Guidance for Industry 

Acute Bacterial Sinusitis: 

Developing Drugs for 

Treatment 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
October 2012 
 
Clinical Antimicrobial 
 
 
 
   
Guidance for Industry 

Acute Bacterial Sinusitis: 

Developing Drugs for 

Treatment 

 
 
 
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) 

 
October 2012 

Clinical Antimicrobial 
 
 
 
   
TABLE OF CONTENTS 

 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Considerations .................................................................................................................2
  
1.  Nonclinical Development Considerations........................................................................................2
  
2.  Drug Development Population.........................................................................................................3
  
3.  Efficacy Considerations ...................................................................................................................3
  
4.  Safety Considerations.......................................................................................................................4
  
B.   Specific Efficacy Trial Considerations .........................................................................................4
  
1.  Clinical Trial Design........................................................................................................................4
  
2.  Trial Population ...............................................................................................................................5
  
3.  Inclusion Criteria .............................................................................................................................6
  
a.   Symptoms..................................................................................................................................6
	 
b.   Signs..........................................................................................................................................6
	 
c.   Generalized signs and symptoms ..............................................................................................6
	 
4.  Exclusion Criteria ............................................................................................................................7
  
5.  Additional Clinical Trial Entry Procedures .....................................................................................8
  
a.   Radiography ..............................................................................................................................8
	 
b.   Baseline sinus aspiration and endoscopy ..................................................................................8
	 
6.  Randomization, Stratification, and Blinding....................................................................................8
  
7.  Special Populations..........................................................................................................................9
  
8.  Dose Selection ..................................................................................................................................9
  
9.  Concomitant Medications.................................................................................................................9
  
10.   Efficacy Endpoints.....................................................................................................................10
  
11.   Trial Visits and Timing of Assessments .....................................................................................12
  
a.   Entry visit................................................................................................................................12
	 
b.   On-therapy  visits.....................................................................................................................13
	 
c.   Early follow-up visit................................................................................................................14
	 
d.   Late follow-up assessment......................................................................................................14
	 
e.   Safety evaluations ...................................................................................................................15
	 
12.   Statistical Considerations..........................................................................................................15
  
a.   Analysis populations ...............................................................................................................15
	 
b.   Noninferiority margins............................................................................................................16
	 
c.   Sample size..............................................................................................................................16
	 
d.   Missing data............................................................................................................................17
	 
e.   Statistical analysis plan ...........................................................................................................17
	 
13.   Ethical Considerations ..............................................................................................................17
  
14.   Labeling Considerations ...........................................................................................................17
  
 
  Contains Nonbinding Recommendations 
1
 
Guidance for Industry  
Acute Bacterial Sinusitis: 

Developing Drugs for Treatment 

 
 
 
 
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 assist sponsors  in the clinical development of drugs2  for the 
treatment of acute bacterial sinusitis (ABS).  This guidance defines ABS as inflammation of the 
paranasal sinuses as a result of the presence of a bacterial pathogen within the sinus space when 
the duration of  illness is less than 4 weeks.   
 
Specifically, this guidance addresses the Food and Drug Administrations (FDAs) current 
thinking regarding the overall development program  and clinical trial designs for drugs to 
support an indication for treatment of ABS.  This guidance does not address the development of 
drugs for other purposes such as prevention of ABS or treatment of chronic sinusitis, or 
developing drugs for the nonantimicrobial treatment of sinusitis.   
 
This guidance does not contain discussion of the general issues of clinical trial design or 
statistical analysis.  Those topics are addressed in the ICH guidances for industry E9  Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials.3   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
                                                 
1 This  guidance has been  prepared by the Division of  Anti-Infective Products in the Center  for Drug Evaluation and  
Research (CDER) at the  Food and Drug Administration.  
 
2  For the purposes of this  guidance, all references to drugs  include  both  human  drugs and  therapeutic biological 
products  unless otherwise specified. 
 
