#204 
 
Guidance for Industry 
 
Active Controls in Studies to Demonstrate 
Effectiveness of a New Animal Drug 
for Use in Companion Animals 
 
This version of the guidance replaces the version made available in October 2013. This 
document has been revised to update contact information, references, and standard disclosures. 
 
Submit comments on this guidance at any time.  Submit  electronic comments on the guidance to 
http://www.regulations.gov.   Submit written comments to the Division  of Dockets Management 
(HFA-305), Food and Drug Administration,  5630 Fishers Lane, Rm. 1061, Rockville,  MD  
20852.  All comments should be identified  with the Docket No. FDA-2012-D-0419. 
 
For further information  regarding this document, contact Lisa Troutman, Center for Veterinary 
Medicine (HFV-110), Food and Drug Administration,  7500 Standish Place, Rockville,  MD 
20855, 240-402-0695,  e-mail:   lisa.troutman@fda.hhs.gov. 
 
Additional  copies of this guidance document can be requested from the Policy and Regulations 
Staff (HFV-6), 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/default.htm  or http://www.regulations.gov. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
December 2015 
    Contains Nonbinding  Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION ........................................................................................................... 3 
II.  BASIC TERMINOLOGY AND DESCRIPTIONS............................................................ 3 
A.   What is a placebo or untreated concurrent control? .................................................. 3 
B.  What is an active control? ....................................................................................... 3 
C.  What is the target population? ................................................................................. 4 
D.  How does the clinical study relate to the target population?...................................... 4 
E.  What is a superiority evaluation?............................................................................. 4 
F.  What is a non-inferiority evaluation?....................................................................... 4 
G.  What is the margin of difference ()? ...................................................................... 5 
H.  How is the margin of difference determined for a non-inferiority study?................... 5 
I.  How is a non-inferiority study conducted?............................................................... 5 
J.  What factors affect study sample size? .................................................................... 6 
III.  GENERAL CONSIDERATIONS RELATED TO STUDIES USING AN ACTIVE 
CONTROL ............................................................................................................................. 6 
A.  Animal welfare....................................................................................................... 6 
B.  Owner acceptability and compliance ....................................................................... 6 
C.  Certain diseases or conditions for which a placebo control should be used ................ 7 
D.  Diseases or conditions that may improve spontaneously in the study population ....... 7 
IV.  DESIGNING THE STUDY.............................................................................................. 7 
A.  What characteristics should a drug have to serve as an active control? ...................... 7 
B.  What is assay sensitivity? ....................................................................................... 8 
C.  What design characteristics should a study with an active control have? ................... 8 
D.  What type of analysis should be used when the active control is not an approved 
veterinary product? ................................................................................................. 9 
E.  What are some characteristics of response variables used in a non-inferiority    
evaluation? ............................................................................................................. 9 
F.  How should a study with an active control be designed? .........................................10 
G.  How many animals should be enrolled in a study with an active control?.................10 
H.  How does bias affect a study using an active control? .............................................10 
APPENDIX:  EXAMPLE OF NON-INFERIORITY STUDIES ...............................................12 
REFERENCES.......................................................................................................................16 
 
2  Contains Nonbinding  Recommendations 
Guidance for Industry 
 
Active Controls in Studies to Demonstrate 
Effectiveness of a New Animal Drug 
for Use in Companion  Animals 
 
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 
 
This guidance document advises industry on the use of active controls in studies intended to 
provide substantial evidence of effectiveness to support product approval for new animal drugs 
used in cats, dogs, and horses (i.e., companion animals).  This guidance document is directed at 
clinical  investigators who conduct studies using active controls and have a basic understanding 
of statistical principles.  In this document, CVM compares studies that use active controls to 
studies that use either placebo concurrent controls or untreated concurrent controls.  CVM uses 
these comparisons to illustrate the appropriate use of an active control. 
 
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. 
 
II.  BASIC TERMINOLOGY AND DESCRIPTIONS 
 
A.  WHAT IS A PLACEBO OR UNTREATED CONCURRENT CONTROL? 
 
A placebo concurrent control is an inactive preparation designed to resemble the new animal 
drug as far as possible (see 21 CFR 514.117(b)(4)(i)).   An untreated concurrent control is the 
absence of any treatment (see 21 CFR 514.117(b)(4)(ii)).   For the purposes of this document, 
placebo concurrent controls and untreated concurrent controls are referred to as placebo controls.  
In general, animals will be randomized  to the investigational  new animal drug or the placebo 
control. 
 
