 
screen of available literature with considerations such as dose, formulation, 
endpoints appropriate for an animal safety evaluation, conditions of use, and 
inferential value for the target population.  This screen should be performed in a 
way that minimizes bias in case a future SR and/or meta-analysis will be 
performed; the person or persons performing the high-level screening should not 
be involved in the design of the protocol for the conduct of the regulatory SR. 
An SR of the literature may provide a broader overview of the safety of the drug 
in the target animal population when compared to a more comprehensive 
evaluation in a small number of individual animals (e.g., a laboratory margin of 
safety study).  For some drugs and indications, an assessment under more variable 
conditions of use may be preferable for the evaluation of animal safety.  Typical 
assessment of animal safety relies substantially on clinical outcomes, assessments 
of those outcomes, and impacts on the animal with regard to determining the 
 
30 Per GFI #185, even if a margin of safety study is not needed, a safety study at the site of administration is 
recommended. 
33  Contains Nonbinding Recommendations 
margin of safety.  Statistical analyses may be of more importance in identifying 
dose response trends or observations of most interest. 
For an SR and/or meta-analysis to evaluate safety, the review question may be 
broad, to capture any abnormal observations related to administration of the new 
animal drug, or specific, to address a certain safety-related endpoint.  An adequate 
target animal safety assessment will include the identification of target organs, 
where possible, and confirmation of the margin of safety for the labeled dosage 
regimen (dose, route, frequency, duration) in the intended species/class(es). 
The SR should evaluate a specific formulation of drug produced in accordance 
with appropriate manufacturing practices.  Formulation should be taken into 
consideration when selecting the studies that are appropriate for inclusion.   
A meta-analysis may not be appropriate for all submissions that include a 
literature or systematic review.  Other types of analyses (i.e., a multicriteria 
decision analysis or a weight-of-evidence analysis) or a qualitative assessment 
may be more appropriate.  The available information should be used to determine 
what conclusions can be drawn, such as an evaluation of the risk of adverse 
events or safety concerns for the animal associated with the use of the drug at the 
proposed dose under the intended conditions of use, and identify any gaps 
remaining in the target animal safety evaluation.  Using the literature to develop a 
hazard characterization may be adequate to frame the further studies and study 
designs needed to meet the target animal safety requirements.  The strength of 
support provided by the body of available literature is useful in determining the 
number and type of necessary studies and the potential adverse reactions or safety 
impacts that may be observed.  If gaps are identified, the available information 
can be used to inform methods used to address the gaps and the design of one or 
more studies to address the gaps, which include alternative or non-traditional 
studies.  Information from the literature may be used to inform the design of the 
margin of safety study in an evaluation and the prediction of potential adverse 
effects that may occur in the target species. 
4.  Other Laboratory Safety Studies 
For certain indications or conditions of use and for certain dosage forms, additional 
safety studies, such as evaluation of injection sites or application sites for topically 
administered drugs, a reproductive safety study, or other specific studies, may be 
needed in addition to a margin of safety study.  Literature may be appropriate for 
addressing the requirements for these specifically designed studies as described in 
GFI #185. 
a.  Safety information from field studies: 
Studies conducted to evaluate effectiveness may provide a source of information 
which addresses important safety endpoints.  Studies included in an SR to address 
effectiveness, or the combination of sponsor-conducted studies and studies 
34  Contains Nonbinding Recommendations 
reported in the published literature, may provide adequate information to address 
certain animal safety considerations. 
b.  Standard of conduct 
CVM expects nonclinical laboratory studies intended for target animal safety to 
be conducted in accordance with GLPs.  An SRMA for target animal safety is not 
considered a nonclinical laboratory study, as defined by 21 CFR 58.3, but may 
include one or more nonclinical laboratory studies.  Generally, published studies 
do not state a standard of conduct and do not include the level of detail that permit 
assessment of all GLP requirements (or components).  Depending on the question 
asked for the SRMA, studies of multiple types or designs may be included in an 
SRMA for target animal safety.  
F.  Human Food Safety 
Published literature is normally considered in the human food safety evaluation of 
products regulated by CVM.  Information extracted from the literature can be used either 
as pivotal or as corroborative information in the human food safety assessment. 
1.  Microbial food safety (antimicrobial resistance) 
CVMs draft revised Guidance for Industry (GFI) #152, Evaluating the Safety of 
Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on 
Bacteria of Human Health Concern (December 2022), outlines a risk assessment 
approach to evaluate the microbial food safety of antimicrobial new animal drugs.  It 
states, [w]ithin the context of risk assessment, many possible mechanisms to address 
the development of antimicrobial resistance resulting from the use of antimicrobial 
new animal drugs in food-producing animals are available to the sponsor.  Alternative 
processes that may be more appropriate to a sponsors drug and its intended 
conditions of use may be used to characterize the microbial food safety of that drug. 
This guidance states the submission of current and relevant literature can be a source 
of quality data to characterize the hazard and to assess the risk to human health.  GFI 
#152 also provides examples of types of data and information that may be used. 
2.  Toxicology and residue chemistry 
CVM recommends a standard series of toxicology and residue chemistry studies (see 
GFI #3, General Principles for Evaluating the Human Safety of New Animal Drugs 
Used in Food-Producing Animals (June 2018)), but also accepts alternative 
approaches, such as risk-based or weight-of-evidence approaches that may include 
consideration of information from published literature.  Literature-based, 
scientifically valid evidence is often considered as supportive information in the 
review process.  Literature-based information may be accepted as the sole basis to 
satisfy toxicology and residue chemistry requirements on a case-by-case basis.  The 
type of information (level of details, study and data quality, etc.) in the published 
literature should be adequate to allow CVM to address a specific toxicology or 
35  Contains Nonbinding Recommendations 
residue chemistry question with reasonable certainty or be sufficient to meet the 
toxicology and residue chemistry requirements. 
V.  GLOSSARY 
For purposes of this guidance, the following definitions apply: 
 
