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Guidance for Industry 
 
DEVELOPMENT OF TARGET ANIMAL SAFETY AND 
EFFECTIVENESS DATA TO SUPPORT APPROVAL OF 
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) 
FOR USE IN ANIMALS 
 
This guidance is intended to provide specific recommendations regarding the development of 
target animal safety and effectiveness data to support approval of veterinary NSAIDs, specifically 
cyclo-oxygenase (cox) inhibitors.  
 
Comments and suggestions regarding this guidance should be sent to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, 
Rockville, MD 20852. All comments should be identified with the Docket No. 2004D-0468. 
Comments may also be submitted electronically via the Internet at http://www.regulations.gov.  
 
For questions regarding this document, contact Dr. Linda Wilmot, Center for Veterinary 
Medicine (HFV-120), Food and Drug Administration, 7500 Standish Place, Rockville, MD 
20855, 240-276-8101, e-mail: linda.wilmot@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 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
efault.htm.   
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
January 5, 2006  DEVELOPMENT OF TARGET ANIMAL SAFETY AND EFFECTIVENESS DATA TO 
SUPPORT APPROVAL OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS 
(NSAIDS) FOR USE IN ANIMALS 
 
 
 
I. Introduction   3  
II. Dosage Characterization   4  
III.  Target Animal Safety 5  
IV.   Field Study 5  
V.   Use of Pharmacokinetics In Drug Development 6  
VI.  Labeling 6 
A. General Approach to the Indication Section of Labeling  6  
l. Inflammation   7 
2. Pain  7 
3. Pyrexia (Fever)   9  
B. Precaution Statement   9  
C. Comparison of COX-1 and COX-2   9   DEVELOPMENT OF TARGET ANIMAL SAFETY AND EFFECTIVENESS DATA TO 
SUPPORT APPROVAL OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) 
FOR USE IN ANIMALS  
 
This guidance represents the Food and Drug Administrations current thinking on the 
development of target animal safety and effectiveness data to support approval of non-steroidal 
anti-inflammatory drugs for use in animals. It does not create or confer any rights for or on any 
person and does not operate to bind FDA or the public. You may use an alternative approach if 
the approach satisfies the requirements of applicable statutes and regulations. If you want to 
discuss an alternative approach, contact Dr. Linda Wilmot at 240-276-8101.  
 
I. INTRODUCTION  
 
This guidance document provides our (the Food and Drug Administrations Center for Veterinary 
Medicine) recommendations on  approaches for developing target animal safety and effectiveness 
data to support approval of veterinary non-steroidal anti-inflammatory drugs (NSAIDs) -- 
specifically, approval of NSAIDs that reduce the production of prostaglandins by inhibiting the 
cyclo-oxygenase (COX) pathway. These recommendations are based on the premise that NSAIDs 
are not tissue-specific, and important clinical effects associated with toxicity of NSAIDS 
frequently manifest themselves in the gastrointestinal and renal systems.    
In addition, alternative strategies for generating safety and effectiveness data for NSAIDs that 
inhibit lipo-oxygenase, or both lipo-oxygenase and cyclo-oxygenase, or act as cytokine 
antagonists may be appropriate.     
 
We recommend that you discuss your product development plan and study protocols with us 
before you initiate any studies that you intend to use to support approval.  
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.  
 