3  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.  
1 
 Contains Nonbinding Recommendations 
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.  BACKGROUND 
 
There have been a number of public discussions regarding the design of clinical trials to study 
ABS.4   These discussions have focused primarily on trial designs for ABS and other important 
issues such as the following:  
 
   Inclusion criteria 
   Application of appropriate diagnostic criteria   
   Use of appropriate definitions of clinical outcomes 
   Timing of outcome assessments 
   Use of concomitant medications 
   Role of microbiological outcomes 
   Noninferiority and superiority trial designs 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Nonclinical  Development Considerations 
 
New drugs being studied for ABS should have nonclinical data documenting activity against the 
most commonly implicated pathogens associated with ABS (i.e., Streptococcus pneumoniae, 
Haemophilus influenzae, and Moraxella catarrhalis).  Animal models of ABS have been 
developed, particularly for S. pneumoniae infection, and pathological and histological responses 
to antibacterial treatment have been shown in animals.  Although these models may contribute to 
the scientific understanding of ABS and its treatment, the results should be carefully interpreted 
when being used to help design subsequent human trials.  Because clinical trials can be  
conducted in patients with ABS, animal studies cannot substitute for the clinical trials that must 
be conducted to evaluate drug safety and efficacy.5  
 
                                                 
4  In  October 2003, the Anti-Infective Drugs Advisory Committee (AIDAC) discussed  ABS clinical trials with  a 
focus on  the use of noninferiority designs (see http://www.fda.gov/ohrms/dockets/ac/cder03.html#Anti-Infective).  
In September 2006, the AIDAC addressed appropriate use of  noninferiority trials for ABS in  the context of  a 
specific drug (see http://www.fda.gov/ohrms/dockets/ac/cder06.html#AntiInfective).  In a December 2006 joint 
meeting of the  AIDAC  and the Drug Safety  and Risk Management Advisory  Committee, the issue of noninferiority 
trial design  was discussed  in the context of evaluating  the risk-benefit profile of  a drug.  In this  case, three 
indications  were under discussion:   ABS, acute bacterial exacerbation  of  chronic bronchitis, and community-
acquired bacterial pneumonia (see http://www.fda.gov/ohrms/dockets/ac/cder06.html#AntiInfective). 
 
5  21 CFR 314.600 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=314.600)   
2 
 Contains Nonbinding Recommendations 
2.  Drug Development Population 
 
As previously noted, this guidance defines ABS as inflammation of the paranasal sinuses as a 
result of the presence of a bacterial pathogen within the sinus space  when the duration  of  illness 
is less than 4 weeks.  This guidance  also considers ABS to be restricted  to maxillary  disease 
with or without involvement of other sinuses, which is the most common presentation of ABS.  
Although isolated disease of the frontal or sphenoid sinus exist as clinical entities, they are rare 
and have a different pathophysiology, microbiology, and clinical course from maxillary sinusitis.  
Sponsors should discuss with the FDA if patients with maxillary ABS and concurrent 
nonmaxillary  ABS are being considered for clinical trial enrollment. 
 
In addition, although the medical literature commonly refers to  disease of the sinuses in 
conjunction with nasal symptoms as acute rhinosinusitis, we consider rhinitis and sinusitis to be 
distinct disease entities.  The administration of antimicrobial drugs is appropriate only for study 
of bacterial infection of the sinuses.  Rhinitis symptoms without sinus disease are most 
commonly caused by viral infection, allergic rhinitis, and/or  vasomotor instability.  Because we 
have approved nonantimicrobial drugs specifically for rhinitis symptoms alone, it is important to 
separate the effect of  antimicrobial therapy on ABS from treatment of nasal symptoms caused by 
nonbacterial sources. 
 
3.   Efficacy Considerations   
 
We have not been able to establish a reliable estimate of  the magnitude of  benefit for treatment 
of ABS with antimicrobial drugs from reviewing previous ABS trials.  Such an estimate would 
be a precondition for a noninferiority trial.  Accordingly, we recommend only superiority trials 
for ABS. 
 