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) and GFI #204, 
Active controls in studies to demonstrate effectiveness of a new animal drug for use in 
companion animals (December 2015)).  
Attrition bias: Bias due to systematic differences between treatment and comparison groups in 
withdrawals or exclusions from the results of a study (Hoffmann et al. 2017).31 
Citation bias: Citation bias refers to bias due to the citation or non-citation of research findings, 
depending on the nature and direction of the results (https://methods.cochrane.org/bias/reporting-
biases  Accessed on December 6, 2022). 
Critical Quality Attribute (CQA): a physical, chemical, biological, or microbiological property 
or characteristic that should be within an appropriate limit, range, or distribution to ensure the 
desired product quality.  CQAs are generally associated with the drug substance, excipients, 
intermediates (in-process materials), and drug product. 
Detection bias: Detection bias refers to bias due to systematic differences between groups in how 
outcomes are determined (Hoffmann et al. 2017). 
Grey literature: (1) studies not indexed in commercial bibliographic databases32; (2) materials 
and research produced by organizations outside of the traditional commercial or academic 
publishing and distribution channels.  Common grey literature publication types include reports 
(annual, research, technical, project, etc.), working papers, government documents, white papers 
and evaluations33; (3) conference proceedings; and (4) for the purposes of this guidance, grey 
literature may also include research produced by the sponsor (e.g., pilot studies and other 
proprietary reports). 
 