B.  WHAT IS AN ACTIVE CONTROL? 
 
An active treatment concurrent control (active control) is a known effective therapy (see 21 CFR 
514.117(b)(4)(iii)).   The Center for Veterinary Medicine (CVM) recommends that the active 
control be a new animal drug approved for the same indications  of the disease or condition  in the 
3  Contains Nonbinding  Recommendations 
target species.  A non-inferiority  study measures the effectiveness of an investigational  new 
animal drug by comparing it to an active control.  In general, animals will  be randomized  to the 
investigational  new animal drug or the active control. 
 
C.  WHAT IS THE TARGET POPULATION? 
 
The target population refers to the animal population  for which the new animal drug is intended.  
One example of a target population  would be all horses of a class(es)/breed(s), size, weight 
range, sex, or age with the clinical  disease or condition  that the new animal drug is intended to 
treat. 
 
D.  HOW DOES THE CLINICAL STUDY RELATE TO THE TARGET POPULATION? 
 
The applicant should enroll a representative sample of the target population.   This process allows 
the applicant and CVM to make inferences from the results of the study to the overall target 
population,  which is referred to as the inferential value of the study.  Inferential value is 
considered in the context of all effectiveness study data, regardless of the type of control used. 
 
E.  WHAT IS A SUPERIORITY EVALUATION? 
 
Studies with a placebo control as the comparison group use a superiority  evaluation.  An analysis 
for superiority uses measures of clinical  improvement  and statistical evidence from the study to 
determine whether the investigational  new animal drug is superior to the control in the target 
population. 
 
Under some circumstances, a study with an active control may also use this type of evaluation 
(see IV. D.). 
 
In a study with an active control, if the investigational  new animal drug is shown to be 
statistically  and clinically  superior to the active control, then the conclusion can be made that the 
investigational  new animal drug is more effective than the active control.  In this case the active 
control is treated like a placebo control. 
 
F.  WHAT IS A NON-INFERIORITY EVALUATION? 
 
Most commonly  the goal of studies using an active control is to show that the investigational 
new animal drug is non-inferior  to the control.  The conclusion  of a non-inferiority  analysis 
should be interpreted carefully.  The only way to rule out absolutely any inferiority  is to show 
superiority.  The non-inferiority  study seeks to overcome this dilemma by showing statistically 
that:  a defined portion of the known effect of the active control is retained by the investigational 
new animal drug; and the difference between the investigational  new animal drug and the active 
control is no worse than a predefined margin.  The margin of difference is referred to 
symbolically  as .1 
                                              
1 Other sources may refer to the margin of difference or the non-inferiority margin as M. 
4  Contains Nonbinding  Recommendations 
G.  WHAT IS THE MARGIN OF DIFFERENCE ()? 
 
The margin of difference or , defines the extent to which the investigational  new animal drug 
can be less effective than the active control and still allow the applicant and CVM to conclude 
that it is non-inferior.   The margin of difference is specified before conducting the study 
because it will determine whether a study supports the effectiveness of the investigational  new 
animal drug.  In the active control comparison,  the results provide a point estimate of the 
difference between treatments and a confidence interval around that difference.  In general, the 
study seeks to show that the upper bound of that confidence interval is less than the acceptable 
Delta (). 
 
H.  HOW IS THE MARGIN OF DIFFERENCE DETERMINED FOR A NON-INFERIORITY STUDY? 
 
The margin of difference () for a non-inferiority  study is critically  dependent on the effect size 
of the active control, which is known from previous placebo-controlled  studies that evaluated the 
effectiveness of the active control.  Reliance on a non-inferiority  study assumes that the active 
control drug will  have a similar effect in the non-inferiority  study to the effect it had in the 
placebo control study that established its effectiveness.  Because this is an assumption,  the active 
control effect size estimate is generally chosen conservatively,  e.g., as the lower bound of the 
two sided 95% confidence interval estimated from the success rate of the active control minus 
the success rate of the placebo from the placebo control study.  The lower bound of the 
confidence interval becomes Delta  ( ), the difference between the investigational  new animal 
1 1
drug and the active control (AC-ID), that should not be exceeded, generally by showing that the 
95 percent upper bound of the confidence interval for AC-ID is less than    If this is shown, the 
1.
study results will demonstrate that the investigational  new animal drug has some effect (greater 
than 0) and that not all of the effect of the active control has been lost. 
 