II. DOSAGE CHARACTERIZATION  
 
Dosage includes the dose or dose range, the dosing frequency, and the dosing duration. Before we 
can approve a new animal drug, you must demonstrate by substantial evidence 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 proposed labeling. 21 U.S.C.  360b(d)(1)(E).  For 
a new animal drug intended for use in the diagnosis, cure, mitigation, treatment, or prevention of 
disease over a dosage range, you must demonstrate by substantial evidence that the new animal 
drug will be effective for the intended use at the lowest dose of the dosage range suggested in the 
proposed labeling for that intended use.  21 CFR  514.4(b)(2)(i). We recommend basing the 
upper limit of the dosage range for a new animal drug on safety in the target animal (and human 
food safety in appropriate species) as well as on dosing practicality.   
Since the enactment of the Animal Drug Availability Act of 1996 (ADAA), we no longer require 
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dosage optimization.   However, we recommend that you characterize the critical aspects of the 
dosage-response relationship for those parameters relevant to the proposed indication in the new 
animal drug application.  The parameters measured in the characterization of the dosage or  dosage range should specifically relate the proposed dosage or dosage range to the proposed 
indication.  For some new animal drugs, this characterization information may be particularly 
useful to us in evaluating the adequacy of protocols for effectiveness studies.  These parameters 
may suggest the appropriate study endpoints for the one or more adequate and well-controlled 
studies necessary to provide substantial evidence of effectiveness.  Methods for gathering 
information to characterize the dose response relationship may include dose titration studies, pilot 
studies, in vitro studies, scientific literature, and assessments based upon the modeling of 
pharmacokinetic and pharmacodynamic data. Although you are required to demonstrate by 
substantial evidence that the new animal drug is effective at the dose or over the dose range 
selected (see 21 U.S.C.  360b(d)(1)(E)), you need not demonstrate dosage characterization by 
substantial evidence. You should, however, submit sufficient information to characterize the 
critical aspects of the dose response relationship so that qualified experts can make an informed 
risk-benefit assessment of the new animal drug and ensure that the proposed labeling is not false 
or misleading.  You should discuss the appropriate timing for submitting information to 
characterize the dosage-response relationship with us.  
 
1
 Before the enactment of the ADAA, under 21 U.S.C.  360b(d)(1)(F), FDA could not approve a 
new animal drug for use at a particular dose or over a dose range that exceeded the dose 
reasonably required to accomplish the physical or other technical effect for which the new animal 
drug was intended.  In order to demonstrate by substantial evidence the minimal amount of a new 
animal drug reasonably required to accomplish the physical or other technical effect (i.e., the 
optimal dose), dose optimization, typically supported by adequate and well-controlled dose 
titration studies that characterize the critical aspects of the dose response relationship, was 
required. With the enactment of the ADAA, the requirement for dose optimization was 
eliminated.   
 
You must submit all information, including published and unpublished studies, relating to safety 
and effectiveness, that led to your selection and characterization of the proposed dosage or dosage 
range (21 CFR  514.1(b)(8)(iv)).  
 
We encourage you to summarize the dosage characterization so that we can include it in the 
Freedom of Information Summary.  
 
III. TARGET ANIMAL SAFETY (TAS)  
 
We recognize that there are many valid ways to evaluate the target animal safety (TAS) of 
NSAIDs. We recommend that you meet with us to discuss TAS study design prior to initiating 
any studies.  
 
TAS studies for novel chemical entities should identify the toxic syndrome associated with the 
formulation and identify a safe upper limit of the dose.  You should identify the minimum toxic 
dose (the dose at which adverse reactions begin to manifest), unless multiples of the intended 
dose show no toxic effects.  In general, we recommend that you follow CVMs Target Animal 
Safety Guidelines for New Animal Drugs (Guidance #85), testing at multiples of the intended 
dose.  For drugs intended for long term use, we recommend that you conduct safety studies for a 
minimum of six months.  
 
We also recommend that TAS studies for NSAIDs incorporate specific tests or examinations to  identify signs of either local gastrointestinal toxicity (e.g., endoscopy) or renal toxicity (e.g., 
specific gravity, BUN, and creatinine).     
 
In addition, we recommend that you evaluate potential drug effects on platelet aggregation via 
appropriate methods, including Buccal Mucosal Bleeding Time or a similar test.  
Local gastrointestinal irritation caused by NSAIDs may be mitigated by administration with food.  
However, food may affect the bioavailability of oral dosage forms. Therefore, we encourage you 
to submit information concerning the safety and bioavailability of the drug in fed versus fasted 
conditions.  If the drug is labeled for administration with food as a condition of use, we will 
require data to demonstrate substantial evidence of the drug's effectiveness in the presence of 
food (21 U.S.C.  360b(d)(1)(E)).  
 
IV. FIELD STUDY  
 
We recommend that you conduct a field study to demonstrate that an NSAID is safe and effective 
for the target animal under the actual conditions of use for which it is labeled. Field studies 
should confirm results from any laboratory studies that were used to provide substantial evidence 
of effectiveness.    
 