31 Hoffmann, S., R. B. M. de Vries, M. L. Stephens, N. B. Beck, Haam Dirven, J. R. Fowle, 3rd, J. E. Goodman, T. 
Hartung, I. Kimber, M. M. Lalu, K. Thayer, P. Whaley, D. Wikoff, and K. Tsaioun. 2017. A primer on systematic 
reviews in toxicology. Arch Toxicol no. 91 (7):2551-2575. doi: 10.1007/s00204-017-1980-3. 
32 See footnote 19 on p. 12. 
33 Grey Literature. Available at: https://en.wikipedia.org/wiki/Grey_literature - Accessed on March 2, 2023. 
36  Contains Nonbinding Recommendations 
Historical control: The results of treatment with the new animal drug are quantitatively 
compared with experience historically derived from the adequately documented natural history 
of the disease or condition or with a regimen (therapeutic, diagnostic, prophylactic) whose 
effectiveness is established in comparable animals.  Because historical control populations 
usually cannot be as well assessed with respect to pertinent variables as can concurrent control 
populations, historical control designs are usually reserved for special circumstances.  Examples 
include studies in which the effect of the new animal drug is self-evident or studies of diseases 
with high and predictable mortality, or signs and symptoms of predictable duration or severity, 
or, in the case of prophylaxis, predictable morbidity (21 CFR 514.117(b)(4)(iv)).  
Intervention: The act of intervening, interfering, or interceding with the intent of modifying the 
outcome.  In medicine, an intervention is usually undertaken to help treat or cure a condition 
(https://www.medicinenet.com/script/main/art.asp?articlekey=34214). 
Language bias:  The publication of research findings in a particular language, depending on the 
nature and direction of the results (http://methods.cochrane.org/bias/reporting-biases). 
Location bias: The publication of research findings in journals with different ease of access or 
levels of indexing in standard databases, depending on the nature and direction of results 
(http://methods.cochrane.org/bias/reporting-biases). 
Meta-analysis: A meta-analysis is the statistical combination of results from multiple individual 
studies. 
Negative control (untreated concurrent control): The new animal drug is compared with the 
absence of any treatment.  The use of this control may be appropriate when objective 
measurements of effectiveness, not subject to observer bias, are available (21 CFR 
514.117(b)(4)(ii)). 
Non-inferiority: A Non-Inferiority (NI) study is designed to demonstrate the effectiveness of a 
new drug by showing that the new drug is no worse than a known effective therapy based on an 
appropriate endpoint (see GFI #204). 
Outcome bias: The selective reporting of some outcomes but not others, depending on the nature 
and direction of the results (http://methods.cochrane.org/bias/reporting-biases). 
Performance bias: Performance bias refers to bias due to systematic differences between groups 
in the care that is provided or in exposure to factors other than the interventions of interest 
(Hoffmann et al. 2017). 
Placebo control: The new animal drug is compared with an inactive preparation designed to 
resemble the new animal drug as far as possible (21 CFR 514.117(b)(4)(i)). 
Raw data: Any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that 
are the result of original observations and activities of a nonclinical laboratory study and are 
necessary for the reconstruction and evaluation of the report of that study (21 CFR 58.3(k)).  
37  Contains Nonbinding Recommendations 
Research question: The objective of the scoping or systematic review that defines the 
parameters of the study from which search terms and inclusion/exclusion criteria are created.  
Reporting bias: Reporting bias is introduced when only selected outcomes are reported (applying 
both to systematic reviews and primary studies) (Hoffmann et al. 2017).  Reporting bias occurs 
when dissemination of study results is influenced by the study outcome.  Reporting bias includes 
the following types of bias: publication bias, time lag bias, location bias, citation bias, language 
bias, and outcome bias (http://methods.cochrane.org/bias/reporting-biases). 
Review question: A well-focused question stating the objective of the review. 
Risk of bias: The degree of bias susceptibility of a study (Hoffmann et al. 2017). 
Scoping review: The process of systematically and qualitatively synthesizing available evidence.  
Scoping reviews have been described as a process of mapping the existing literature or evidence 
base (Armstrong et al. 2011). 
Selection bias: Selection bias refers to bias due to systematic differences between baseline 
characteristics of the groups that are compared (Hoffmann et al. 2017). 
Statistical bias: For a point estimator, statistical bias is defined as the difference between the 
parameter to be estimated and the mathematical expectation of the estimator.  Statistical bias can 
result from methods of analysis or estimation.  For example, if the statistical analysis does not 
account for prognostic factors (variables known to affect the outcome variable), then it is 
possible that the estimated treatment effects will be biased (Hoffmann et al. 2017). 
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)). 
Superiority: the primary objective of a superiority study is showing that the response to the 
intervention is superior to a comparator (control).34 
 
34 ICH Topic E9. Statistical Principles for Clinical Trials. 1998. European Medicines Agency. 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-9-statistical-principles-clinical-trials-step-
5_en.pdf. 
38  Contains Nonbinding Recommendations 
Systematic review: an overview of existing evidence pertinent to a clearly formulated question, 
which uses pre-specified and standardized methods to identify and critically appraise relevant 
research, and to collect, report, and analyze data from the studies are included in the review.35  
Time lag bias: time of publication depending on the results (Hoffmann et al. 2017). 
   