Basing the margin of difference only on  , i.e., showing that the effect is greater than zero and 
1
that not all of the effect of the active control has been lost, may not be sufficient to demonstrate 
non-inferiority.   In addition,  CVM may want assurance that a sufficient proportion  of the effect 
of the active control is preserved.  In general, the margin of difference should conserve 50 
percent of the effect size, a value often called Delta  ( ).  For example, if a conservative 
2 2
estimate of the effect size of the active control versus the effect size of the placebo in the 
placebo-controlled  study mentioned  above was 20 percent, the margin of difference in the non-
inferiority  study would be no greater than 10 percent. 
 
In cases where the active control was not tested against a placebo, an applicant could use 
information  from historical  evidence, such as scientific literature, expert opinion,  and previous 
studies, to determine a clinically  relevant margin of difference. 
 
I.  HOW IS A NON-INFERIORITY STUDY CONDUCTED? 
 
In a non-inferiority  study, one should calculate the difference between the success rate in animals 
treated with the active control and the success rate in animals treated with the investigational 
new animal drug (AC-ID), and calculate a two-sided 95 percent confidence interval for this 
difference.  If the upper bound of this confidence interval (i.e., the degree of inferiority  of the 
5  Contains Nonbinding  Recommendations 
new drug) is less than the margin of difference, then one can conclude statistically  that the 
investigational  new animal drug is non-inferior.   For an example of a non-inferiority  evaluation 
with a margin of difference, see Appendix 1. 
 
J.  WHAT FACTORS AFFECT STUDY SAMPLE SIZE? 
 
Sample size in a non-inferiority  study is determined by multiple  factors, such as the estimated 
success rate of both the active control and the investigational  new animal drug, the margin of 
difference, and the variance.  For  example, holding  all other factors constant except the margin 
of difference, the smaller the margin of difference the larger the sample size, and vice versa.  
Also, if the estimated success rate of the investigational  drug is less than the estimated success 
rate of the active control, the sample size would need to be larger than if the estimated success 
rate of the investigational  new animal drug is greater than the estimated success rate of the active 
control (See Appendix 1). 
 
III.  GENERAL CONSIDERATIONS RELATED TO STUDIES USING AN ACTIVE 
CONTROL 
 
Applicants should consider a number of issues when deciding  to use a study with an active 
control or a placebo control.  Some of the key issues are discussed here.  Typically,  placebo- 
control studies are preferable to non-inferiority  studies in that they make fewer assumptions and 
can almost always have a smaller sample size. 
 
A.  ANIMAL WELFARE 
 
The welfare of the animals enrolled in the study should be a major factor in determining  whether 
to design the study with an active or a placebo control.  In certain disease states or conditions,  if 
an approved new animal drug is available, ethical considerations  (mainly harm to the animal 
from getting no treatment) could predispose an applicant to design a non-inferiority  study rather 
than a placebo-controlled  study.  The acceptability of a non-inferiority  study versus a placebo-
controlled  study may vary depending on the disease or condition,  the existence of approved new 
animal drugs that treat the disease or condition,  the study design, and the patient population.  For 
many studies, the protocol is reviewed by an Institutional  Animal Care and Use Committee 
(IACUC) for evaluation of the welfare of the animal subjects. 
 
B.  OWNER ACCEPTABILITY  AND COMPLIANCE 
 
A non-inferiority  study could have a higher enrollment and retention of client-owned animals 
compared with a placebo-controlled  study.  Animal owners could be more likely  to enroll and 
less likely  to remove their animals if they know their animals will receive treatment with an 
investigational  new animal drug or an active control drug.  Fewer dropouts facilitate the analysis 
and interpretation  of the results; however, this potential benefit should be weighed against the 
disadvantages of a non-inferiority  study. 
   
