#215 
 
 
 
Guidance for Industry 
 
 
Target Animal Safety and Effectiveness 
Protocol Development and Submission 
 
 
 
Submit comments on this guidance at any time.  Submit written comments to the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 
1061, Rockville, MD 20852.  Submit electronic comments on the guidance at 
http://www.regulations.gov.  All written comments should be identified with the Docket No. 
FDA-2011-D-0023. 
 
For further information regarding this document, contact:  Angela Clarke, Center for 
Veterinary Medicine (HFV-112), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 240-276-8318; e-mail: angela.clarke@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Communications 
Staff (HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 
Standish Place, Rockville, MD 20855, and may be viewed on the Internet at either 
http://www.fda.gov/AnimalVeterinary/default.htm or http://www.regulations.gov.   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
September 29, 2011
   
 
 
TABLE OF CONTENTS 
 
 
I.  Introduction.............................................................................................................................1 
II.  Protocol Development and Review Process...........................................................................2 
A.  Meetings Surrounding Protocol Development....................................................................2 
B.  Protocol Development and Submission..............................................................................3 
C.  Protocol Review and Amendments.....................................................................................4 
D.  Protocol Concurrence or Non-concurrence........................................................................5 
  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Target Animal Safety and Effectiveness Protocol Development and 
Submission 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing this guidance.  If you cannot 
identify the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance. 
 
 
 
I.  Introduction 
 
To facilitate the drug development process, the Center for Veterinary Medicine (CVM) 
recommends that sponsors submit protocols to CVMs Office of New Animal Drug Evaluations 
(ONADE) Division of Therapeutic Drugs for Non-Food Animals, Division of Production Drugs, 
or Division of Therapeutic Drugs for Food Animals to review study designs before initiating a 
study to support substantial evidence of effectiveness or target animal safety.  This guidance 
makes recommendations to aid in the preparation of protocols used to generate data to support 
new animal drug applications, specifically target animal safety and substantial evidence of 
effectiveness.  The recommendations are intended to reduce the time to protocol concurrence by: 
 
  Recommending a path to protocol concurrence, 
  Enhancing quality of protocol submissions by focusing on agreements on study design 
and statistical analysis, and 
  Making use of opportunities to meet with CVM before and during protocol development. 
 
FDAs guidance documents, including this guidance, 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. 
 
  1 Contains Nonbinding Recommendations 
II.  Protocol Development and Review Process 
 
Protocol submission and CVM concurrence are not required before conducting studies intended 
to support substantial evidence of effectiveness or target animal safety.1  However, if a sponsor 
conducts a study using a protocol that did not receive CVM concurrence, the study design may 
not be adequate to collect appropriate data to support substantial evidence of effectiveness or 
target animal safety.  FDA recommends that sponsors meet with the appropriate ONADE 
division (i.e., Division of Therapeutic Drugs for Non-Food Animals, Division of Production 
Drugs, or Division of Therapeutic Drugs for Food Animals) to discuss their study designs before 
initiating a study to support substantial evidence of effectiveness or target animal safety.   
 
A.  Meetings Surrounding Protocol Development 
 
CVM encourages sponsors to have frequent and early contact with CVM, through both formal 
meetings and informal communication, as they are developing their study protocols.  When 
requesting a formal meeting with an ONADE division, the sponsor should articulate the intended 
purpose and expected outcome of the meeting.  CVM recommends that a sponsor schedule a 
presubmission conference to discuss the development plan for the drug product.  A protocol 
development meeting may be scheduled to discuss the protocol design in greater detail. 
1.  Presubmission Conference(s) 
 
After the investigational new animal drug (INAD) file is established, the sponsor should 
request a presubmission conference with the appropriate ONADE division to discuss the 
general development plan, intended indication(s), and proposed studies to support 
approval of the new animal drug.  A presubmission conference enables two-way 
communication between the sponsor and CVM regarding the development of the product.  
The purpose of this conference is for the sponsor and CVM to come to agreement on the 
number, types, and general design of studies that are necessary to demonstrate the safety 
and effectiveness of a new animal drug (21 CFR 514.5(e)). 
 
