Guidance for Industry 

Antibacterial Drug Products: 

Use of Noninferiority Trials to 

Support Approval 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
November 2010 

Clinical/Antimicrobial 
 
 
   
Guidance for Industry 
 
Antibacterial Drug Products: 

Use of Noninferiority Trials to 

Support Approval 
 
 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 
 
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 
 
Silver Spring, MD   20993-0002 
 
Tel:  301-796-3400; Fax: 301-847-8714; E-mail:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
 
Food and Drug Administration 
 
Center for Drug Evaluation and Research (CDER)  

 
November 2010 
 
Clinical/Antimicrobial
   
   
TABLE OF CONTENTS 
 
I.	   INTRODUCTION............................................................................................................. 1 
 
II.	   BACKGROUND ............................................................................................................... 2 
 
III. 	  PROVIDING EVIDENCE TO SUPPORT JUSTIFICATION FOR ACTIVE-
CONTROLLED TRIALS DESIGNED TO SHOW NONINFERIORITY ................. 3 
 
A.   Trials Proposed During Protocol Development...........................................................................3 
 
B.   Ongoing or Completed Trials Intended for Submission to a New Drug Application ..............3
  
 
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Antibacterial Drug Products:  Use of Noninferiority 

Trials to Support Approval 

 
 
 
 
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  
 
The purpose of this guidance is to inform  industry of the Food and Drug Administrations 
(FDAs) current thinking regarding appropriate clinical trial designs to evaluate antibacterial 
drug products, and to provide an opportunity for sponsors to amend ongoing or completed trials 
accordingly.  This guidance is in response to a number of public discussions in recent years 
regarding the use of active-controlled trials designed to show noninferiority (NI) as a basis for 
approval of antimicrobial drug products.  These discussions initially focused on the indications 
acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and 
acute bacterial otitis media (ABOM).  However, the science of active-controlled trials designed 
to show NI and the selection of appropriate NI margins in circumstances where an active-
controlled trial designed to show NI is an appropriate trial design has been a focus of recent 
discussions in other antimicrobial drug product indications and in other therapeutic areas as 
well.2   
 
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 
                                                 
1 This guidance has been  prepared by the Office of Antimicrobial Products, representing the Division  of  Anti-
Infective and Ophthalmology Products and the Division  of Special Pathogen and Transplant Products, in the Center  
for Drug Evaluation and Research (CDER) at the Food and Drug Administration.   
 
2 See the draft guidance for industry Non-Inferiority Clinical Trials. When  final, this guidance will represent the 
FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA Drugs guidance  
Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.    
1 
 Contains Nonbinding Recommendations 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
 
II.  BACKGROUND  
 
There have been public discussions on the use of NI clinical trial designs for antibacterial drug 
products at the Anti-Infective Drugs Advisory Committee meetings and workshops sponsored or 
co-sponsored by the FDA. Based on these deliberations and a review of available data for ABS, 
ABECB,3 and ABOM, the FDA has not found it possible to define an NI margin for active-
controlled NI trials in these three infectious disease therapeutic areas because a consistent and 
reliable estimate of the efficacy of active treatment relative to placebo has not been established.   
 
These public discussions have contributed to the FDAs evolving understanding of the science of 
clinical trials and, in particular, the appropriate role of active-controlled trials designed to show 
NI in the development of antibacterial drug products.  We anticipate that continued discussions 
on the role of active-controlled trials designed to show NI will provide further advancement in 
the field with regard to the use of NI trials.  The draft guidance for industry Non-Inferiority 
Clinical Trials contains general guidance on the use of NI trials and provides more specific 
methodological advice.  Sponsors also should review the ICH guidance for industry E10 Choice 
of Control Group and Related Issues in Clinical Trials,4 which provides a general discussion on 
the selection of control groups, including consideration of conditions under which active-
controlled trials designed to show NI can be informative.  
 
For some other infectious disease therapeutic indications (generally for more serious infections, 
such as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, 
community-acquired bacterial pneumonia, and acute bacterial skin and skin structure infections), 
available data and deliberations make it possible to define a consistent and reliable estimate of 
the efficacy of active treatment relative to placebo to serve as the basis for defining a new 
inferiority margin for an active-controlled NI trial.5  
 
 
                                                 
3 Patients enrolled in ABECB trials in  new drug applications have, in  general, included  patients with outpatient, 
milder, or less well-characterized disease. 
 