6  Contains Nonbinding  Recommendations 
C.  CERTAIN DISEASES OR CONDITIONS FOR WHICH A PLACEBO CONTROL SHOULD BE USED 
 
A placebo control should be used for those diseases or conditions that can be left untreated for a 
certain period of time.  Applicants could design studies with an escape or rescue clause that 
switch all non-responders after a certain time point during the study either to the investigational 
new animal drug or standard of care if they had been assigned to the placebo group, or to 
standard of care if they had been assigned to the investigational  new animal drug.  The non-
responders would be considered treatment failures. 
 
D.  DISEASES OR CONDITIONS THAT MAY IMPROVE SPONTANEOUSLY IN THE STUDY 
POPULATION 
 
Some diseases or conditions  have a high self-cure rate and improve without treatment.  In studies 
involving  such diseases or conditions,  it will rarely be possible to determine a credible margin of 
difference (Delta, ) for the non-inferiority  study (see Draft Guidance for Industry:  
Antibacterial Drug Products:  Use of Noninferiority  Studies to Support Approval, Center for 
Drug Evaluation and Research (CDER), October 2007).  In these instances, it will be necessary 
to use a placebo control instead of an active control. 
 
IV.  DESIGNING THE STUDY 
 
A.  WHAT CHARACTERISTICS SHOULD A DRUG HAVE TO SERVE AS AN ACTIVE CONTROL? 
 
An active control should be an approved new animal drug in the target species for the same 
indication  as the investigational  new animal drug.  For example, the active control in a study 
evaluating a new oncology  drug should be effective against the same tumor type. 
 
The active controls level of effectiveness was established at the time of its approval.  The 
effectiveness should have been established, at least in part, from studies in which the drug was 
compared to a placebo control.  In addition,  for a drug to be an appropriate active control, the 
difference in effectiveness between that drug and its placebo control, is assumed to apply to the 
current study (the constancy assumption).  Support for the constancy assumption  is best 
provided by using as the active control a drug that was shown to be effective with placebo-
controlled  data.  This approach should help support assay sensitivity  (see B. below) and avoid a 
phenomenon known as bio-creep.  Bio-creep refers to a sequential lowering of standards of 
effectiveness that happens when drugs are continually  evaluated and approved using active 
controls in a sequence such as the following: 
 
Step 1:  Drug A is evaluated for effectiveness in a study with a placebo, and the conclusion is 
Drug A is superior to the placebo. 
 
Step 2:  Drug B is evaluated for effectiveness in a study with Drug A as the active control, and 
Drug B is considered non-inferior  to Drug A, within the defined margin of difference. 
 
Step 3:  Drug C is evaluated for effectiveness in a study with Drug B as the active control, and 
Drug C is considered non-inferior  to Drug B, within the defined margin of difference. 
7  Contains Nonbinding  Recommendations 
However, Drug C may be outside the non-inferiority  margin that would have been established 
for a comparison with Drug A, resulting in a favorable statistical analysis for a drug that appears 
to be effective in the non-inferiority  study when, in fact, it is not effective when used in the target 
population.  It is thus critical that the choice of   reflect actual data with the active control vs. 
1
placebo. If drug B were shown to be superior to drug A, there would not be a problem. 
 
In special circumstances, a drug that has not been evaluated for effectiveness against a placebo 
could be selected as an active control.  However, when this choice is made, both the applicant 
and CVM should evaluate the circumstances carefully and confirm the criteria for an evaluation 
of effectiveness are appropriate.  The applicant should consider a superiority study comparing 
the investigational  new animal drug to the active control (see IV. C.) or other modifications  to 
the study design. 
 
B.  WHAT IS ASSAY SENSITIVITY? 
 
Assay sensitivity  is a study property defined as the ability  to distinguish  an effective treatment 
from a less effective or ineffective treatment.  Studies that lack assay sensitivity  may conclude 
that an ineffective new animal drug is non-inferior  to the active control because neither drug had 
any effect in the study, so that AC-ID is small.  In this case, a small AC-ID is meaningless 
because neither drug would be found to be superior to placebo if a placebo group had been 
included in the study. 
 
Assay sensitivity  is determined from two sources:  1) historical evidence of effectiveness of the 
active control and 2) design of the proposed non-inferiority  study.  Historical evidence of 
effectiveness examines how the active control was originally  determined to be effective.  
Preferably, effectiveness was determined by comparing the active control to a placebo control in 
a well-controlled  study, making it likely  that it would be superior to placebo in a non-inferiority 
study (although this superiority  would not actually be measured).  Identification  of the smallest 
effect size that the active control can reliably be assumed to have is used to support the margin of 
difference.  The proposed non-inferiority  study design is appropriate when the historical  estimate 
of the drug effect size is well supported by results of previous studies using the active control.  
The previous studies should conclude that the active control can consistently  be distinguished 
from a placebo. 
 