The goal of ABS clinical trials should be to demonstrate an effect of antibacterial therapy on the 
clinical course of ABS caused by S. pneumoniae, H. influenzae, or M. catarrhalis.  If sponsors 
wish to add additional organisms to this indication, they should provide data sufficient to 
substantiate the clinical relevance of the particular organism  as a pathogen in ABS.  For 
example, some trials have implicated Staphylococcus aureus as a pathogen in ABS in a setting 
where this has been the sole pathogen isolated.  Sponsors should discuss with the FDA during 
drug development the methods to provide data on relevant bacterial pathogens that cause ABS.  
For example, microbiological data can be obtained by one or more of the following approaches:  
(1) baseline sinus puncture and aspiration (or endoscopy) performed on all patients enrolled in 
the phase 3 trial (see section III.B.5.b., Baseline sinus aspiration and endoscopy); (2) a subset of 
patients who have baseline sinus  puncture and aspiration (or endoscopy) performed in the phase 
3 trial; (3) baseline sinus puncture and aspiration (or endoscopy) performed on patients enrolled 
in a phase 2 trial; or (4) microbiological data obtained during clinical development of the 
investigational drug for treatment of another infectious disease in which the bacterial pathogens 
are identical or similar to bacterial pathogens known to cause ABS.   
 
The number of trials needed for approval of an ABS indication depends on the overall 
development plan for the drug under consideration.  If the development plan for a drug has ABS 
3 
 Contains Nonbinding Recommendations 
as the sole marketed indication, we recommend that two adequate and well-controlled trials 
establishing safety and efficacy be conducted for this indication.  
 
A single trial for an ABS indication may be appropriate if:  (1) there are data from  other clinical 
trials demonstrating effectiveness in other respiratory tract diseases; and (2) there is additional 
supportive information such as pharmacokinetic  and pharmacodynamic studies demonstrating 
concentration of the antibacterial drug  in the sinuses at a level expected to be active against the 
common pathogens causing ABS.  For example, evidence of efficacy from community-acquired 
bacterial pneumonia (CABP) trials may be supportive of a single superiority trial of  ABS 
because of the similar microbiology and greater seriousness of  CABP relative to ABS.   
 
The disease course and treatment for ABS is of a  short-term  duration.  Direct assessment of ABS 
symptoms to  support a conclusion of treatment benefit in response to antibacterial drug therapies 
is readily measured.  As such, there are no surrogate markers accepted by the FDA.  Sponsors 
who wish to propose a surrogate marker for clinical outcome or the initial diagnosis of ABS 
should discuss this with the FDA early in the drug development process. 
 
4.  Safety Considerations 
 
Antimicrobial drugs with clinically significant toxicity should not be considered appropriate for 
study of this indication unless treatment of a more seriously ill patient population is being 
considered.  
 
A sufficient number of patients should be studied at the exposure (dose and duration) proposed 
for use to draw appropriate conclusions regarding drug safety.  This information can be derived 
from  trials of the new drug for infections other than ABS if exposure is similar to or greater than 
the exposure for ABS. However, if ABS is the sole indication being studied, it is likely that 
additional patients may need to be studied for safety beyond the number of patients needed to 
show clinical efficacy for ABS.  This can be accomplished either by enhancing clinical trial 
enrollment to arrive  at a sufficient sample size for safety evaluations or by enrolling an 
appropriate number of patients in another trial designed to evaluate  safety.  The total number of  
patients needed for a drug development program that includes an ABS indication should be 
discussed with the FDA early in the drug development process.  
 
B.  Specific Efficacy Trial Considerations 
 
1.  Clinical Trial Design 
 
Currently, we recommend only superiority trials for ABS.  Sponsors who are considering a 
noninferiority trial for ABS should justify a proposed noninferiority margin to the FDA as early 
as possible during protocol development and before trial initiation.  This situation is discussed 
further in section III.B.12., Statistical Considerations.  
 