To facilitate the discussion, the sponsor should provide background information specific 
to the product to allow CVM to obtain knowledge about the product and to understand 
the concepts proposed for product development.  Sufficient time should be allotted 
between the submission of background material and the meeting to enable complete 
review of the material by CVM.  CVM must receive the meeting request with the 
following items at least 30 days in advance of the conference date (21 CFR 514.5): 
 
  A detailed agenda that clearly outlines the scope, purpose, and objectives of the 
meeting, 
  A copy of any materials to be presented at the meeting, 
  A list of proposed indications, 
  A copy of the proposed labeling (if available) for the product under consideration, 
                                                 
1 See Animal Drug User Fee Act (ADUFA) Reauthorization Performance Goals and Procedures, 
(http://www.fda.gov/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/ucm044941.htm). 
  2 Contains Nonbinding Recommendations 
  Copies of materials evaluated or referenced relative to issues listed in the agenda, and 
  A list of names and positions of the representatives who are expected to attend. 
 
Outcomes of this conference will be documented in a memorandum of conference 
(MOC) as specified in 21 CFR 514.5. 
 
2.  Protocol Development Meetings 
 
Sponsors can request the scheduling of a protocol development meeting to discuss the 
specific details of a protocol.  CVM strongly encourages a protocol development meeting 
for novel indication(s), novel products, and complex study designs.  When requesting a 
protocol development meeting, sponsors should consider the timing of the meeting in 
relation to the submission of the protocol and any additional supportive information that 
may be needed (H submission2). 
 
The sponsors request for a formal protocol development meeting should provide a 
detailed agenda, objectives, and a list of participants, including their expertise.  CVM will 
not review or provide concurrence on a protocol during the meeting.  However, CVM 
will provide feedback on the proposed study design. 
 
The purpose of this meeting is to discuss specific details of the proposed study design 
including, but not limited to, the following: 
 
  The proposed indication, 
  Issues that are unique to the study design, 
  The impact of initial supportive data or literature on the study design, and 
  Previously identified areas of concern with related protocols. 
 
B.  Protocol Development and Submission 
 
The following guidances should be used for general protocol development and design, as 
applicable, for the specific study: 
 
  CVM Guidance for Industry 56:  Protocol Development Guideline for Clinical Effectiveness 
and Target Animal Safety Trials 
  CVM Guidance for Industry 85:  Good Clinical Practices: (VICH GL9) 
  CVM Guidance for Industry 185:  Target Animal Safety for Veterinary Pharmaceutical 
Products (VICH GL43). 
 
                                                 
2 CVM will code the submission of data that support a protocol as an H submission.  The H submission has a 100-
day review time and should be submitted before the protocol to allow sufficient time for review of the supporting 
data. 
  3 Contains Nonbinding Recommendations 
Additionally, the following should be considered when developing a protocol. 
 
Issues pertinent to study design, as stated in the presubmission conference MOC, should be 
incorporated into the protocol.  Protocol non-concurrence may occur if issues that were discussed 
in previous meeting(s) are not addressed in the protocol. 
 
Protocols should be well-written, clear, concise, and consistent across all sections so the 
investigator has a document outlining the study methodology and procedures.  Data collection 
forms (e.g., case report forms, owner consent forms) should be included with the protocol and 
referenced in the section of the protocol where they are discussed.  Relevant standard operating 
procedures (SOPs) for laboratory studies related to the collection of data should be appended to 
the protocol or an adequate description of the procedure should be incorporated into the protocol 
(for example, SOPs for describing parasite collection for anthelmintic studies or SOPs for culture 
and sensitivity microbiological procedures).  If unsure, the sponsor should contact CVM to 
discuss which, if any, SOPs should be included with the protocol.  Lack of detail in a study 
protocol may result in a refusal to review by CVM. 
 