Using a study design similar  to the design used to determine effectiveness of the active control 
enhances assay sensitivity,  as discussed in the following  section. 
 
C.  WHAT DESIGN CHARACTERISTICS SHOULD A STUDY WITH AN ACTIVE CONTROL HAVE? 
 
The proposed study design for evaluating the effectiveness of the investigational  new animal 
drug should be broadly similar  to the study design originally  used to evaluate the active control.  
Study design information  may be obtained from published  literature, Freedom of Information 
(FOI) Summaries, and labeling.   In the absence of a placebo-controlled  study for comparison, 
both CVM and the applicant should be confident the non-inferiority  study will resemble the 
situation in which the active control was originally  shown as effective as much as possible (the 
constancy assumption).  Important similarities  could include characteristics of the enrolled 
8  Contains Nonbinding  Recommendations 
animal subjects in the study, the severity of the condition  or disease being treated, the use of 
similar response variables for measuring effectiveness, and similar  concomitant therapy. 
CVM acknowledges that medical advancements in the treatment of disease conditions  and 
changes in variables used to evaluate the effectiveness of the investigational  new animal drug 
may result in necessary changes to a study design.  Therefore, when there are important 
differences between the studies used to evaluate the effectiveness of the active control and the 
current proposed study, the applicant and CVM should discuss these differences in advance to 
ensure that the proposed non-inferiority  study will result in a valid conclusion  about the 
effectiveness of the investigational  new animal drug. 
 
The conduct of the non-inferiority  study should mimic the conduct of the previous studies used 
to evaluate the active control as closely as possible.  Any deviations could affect assay 
sensitivity.   To ensure assay sensitivity,  the study should actually enroll, treat, and evaluate 
patients in a manner similar to the studies used to support historical evidence of effectiveness. 
 
D.  WHAT TYPE OF ANALYSIS SHOULD BE USED WHEN THE ACTIVE CONTROL IS NOT AN 
APPROVED VETERINARY  PRODUCT? 
 
For those diseases or conditions  for which the standard of care is a drug not approved by the 
CVM for the indication  in the intended target species, an applicant should consider designing  a 
study with the standard of care drug as the active control using a superiority  analysis.  However, 
its extralabel use must meet the requirements of 21 CFR  530.30.  The effectiveness study 
should demonstrate that the investigational  new animal drug is clinically  and statistically 
superior to the active control to be able to conclude effectiveness. 
 
E.  WHAT ARE SOME CHARACTERISTICS OF RESPONSE VARIABLES USED IN A NON-
INFERIORITY EVALUATION? 
 
As with any effectiveness study, an applicant should select clinically  relevant response variables 
that are widely accepted as valid and having well understood characteristics.  The measurement 
scale of each response variable should be sufficiently  unbiased and reliable to provide 
meaningful  distinctions  between animals having different levels of the characteristic measured.  
These principles apply to all types of measurements, including  dichotomous  scales, such as 
treatment success/treatment failure, yes / no; ordinal  scales such as normal / mildly 
affected / moderately affected / severely affected; and variables that are continuously 
distributed,  such as blood glucose or serum alkaline  phosphatase.  If more than one primary 
variable is used to assess effectiveness, each variable should support evidence of non-inferiority 
and clinical  improvement.   The criteria for assessing effectiveness should be determined in the 
protocol prior to initiating  the study. 
 
A non-inferiority  study should use the response variables used in previous studies establishing 
the effectiveness of the active control because the historical experience used to support the non-
inferiority  margin is generally pertinent only to those variables. 
 
However, if the applicant chooses to use variables in a non-inferiority  evaluation  that are 
different from the variables used in previous studies to evaluate the active control, the applicant 
9  Contains Nonbinding  Recommendations 
should use other sources, such as literature or other studies with a similar design, to support the 
choice of margin. 
 