4 
 Contains Nonbinding Recommendations 
Superiority trials in the treatment of  ABS can consist of the following general forms: 
 
 
	   Placebo-controlled trial with a background of best available nonantimicrobial 
therapy   This design tests the safety and efficacy of  an investigational antimicrobial  
drug as an addition to a standardized regimen of the best  available analgesic and 
decongestant medications compared to the same  standardized regimen plus placebo. 
 
	   Dose-response  Patients in each arm receive different antimicrobial drug doses (or 
dosing regimens) for which there is equipoise together with a standardized regimen of the 
best available nonantimicrobial therapy.  To demonstrate efficacy, the arm receiving a 
higher dose (or more intensive therapy) should be superior to the lower dose (or less 
intensive) regimen. 
 
	   Superiority of the investigational antimicrobial to another antimicrobial  Patients 
in one arm  receiving the investigational drug (with standardized regimen of the best 
available background nonantimicrobial therapy) are compared with patients in a control 
arm  receiving  another antimicrobial drug (with standardized regimen of the best available 
background nonantimicrobial therapy).  To demonstrate efficacy, the arm receiving the 
investigational antimicrobial drug should demonstrate superiority to the arm  receiving  the 
control antimicrobial drug.  
 
A three-arm trial with the investigational treatment arm,  an active-controlled arm (e.g., an 
antibacterial drug approved for ABS), and a placebo-controlled arm permits the demonstration of 
superiority and also can provide  risk-benefit information relative to an approved comparator. 
 
ABS trials should be parallel group designs, because  crossover designs may be subject to carry-
over and period effects.  Other trial designs to demonstrate superiority can  be discussed with the 
FDA. 
 
2.  Trial Population 
 
ABS trials should include patients of both sexes and all races.  ABS should be diagnosed by a 
combination of signs and symptoms with radiographic imaging included with the initial 
assessment to increase diagnostic specificity for bacterial disease.  If it is feasible to perform  
sinus puncture and aspiration, documenting the presence of bacteria in the sinus cavity can be an 
important means of enriching the trial population for analysis, and can also serve to confirm  that 
enrollment procedures have succeeded  in enrolling an adequate percentage  of patients with 
bacterial disease.   
 
To improve specificity for ABS (i.e., to better select for bacterial rather than viral sinusitis), 
patients should have a history of symptoms for a minimum of 7 to 10 days before enrollment, 
without improvement over the 3 days immediately before enrollment.  
 
An alternative trial design can be used where patients are enrolled at days 4 to 7 and a 3-day run-
in period is used before randomization.  Randomization of patients with symptoms that have not 
5 
 Contains Nonbinding Recommendations 
improved over the 3-day run-in period may enrich the trial population for patients with a 
bacterial etiology of sinusitis. 
 
We do not recognize different forms of ABS based on disease severity at presentation.  However, 
we recognize that investigators in  a placebo-controlled trial may be less likely to enroll patients 
presenting with severe  disease than patients with milder symptoms, and that enrollment of 
hospitalized patients may be incompatible with a placebo-controlled trial.  Current practice 
guidelines state the following conclusions and research needs:  More placebo-controlled RCTs 
[randomized clinical trials] that incorporate both pre- and posttherapy [sic] sinus cultures and a 
clinical severity scoring system  are urgently needed to provide critical information regarding the 
natural history of ABRS [acute bacterial rhinosinusitis] as well as the timeliness and efficacy of 
antimicrobial therapy.6   If sponsors wish to study patients with severe disease (or hospitalized 
patients), we strongly encourage discussion with the FDA regarding protocol design and 
adherence to current practice guidelines.   
 