V. USE OF PHARMACOKINETICS IN NSAID DEVELOPMENT  
 
We encourage you to provide information to describe the mechanism of action and 
pharmacokinetics (PK) of the drug entity.  You may use such information to establish the dosing 
regimen to use in safety and effectiveness studies.  This information can also provide support for 
dosage selection and conditions of use.  The generation of PK data during safety and 
effectiveness trials may provide information to assist us in identifying any potential exposure
response relationship and in further elucidating the products margin of safety.  
 
Appropriate pharmacokinetic information may include effects of prandial state and factors that 
may affect the rate and extent of bioavailability, magnitude of  accumulation of the active 
moiety(ies) with repeated administration, terminal elimination half-life, clearance mechanisms, 
protein binding, partitioning characteristics, and volume of distribution.  Of interest are both the 
average kinetic properties and the variability in the PK characteristics that may be anticipated 
under clinical use conditions. You may derive this information from in vitro or in vivo studies that 
have been published in peer-reviewed journals or contemporary studies you conduct during drug 
development.     
 
Because our recommendations about the generation of PK data may vary based on the type of 
product, we encourage you to meet with us to discuss proposals for conducting PK studies. In 
determining what type of studies may be appropriate, we recommend that you consider such 
factors as the proposed conditions of use, release characteristics of the dosage form, the intended 
target animal species, and the drugs therapeutic considerations. For example, for products 
intended for repeated administration, we recommend a multiple dose study to address questions 
regarding nonlinear kinetics with repeated administration.  You may generate these data by 
obtaining blood samples during the target animal safety studies.  In addition, if you develop 
multiple dosage forms in a single target species, we recommend that you evaluate the 
interchangeability and sequential use of the dosage forms.    
 
VI. LABELING   A. General Approach to the Indication Section of Labeling  
 
We recommend that you tailor the development plan for an NSAID to the proposed intended 
uses. In general, inflammation, pain, and pyrexia are three common pathophysiologic processes 
associated with tissue injury and animal illness that may be controlled by NSAIDs.  Generally, 
NSAIDs ameliorate pathophysiologic responses, but do not cure the underlying disease. 
Therefore, we recommend that NSAIDs be labeled for control, not treatment, of the disease.  An 
NSAID may be labeled for control of any single process or any combination of physiologic 
processes for which it is demonstrated to be safe and effective.    
 
The criteria you use to measure effectiveness of the NSAID should be objective,  
repeatable, and clearly stated. You may use naturally occurring disease and/or established 
experimental (target animal) models to demonstrate effectiveness.  
We recommend that labeling include the time to onset of drug effect, if appropriate, so that 
interim care can be initiated if onset of effect is delayed.  You should not make any representation 
regarding the safety and/or effectiveness of long-term use of the product in labeling, unless you 
conducted long-term safety and/or effectiveness studies during the approval process.   
The following hypothetical label indications and approaches are illustrative; you should not 
construe them as definitive indications or approaches.  Following each example, a brief 
description of studies that you may use to support the indication appears in italics.  
 
1. Inflammation  
We recommend that you base the indication on the control of clinical signs of inflammation 
associated with a disease.  You may confirm the indication through demonstration of control of 
one or more of the cardinal signs of inflammation clinically significant to the disease process.  
The cardinal signs of inflammation are pain (dolor), heat (calor), redness (rubor), swelling 
(tumor), and loss of function (function laesa).  
Example:  Indication: NSAID is indicated for the control of inflammation associated with soft 
tissue surgery in horses.  
You may demonstrate the effectiveness of NSAID as an anti-inflammatory agent using a validated 
laboratory model such as carrageenan sponge or tissue cage.  The field study variables should 
support the model; for example, a post-castration field study in horses may support the model by 
demonstrating control of clinical signs of inflammation (swelling).  
 
2. Pain  
We recommend that this indication be based on the control of clinical signs of pain associated 
with a disease. We encourage the use of validated methods of pain assessment in the target 
species.  Two indications of frequent concern are control of pain associated with osteoarthritis 
and postoperative pain.   
We recommend using radiographs or other appropriate diagnostic modalities to confirm the 
diagnosis of osteoarthritis.  We suggest that clinical cases include an adequate number of 
representative osteoarthritic joints.  
Postoperative pain is expected to be most intense in the immediate post-operative period, and to 
2,3 
subside substantially within approximately 72 hours. Therefore,  
2
 Boothe, D., Tranquilli, W., and Radasch, R., Overview of Pain Management Options, 
Proceedings of  
we recommend that effectiveness studies include evaluation of the response to treatment within 
the first 72 hours after surgery.  The intensity of pain and the expression of pain vary greatly  depending on the type of surgical procedure, as well as from animal to animal.  NSAIDs alone 
may not provide sufficient analgesia following procedures that are expected to induce intense 
pain; therefore, evaluation of drug combinations is also acceptable.   
 