F.  HOW SHOULD A STUDY WITH AN ACTIVE CONTROL BE DESIGNED? 
 
Studies using active controls should use a parallel arm effectiveness study design.  In a parallel 
arm study, animals are randomly assigned to treatment groups and receive either the 
investigational  new animal drug or the active control.  Study personnel, who are masked to the 
treatment assignment, evaluate the animals in the study.  The study is generally carried out at 
multiple  locations to support independent substantiation  of evidence.  In such cases, the applicant 
would usually design a randomization  plan for each location.  Generally, each location has 
approximately  the same ratio of animals assigned to the investigational  new animal drug and to 
the active control.  However, the ratio does not have to be a 1:1 allocation  between the 
investigational  new animal drug and the active control.  The sample size and allocation  ratio 
should be based upon the initial  estimates for effectiveness. 
 
G.  HOW MANY ANIMALS SHOULD BE ENROLLED IN A STUDY WITH AN ACTIVE CONTROL? 
 
To estimate the appropriate sample size, the margin of difference, the estimated success rate for 
the investigational  new animal drug, and the estimated success rate for the active control is 
determined.  Sources of variability  in the study are to be considered.  These include, but are not 
limited  to: variability  of the response variables, variability  among locations in a multi-location 
study, and variability  within and among households or other grouping  factors.  It is difficult  to 
make generalizations  about the size of the studies for all types of drugs, diseases or conditions, 
types of animals, and settings.  Statisticians  use a variety of formulas and simulations  to develop 
a recommendation  for the number of animals that should be included  in a non-inferiority  study.  
Inferential value should also be considered when determining  the number of animals to enroll in 
a study to provide meaningful  conclusions and inferences to the target population  from the 
results (see II.J.).  In general, to achieve adequate statistical power, a study with an active control 
usually has more subjects in each group than a study with a placebo control. 
 
For example, generally more subjects would be necessary if one or more of the following  criteria 
are present: 
 
  A high self-cure rate for the disease 
  The margin of difference is small 
  A lower cure rate for the investigational  new animal drug compared to the active control (i.e., 
inferiority  of the investigational  new animal drug) 
 
H.  HOW DOES BIAS AFFECT A STUDY USING AN ACTIVE CONTROL? 
 
In a non-inferiority  study, investigators (and the animal owners) know that each animal in the 
study is receiving some form of treatment for the disease or condition  evaluated (either with the 
investigational  new animal drug or the active control).  The study investigators and animal 
owners are masked to treatment group, however, the awareness that the animal is receiving either 
an active control or the investigational  drug could lead them to put a positive interpretation on 
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their observations of an animals condition.   Investigators and/or owners could be more likely  to 
score an animal enrolled in the study in the direction of improvement  of the disease or 
condition  than investigators and/or owners who are participating  in a study with a placebo 
control.  This bias could affect both treatment groups equally. 
 
In a non-inferiority  study, the response variables used to assess effectiveness should be based on 
the study that was conducted to approve the active control.  If subjective variables were used to 
assess the effectiveness of the active control, we recommend you discuss with CVM whether 
objective variables now exist that can be used in place of those subjective variables.  Non-
inferiority  studies that use subjective variables are more prone to investigator  and/or owner bias 
than studies that use objective variables. 
   
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APPENDIX:  EXAMPLE OF NON-INFERIORITY STUDIES 
 
This section provides a basic introductory  example of a non-inferiority  study using a 
hypothetical  study with an active control and investigational  new animal drug with different 
outcomes.  These examples are not intended to describe a full statistical analysis for a non-
inferiority  study but to provide an understanding of the process. 
 
Here, the applicant plans to conduct a parallel arm study to evaluate the effectiveness of an 
investigational  new animal drug, using an active control.  Each animal is randomly assigned to 
one of two groups.  One group receives the investigational  new animal drug (ID), and the other 
group receives the active control (AC).  At the end of the study, the applicant calculates the 
percentage of animals that are cures in each treatment group.  This is the primary response 
variable. 
 
Determining the margin of difference.  For this example, the applicant and CVM have agreed 
on a margin of difference () of 0.15 (15%) for the non-inferiority  evaluation.  For a discussion 
on how to choose delta see Section II G & H. 
 