 
35 European Food Safety Authority. Guidance of EFSA: Application of systematic review methodology to food and 
feed safety assessments to support decision making. Available at: 
https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2010.1637 - Accessed on March 2, 2023. 
39  Contains Nonbinding Recommendations 
VI.  Appendix 
Example of screening and eligibility database 
Column ID  Column Data  Definition 
Ref  # (A, B, C)  A=Original search, B=result of hand-
searching, C=result of author contact 
Year  #  Year of publication 
Auth  Last, First Middle  Name of first author 
Title  Study Title  Full title of study as listed in 
publication 
Citation  Full reference  Complete citation for the reference 
Type  RCT, cRCT, NRC, NRTS, NRCS,  RCT=randomized controlled trial, 
O  cRCT=cluster randomized controlled 
trial, NRC=non-randomized, 
controlled before/after study, 
NRTS=non-randomized interrupted 
time series, NRCS=non-randomized 
case series, O 
Full Text  Y/N  Y=Full text available 
N=Full text unavailable 
SC1  0 or 1  0=meets screening criterion  
(Screening  1=does not meet screening criterion 
Criterion 1) 
SC2  0 or 1  0=meets screening criterion  
(Screening  1=does not meet screening criterion 
Criterion 2) 
SC3  0 or 1  0=meets screening criterion  
(Screening  1=does not meet screening criterion 
Criterion 3) 
SC4  0 or 1  0=meets screening criterion  
(Screening  1=does not meet screening criterion 
Criterion 4) 
PE1 (Primary  0 or 1  0=meets primary eligibility criterion  
eligibility  1=does not meet primary eligibility 
criterion 1)  criterion 
PE2 (Primary  0 or 1  0=meets primary eligibility criterion  
eligibility  1=does not meet primary eligibility 
criterion 2)  criterion 
PE3 (Primary  0 or 1  0=meets primary eligibility criterion  
eligibility  1=does not meet primary eligibility 
criterion 3)  criterion 
40  Contains Nonbinding Recommendations 
Column ID  Column Data  Definition 
PE4 (Primary  0 or 1  0=meets primary eligibility criterion  
eligibility  1=does not meet primary eligibility 
criterion 4)  criterion 
Final  I or E  I=Include (meets screening, and 
Assessment     eligibility criteria) 
E=Exclude (does not meet on or more 
screening or eligibility criterion) 
Example of data extraction database for eligible studies used in meta-analysis for 
effectiveness studies).  This table provides an example listing of information that would be 
extracted from the individual publications to create the data extraction database.  The first 
column includes a list of variables that would become column headings in the database, the 
second column includes examples of data extracted from the publication for each column in the 
database, and the third column provides additional clarification for or definition of the variable 
or data coding.  
Column ID  Column Data  Definition 
Ref  # (A, B, C)  A=Original search, B=result of hand-
searching, C=result of author contact 
Year  #  Year of publication 
Auth  Last, First Middle  Name of first author 
Title  Study Title  Full title of study as listed in 
publication 
Citation  Full reference  Complete citation for the reference 
Type  RCT, cRCT, NRC, NRTS, NRCS  RCT=randomized controlled trial, 
cRCT=cluster randomized controlled 
trial, NRC=non-randomized, 
controlled before/after study, 
NRTS=non-randomized interrupted 
time-series, NRCS=non-randomized 
case series 
Study  Establish codes as needed for the  Include definitions as needed 
population (ie.,  systematic review to define the 
animal class,  participants in the study (e.g., by 
breed, age,  animal class, age, gender, 
etc., as  reproductive status) 
applicable to 
the study.)  
Country where  US, CA, EU, Other  US=United States, CA=Canada, 
study  EU=Europe; Other=Other 
conducted 
41  Contains Nonbinding Recommendations 
Column ID  Column Data  Definition 
Exp.  Number  Experiment number within paper 
Group  T, C  T=treatment; C=control as defined in 
study methodology 
Treatment arm   A, B, C,...Z, AA, BB, CC,...N/A  Letter indicates a unique 
identifier for the study arm within the 
meta-analysis treatment group. 
Within a publication number (1, 2, 
3,...) or within a study that is within 
a publication, treatment arms should 
have different letters (A, B, C,...).  If 
the study arm is not used within a 
meta-analysis treatment or control 
group, then N/A will be placed in 
the column. 
Control arm   A, B, C,...Z, AA, BB, CC,...N/A  Letter(s) indicate a unique identifier 
for the study arm within the meta-
analysis treatment group.  Within a 
publication number (1, 2, 3,...) or 
within a study that is within a 
publication, treatment arms should 
have different letters (A, B, C,...).  If 
the study arm is not used within a 
meta-analysis treatment or control 
group, then N/A will be placed in 
the column. 
Enter meta- 0=excluded from meta-  This row may be used to define if 
analysis  analysis, 1=included in  data from this study will be entered 
meta-analysis  into systematic review software such 
as Review Manager36 
Treated  N  Total number of animals originally 
assigned (enrolled) in the treatment 
arm at the start of the study 
Evaluable  N  Total number of animals used in the 
statistical analysis for the endpoint at 
treated the end of the study 
Missing  %  ((# enrolled - # with data reported)/# 
enrolled)) x100 
Drug Product  Product  Proprietary name 
name 
 