4  We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance Web page  at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
5 For links to transcripts from  recent FDA-sponsored or co-sponsored  workshops, see the Meetings, Conferences, & 
Workshops (Drugs) Web site at http://www.fda.gov/Drugs/NewsEvents/ucm132703.htm; and for links to transcripts 
from Anti-Infective Drugs Advisory Committee meetings, see the Advisory Committee Calendar Web site at 
http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm.    
2 
 Contains Nonbinding Recommendations 
III.  	 PROVIDING EVIDENCE TO SUPPORT JUSTIFICATION FOR ACTIVE-
CONTROLLED TRIALS DESIGNED TO SHOW NONINFERIORITY  
 
A. 	 Trials Proposed During Protocol Development  
 
We encourage sponsors contemplating use of an active-controlled NI trial design to consider the 
basis for estimating the treatment effect of a potential active control that will be a critical 
component of choosing the NI margin as early as possible.  This effect is usually estimated from  
previously conducted trials, but other available information can also be useful.  NI trial designs 
are appropriate only when there is adequate evidence of a defined effect size for the control 
treatment so that the proposed NI margin can be supported.  The time point of the assessment of 
the efficacy endpoint in the previous trials used to estimate the treatment effect is an important  
consideration for a proposed NI margin and NI trial design.  For an NI trial to be informative, it 
is critical to have an adequately justified NI margin and to use appropriate efficacy endpoints.  If 
NI trials are being considered, a comprehensive synthesis of the evidence that supports the effect 
size of the active-control drug product and the proposed NI margin should be assembled during 
the period of protocol development and provided to the FDA along with the protocol.  For any 
indication being studied using active-controlled trials designed to show NI, sponsors must 
provide adequate evidence to support the proposed NI margin (21 CFR 314.126).  
 
Any sponsor submitting a protocol for an NI trial under a special protocol assessment (SPA) 
should provide the evidence to support the choice of an NI margin and the choice of primary 
efficacy endpoints.  It should be recognized, however, that for some indications with a high rate 
of resolution without antibacterial drug therapy, such as ABS, ABECB,6 and ABOM, available 
data will not support the use of an NI design, and other trial designs (i.e., superiority designs) 
will be needed to provide evidence of effectiveness in these three indications.7  In some cases, it 
may be useful to compare time for clinical improvement in addition to overall cure rates (e.g., for 
a demonstration of superiority of the test drug to placebo, to an active control, or to delayed 
initiation of the test drug or an active control).  
 
B. 	 Ongoing or Completed Trials Intended for Submission to a New Drug 
Application   
 
Sponsors should re-evaluate all ongoing or completed NI trials that will be submitted in a new 
drug application for antibacterial indications to ensure that there is an adequate scientific basis 
for the established effect size of the active control and the proposed NI margin.  This 
                                                 
6 Patients enrolled in ABECB trials in  new drug applications have, in  general, included  patients with outpatient, 
milder, or less well-characterized disease. 
 
7 See the draft guidances for industry Acute Bacterial Sinusitis  Developing Drugs for Treatment, 
Acute Bacterial Exacerbations of Chronic Bronchitis in  Patients With Chronic Obstructive Pulmonary  
Disease:   Developing Antimicrobial Drugs for Treatment, and Acute Bacterial Otitis Media:  Developing  
Drugs for Treatment. When final, these guidances will represent the FDAs current thinking on these topics.   
For the most recent version of a guidance, check the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
3 
 Contains Nonbinding Recommendations 
recommendation applies to trials that may have been previously reviewed by the Office of 
Antimicrobial Products under an SPA.  If substantial scientific issues essential to determining the 
safety or efficacy of the drug have been identified for the NI trial design used, commitments 
from the FDA under an SPA may no longer be valid.8   
 
If the sponsor concludes that an NI design was appropriate for a completed trial or remains 
appropriate for an ongoing trial, the relevant investigational new drug application (IND) should 
be amended as soon as possible with the scientific evidence and rationale to support the proposed 
NI margin.  If scientific evidence does not support the proposed NI margin, additional trials 
employing other designs (e.g., superiority designs) should be considered to provide evidence of 
effectiveness for the proposed indication.  Proposals for additional trials should be submitted to 
the FDA. See ICH E10 for a discussion on the issues of choice of control group for clinical 
trials. 
 
Any changes to a sponsors development program that result from the recommendations in this 
guidance should be made as early as possible and documented in the sponsors IND.  Sponsors 
who have questions or who are unsure about the status of their development plans should submit 
a meeting request to discuss these issues further with the appropriate review division.  
Alternatively, sponsors should submit a new protocol as part of an SPA, or request a new SPA 
for a previously reviewed SPA. 
                                                 
8 See the guidance for industry Special Protocol Assessment. 
4