Planning the non-inferiority evaluation.  The study will be analyzed by calculating from the 
study data a two-sided 95% confidence interval for  -  2 The upper bound is determined by 
AC  ID.
the following  calculation3: 
 
p (1 p ) p (1 p )
UCL = (p  p )+z  AC AC + ID ID , 
AC ID (10.025) n n
AC ID
 
When the upper bound of the confidence interval is used,  is expressed as a positive value.  If 
the upper bound of this confidence interval is less than 0.15 (or 15%) when the upper confidence 
level (UCL) is expressed as a percentage), then one can conclude statistically  that the 
investigational  new animal drug is non-inferior. 
 
Evaluating the data.  The five rows in Table 1 represent five different possible cases.  ID  and 
1
ID illustrate  the situation in which the investigational  new animal drug is slightly  less effective 
2 
than the active control but sample sizes are different.  ID and ID  illustrate the situation in which 
3  4
both the active control and the investigational  new animal drug have effectiveness in the 90% 
plus range but the investigational  new animal drug is less effective than the active control and 
there is an increased sample size.  ID  illustrates the situation  in which the investigational  new 
5
                                              
2 The symbol  represents the proportion of cures in the target population.  is the proportion of cures with the 
ID 
investigational drug, and   is the proportion of cures with the active control. 
AC
 
3 The symbol p represents the proportion of cures in the observed study, p is the proportion of cures with the 
ID 
investigational drug, and p  is the proportion of cures with the active control.  n is the number of animals that 
AC ID 
received the investigational drug, and n  is the number of animals that received the active control.  Z   is the 
AC (1-0.025)
critical value of a standard normal distribution at 1-0.025.  For simplicity, we assume the difference of proportions 
follows a normal distribution but this may not always be true.  The formula with the square root sign is the estimated 
standard deviation used in the calculation of the confidence interval. 
12  Contains Nonbinding  Recommendations 
animal drug is more effective than the active control (though the study does not show 
superiority). 
 
Table 1.  Five hypothetical  studies with an active control and a non-inferiority  evaluation. The 
margin of difference, , is 15%; randomization  ratio is 1:1; significance level (alpha = 0.05).  
The table depicts the success rate proportions  as percentages for ease of reading. 
ID  N per  p   p   p   p   Upper bound of  Decision Outcome 
AC ID AC ID
group  the two-sided 
95%confidence 
interval of the 
difference 
ID   100  89.0%  83.0%  +6.0%  15.58%1  Insufficient evidence 
1
for a non-inferiority 
conclusion 
ID   125  89.0%  83.0%  +6.0%  14.57%2  Non-inferior 
2
ID   100  99.0%  90.0%  +9.0%  15.19%1  Insufficient evidence 
3
for a non-inferiority 
conclusion 
ID   125  99.0%  90.0%  +9.0%  14.54%2  Non-inferior 
4
ID   100  91.0%  96.0%  -5.0%  1.80%2  Non-inferior 
5
 
ID  Investigational  new animal drug 
AC Active control 
p   Percent cures of investigational  new animal drug in study 
ID
p   Percent cures of active control in study 
AC
p p  Difference in percent cures, active control - investigational  new animal drug 
AC -  ID 
1If the upper bound of the confidence (CI) of the difference is greater than 15% (margin of 
difference), the decision outcome is that there is insufficient  evidence for a non-inferiority 
conclusion  that the investigational  new animal drug is non-inferior  to the active control. 
2If the upper bound of the confidence (CI) of the difference is less than or equal to 15% (margin 
of difference), the decision outcome is that the investigational  new animal drug is non-inferior  to 
the active control. 
13  Contains Nonbinding  Recommendations 
 
If the right side of the horizontal  line crosses the vertical line at 15% (defined margin of 
difference) there is insufficient  evidence to conclude the investigational  new animal drug is non-
inferior to the active control. 
If the right of the horizontal  line does not cross the vertical line at 15% (defined margin of 
difference) there is sufficient evidence to conclude the investigational  new animal drug is non-
inferior to the active control. 
Randomization  ratio is 1:1; significance  level (alpha = 0.05) 
 
Figure 1 illustrates graphically  the non-inferiority  evaluation from the above cases.  The figure 
depicts outcomes for the five investigational  new animal drugs, ID -ID , presented in Table 1.  
1 5
The right end of the line depicts the upper confidence bound.  To conclude that an investigational 
new animal drug is non-inferior  to an active control, the upper bound of the confidence interval 
needs to be less than 15%. 
 