36 https://community.cochrane.org/help/tools-and-software/revman-5  Accessed March 2, 2023. 
42  Contains Nonbinding Recommendations 
Column ID  Column Data  Definition 
Concentration  Conc  Drug product concentration 
Manufacturer  Manf  Drug product manufacturer 
Batch/Lot  #/#  Batch or lot number  
Expiration date  Exp  Drug product expiration date 
ROA  Abbreviations for route of  Define routes of administration 
administration 
ROA Code  1, 2, 3, 9999=unknown  Define routes of administration as 
needed, 9999=unknown 
Dose  # mg   As defined in protocol 
Conc med    Concurrent medication List 
Outcome  Abbreviations for outcome  Outcome measure definition(s) 
measure(s) 
Timing  Hrs, days, etc.  Timing of outcome measure 
Endpoint  #  Number of animals for which 
success  outcome defined as a success 
 
Endpoint  #  Number of animals for which 
failure  outcome defined as a failure failed 
Control type  negN, negS, plb, active, hist, none  negN=negative control, no treatment 
Exp. unit  animal, pen   
Randomized  Y, N, UK  yes, no, unknown 
Observer blind  Y, N, UK  yes, no, unknown 
Quality  GCP, GLP, GSP, unk  Quality standard of 
standard  the study, if provided 
QA  Y, N, UK  Quality assurance used, if 
provided 
CV  Y, N  Curriculum Vitae of investigator 
 
Person  yes, no, unknown   
Raw data   Y, N, UK  yes, no, unknown 
Raw data  code  S=summarized, R=raw Data   
Study  Objective   
Study  methodology, timing, clinical   
observations  exam, clinical pathology, necropsy, 
histopathology 
Endpoint  addl details, method of calc   
 
43  Contains Nonbinding Recommendations 
Column ID  Column Data  Definition 
Safety  Adverse Event description   
observations 
Statistical  Description   
considerations 
Insert rows as  Free text referencing other columns  To report study specific bias such as 
necessary to  related to bias assessment, e.g., rows  selection bias (e.g., were animals 
describe bias  Randomized, Observer blind,  randomized; if so, were the methods 
assessment;  Study observations, Group and  appropriate?); reporting bias (e.g., 
multiple rows  other rows as necessary  were assessment methods selectively 
may be  reported based on outcome?); and 
necessary,  stats bias (e.g., was the variability 
depending on  clearly defined?  Were there missing 
the types of  summary stats?) 
bias evaluated 
in the 
systematic 
review 
Bias code  1=high risk of bias, 2=low risk of   
(repeat this  bias/no impact expected, 
row for  3=unclear risk of bias 
different types 
of bias) 
 
44