If data or other supportive information are used to justify study methodology and procedures, the 
data should be submitted before the protocol and identified as data to support a protocol to 
allow sufficient time for review of the supporting data.  If a sponsor does not allow sufficient 
time for CVM to review this H submission before receiving a protocol, CVM may issue a 
protocol non-concurrence letter.  Previous agreements from presubmission conferences should 
also be summarized and referenced by submission code.  Any deviations from previous 
discussions regarding study design should be explained. 
 
The submission should be addressed to the appropriate division director and state the INAD 
number, the drug name, the type of protocol, and the purpose of the submission. 
 
C.  Protocol Review and Amendments to the Protocol Submission 
 
The sponsor should resolve any major study design issues raised during discussions with CVM 
before submitting the protocol to CVM for review.  While the protocol is under review, CVM 
will address minor issues or request any needed clarification by telephone or e-mail with the 
sponsor. CVM may request minor amendments to facilitate review.    By day 50 of the protocol 
review time, CVM will send the sponsor an email notifying them of concurrence or non-
concurrence with the protocol, or the need for an End-Review Amendment (ERA) to complete 
the review of the protocol3.  
 
  Minor Amendments to the Protocol Submission 
 
A minor amendment is an amendment requested by CVM within the 50-day review cycle that 
provides a relatively modest amount of specific information that corrects one or more 
deficiencies in the parent submission.  The sponsor should submit the minor amendment in the 
                                                 
3 See Animal Drug User Fee Act (ADUFA) Reauthorization Performance Goals and Procedures, 
(http://www.fda.gov/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/ucm044941.htm). 
  4 Contains Nonbinding Recommendations 
form of the full revised protocol by the Amendment Receipt Date (ARD), which is established 
by CVM and transmitted to the sponsor.  Failure to submit the amendment by the ARD may 
result in a non-concurrence letter for the protocol.  The sponsor should only change the requested 
items and corresponding sections affected by the requested items and highlight those items in the 
amended protocol.  Additional changes to the amended protocol that were not discussed with 
CVM may result in protocol non-concurrence. 
 
  End-Review Amendment (ERA) to the Protocol Submission 
 
An ERA is an amendment to the protocol that is requested by CVM after it has completed its 
review of the submitted information and determined that the submission of additional non-
substantial data or information would likely complete the submission and permit a 
concurrence/non-concurrence decision to be made4.  
 
The sponsor should submit a completed, revised protocol with all changes highlighted within the 
text of the protocol, including minor modifications necessary during the incorporation of the 
requested changes.  The sponsor should certify that no other text changes beyond those 
highlighted have been made.  Additional changes in the amended protocol that were not 
discussed with CVM may result in protocol non-concurrence. 
 
If CVM receives the ERA within 10 days of the ERA email request date, CVM will issue a 
protocol concurrence or non-concurrence letter.  Failure to submit the ERA within 10 days will 
result in protocol non-concurrence of the original protocol, and CVM will refuse to review the 
ERA.  If the ERA protocol does not adequately address the ERA request, CVM will issue a 
protocol non-concurrence letter.  If the ERA protocol is unacceptable for review, CVM will issue 
a non-concurrence letter for the original protocol and will issue a refuse to review letter for the 
ERA. 
 
D.  Protocol Concurrence or Non-concurrence 
 
CVM concurrence means that CVM fundamentally agrees with the design, execution, and 
analyses proposed in the protocol and is a commitment that CVM will not later alter the 
perspectives on these issues unless public or animal health concerns appear that were not 
recognized at the time of the protocol assessment.  However, concurrence with the protocol does 
not guarantee that the data obtained from a study that implements the protocol will support an 
approval.  Because concurrence does not extend to any subsequent changes a sponsor makes to 
this protocol, a sponsor may want to seek CVM concurrence on the revised protocol if changes 
were made.  When a sponsor submits a final study report, they should include a copy of the 
protocol under which the study was actually conducted and include any protocol deviations, 
amendments, and explanations.  A sponsor may request a meeting or teleconference to discuss 
non-concurrence issues with CVM. 
                                                 
4 See Animal Drug User Fee Act (ADUFA) Reauthorization Performance Goals and Procedures, 
(http://www.fda.gov/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/ucm044941.htm). 
  5