Using Table 1 and Figure 1, CVM interprets the outcomes as follows: 
 
ID : There is insufficient  evidence to conclude that ID  is non-inferior  to the active control.  The 
1 1
percentage of cures was 83% with ID .  The percentage of cures for ID  is numerically  less than 
1 1
the percentage of cures for the active control (89%).  The percent upper bound of the confidence 
interval of the difference between the active control and ID  is 15.58%, which is outside of our 
1
percent margin of difference (15%).  CVM interprets this upper bound to mean that there is a 
reasonable chance that when ID  is applied to the target population,  it might produce 15.58% 
1
fewer cures than the active control.  This is not acceptable according to the agreed-upon criteria 
established at the protocol stage. 
 
ID : CVM concludes that ID  is non-inferior  to the active control.  The percentage of cures for 
2 2
ID  and the active control are the same as for example one except that the sample size is 
2
increased to 125.  The percent upper bound of the confidence interval of the difference between 
14  Contains Nonbinding  Recommendations 
the active control and ID  is 14.57%, which is just inside of our percent margin of difference 
2
(15%).  CVM interprets this upper bound to mean there is a reasonable chance that when ID  is 
2
applied to the target population,  it might produce 14.57% fewer cures than the active control.  
This is acceptable according to the agreed-upon criteria established at the protocol stage. 
 
Notice that the study with ID  has more animals per group (125) than the study with ID  (100 per 
2 1
group).  ID  is considered non-inferior  even though the study resulted in a lower percentage of 
2
cures (83.0%) for the investigational  new animal drug than for the active control (89.0%). The 
difference between ID and ID  is the sample size.  Thus, given the same study results, a larger 
1  2
number of animals will result in a narrower confidence interval and the conclusion can move 
from insufficient  evidence for a non-inferiority  conclusion to a non-inferior  conclusion. 
 
ID : There is insufficient  evidence to conclude that ID  is non-inferior  to the active control.  The 
3 3
percentage of cures was 90.0% for ID  in this study.  This is numerically  less than the percentage 
3
of cures for the active control (99.0%).  The percent upper bound of the confidence interval for 
the difference between the active control and the ID is 15.19%, which is just outside of our 
3 
percent margin of difference (15%).  CVM interprets this upper bound to mean there is a 
reasonable chance that when ID  is applied to the target population,  it might produce 15.19% 
3
fewer cures than the active control.  This is not acceptable according to the agreed-upon criteria 
established at the protocol stage. 
 
ID : CVM concludes that ID  is non-inferior  to the active control.  The percentage of cures for 
4 4
ID  and the active control are the same as for example three except that the sample size is 
4
increased to 125.  The percent upper bound of the confidence interval of the difference between 
the active control and ID  is 14.54%, which is just inside of our percent margin of difference 
2
(15%).  CVM interprets this upper bound to mean there is a reasonable chance that when ID  is 
4
applied to the target population,  it might produce 14.54% fewer cures than the active control.  
This is acceptable according to the agreed-upon criteria established at the protocol stage. 
 
Notice that the study with ID  has more animals per group (125) than the study with ID  (100 per 
4 3
group).  ID  is considered non-inferior  even though the study resulted in a lower percentage of 
4
cures (90.0%) for the investigational  new animal drug than for the active control (99.0%). The 
difference between ID and ID  is the sample size.  Thus, given the same study results, a larger 
3  4
number of animals will result in a narrower confidence interval and the conclusion can move 
from insufficient  evidence for a non-inferiority  conclusion to a non-inferior  conclusion. 
 
ID : CVM concludes that ID  is non-inferior  to the active control.  The percentage of cures for 
5 5
ID  (96%) is larger than the percentage of course for the active control (91%).  The percent upper 
5
bound of the confidence interval of the difference between the active control and ID  is 1.80%, 
5
which is inside of our percent margin of difference (15%).  CVM interprets this upper bound to 
mean there is a reasonable chance that when ID  is applied to the target population,  it might 
5
produce 1.80% fewer cures than the active control but this is acceptable according to the agreed-
upon criteria established at the protocol stage.  However, it does not demonstrate superiority to 
the active control because the upper bound of the confidence interval is above zero. 
   
15  Contains Nonbinding  Recommendations 
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