Orthopedic procedures frequently result in intense postoperative pain.  You may use a  single 
orthopedic procedure that is historically associated with a high degree of pain to support an 
indication for the control of pain following orthopedic surgery.  
 
Soft tissue surgeries often involve lower levels of pain, but these levels may vary among types of 
soft tissue procedures.  For example, we would expect less pain following ovariohysterectomy 
than following radical mastectomy or thoracotomy.  We recommend that you evaluate a 
minimum of two types of procedures, representing the range of pain associated with soft tissue 
surgeries, to establish a general indication for control of pain following soft tissue surgery.  We 
suggest that you evaluate a sufficient number of cases of each type of soft tissue surgery to 
demonstrate the new animal drugs effectiveness in controlling pain for each procedure. 
Alternatively, you could pursue an indication for a specific type of soft tissue surgery.  
 
Example 1:  Indication: NSAID tablets are indicated for the control of pain associated with 
osteoarthritis in dogs.  
You may demonstrate the effectiveness of NSAID  in adequate and well-controlled field studies 
for control of pain associated with osteoarthritis of the elbows, hips, and stifles in dogs.  
 
Example 2:  Indication: NSAID is indicated for the control of postoperative pain associated 
with orthopedic surgery in dogs.  
You may demonstrate the effectiveness of NSAID in controlled field studies of a representative 
orthopedic procedure (e.g., pain associated with surgical repair of the cranial cruciate ligament).  
 
Example 3:  Indication: NSAID is indicated for the control of pain associated with soft tissue 
surgery in cats.  
You may demonstrate the effectiveness of NSAID in controlled field studies that evaluate post-
operative pain after two representative soft tissue surgeries (e.g., ovariohysterectomy and ocular 
surgery).  
the North American Veterinary Conference, Small Animal Pharmacology, 1998, vol. 12, pp. 571-
3
573.   Hellyer, P.W. and Gaynor, J.S., Acute Postsurgical Pain in Dogs and Cats, The 
Compendium on Continuing Education for the Practicing Veterinarian, February 1998, vol. 20, 
no. 2, pp. 140-153.  
 
3. Pyrexia  
Pyrexia (fever) is defined as a sequela to an elevated set-point in the hypothalamic 
thermoregulatory system in response to circulating pyrogens.  You may use validated target 
species model systems to support this indication.  You should demonstrate a clinically significant 
decrease in core body temperature in field studies. The magnitude of the decrease will depend on 
the animal species, the disease process, and the stage and severity of the disease process.  We 
encourage you to discuss the definition of a clinically significant decrease in temperature with us 
during the protocol review and build it into the protocol design.  
Example 1:  Indication: NSAID is indicated for the control of pyrexia associated with bovine 
respiratory disease.  
  You may demonstrate the effectiveness of NSAID by a validated laboratory target species model 
and confirm the effect in controlled field studies comprised of clinical cases of the specific 
disease.  
 
B. Precaution Statement  
Cyclo-oxygenase-inhibiting NSAIDs generally elicit toxicities that may not be found during 
laboratory Target Animal Safety studies, which are typically conducted in a limited number of 
healthy animals.  We recommend that field studies be designed to ensure detection and 
documentation of adverse events.  Further, you should address adverse reactions that are relevant 
to NSAIDs as a class, but not necessarily identified in the field study, in labeling .  
 
C. Comparison of COX-1 and COX-2 Activity  
 The clinical relevance of quantitative in vitro comparisons of COX-1 and COX-2 activity of 
NSAIDs has not been shown. Therefore, we discourage such quantitative in vitro comparisons in 
labeling. We will continue to carefully review labeling submissions on a case-by-case basis, 
including any such in vitro comparisons and accompanying disclaimers indicating that the 
clinical relevance of this information is unknown.  We welcome further research into the clinical 
relevance of in vitro comparison data.