3.  Inclusion Criteria 
 
a.   Symptoms  
 
At least two of the following symptoms  should be present in patients with ABS:   
 
   Maxillary tooth pain (unilateral findings can be more specific) 
   Facial pain (unilateral findings can be more specific) 
   Frontal headache 
   Purulent nasal discharge (unilateral findings can be more specific) 
   New onset fetor oris (bad breath) 
   Morning cough 
   Nasal obstruction 
 
b.  Signs 
 
At least one of the following signs should be present in patients with ABS:  
 
   Purulent secretions from sinus ostia on examination  
   Abnormal sinus transillumination 
   Pain on palpation over sinuses 
   Facial swelling 
 
c.  Generalized signs and symptoms  
 
Additional generalized signs and symptoms  that are consistent with a diagnosis of ABS but are 
otherwise nonspecific include: 
                                                 
6  Chow,  AW,  MS Benninger,  I Brook et al.,  2012, IDSA Clinical Practice Guideline for Acute Bacterial 
Rhinosinusitis in  Children and  Adults, Clinical Infectious  Diseases, doi: 10.1093/cid/cir1043, published  March  20  
2012, ahead of print.   
6 
 Contains Nonbinding Recommendations 
 
	   Fever (e.g., temperature greater than or  equal to 38 degrees Centigrade) 
	   Malaise 
 
Although review of the medical literature has not identified a combination of patient 
characteristics with high specificity for bacterial sinusitis relative to  other causes of acute 
sinusitis, the presence of a greater number of symptoms is associated with a higher likelihood of 
bacteria being isolated by sinus aspiration. A duration of illness greater than 7 to 10 days at the 
time of presentation and a history of previous episodes of acute sinusitis also improve specificity 
for bacterial disease.  
 
Radiographic findings consistent with acute sinusitis also should be documented to be present at 
baseline (see section III.B.5.a., Radiography). If  baseline sinus puncture and aspiration is 
performed in the trial, the radiographic findings may help to  guide the sinus puncture and 
aspiration procedure (see section III.B.5.b., Baseline sinus aspiration and endoscopy), which 
enhances the ability to identify a bacterial pathogen on culture. 
 
4.  Exclusion Criteria 
 
The following patients should be excluded from ABS trials: 
 
 	  Patients with symptoms attributed to sinus disease for longer than 4 weeks 
 
 	  Patients with disease history consistent with allergic and other types of rhinitis 
 
 	  Patients with isolated frontal  and sphenoidal disease given the different pathophysiology 
and etiologic pathogens7   
 
 	  Patients with cystic fibrosis 
 
 	  Immunocompromised patients or patients with  other medical conditions that may affect 
interpretation of the effect of trial drugs 
 
 	  Patients who are allergic to any of  the trial drugs 
 
 	  Patients with nasal polyposis 
 
Sponsors can exclude patients who have received antimicrobial therapy for the current episode of 
ABS.  If patients who have received prior antimicrobial  therapy are included, they should be 
stratified before enrollment to ensure balance across the treatment arms. 
 
                                                 
7  If sponsors plan  to include patients with  maxillary sinusitis and  evidence of  concurrent  frontal, sphenoidal, or  
ethmoidal sinusitis, they should  discuss with the FDA  the enrollment criteria and  efficacy evaluation  before trial 
initiation.  
7 
 Contains Nonbinding Recommendations 
5.  Additional Clinical Trial Entry Procedures 
 
a.  Radiography 
 
Previous evaluations have attempted to identify radiographic abnormalities associated with 
bacterial causes of sinusitis versus other etiologies.  In general, these modalities, including plain 
sinus radiography, computed tomography, magnetic  resonance imaging, and ultrasound, have 
been nonspecific for the presence of bacteria  by sinus puncture.  However, radiography may 
have a strong  negative predictive value for bacterial sinusitis (i.e., the absence of radiographic 
abnormalities identifies patients with a lower likelihood of a bacterial sinus infection).  Because 
of this, we strongly recommend radiological assessment as a means to enrich the trial population.  
In clinical  trials, the number of patients who are screened for enrollment but then have negative 
radiography should be recorded and included in the trial report.  The clinical characteristics of 
patients screened but not enrolled also should be recorded. 
 
b.  Baseline sinus aspiration and endoscopy 
 
A microbiological diagnosis of ABS can be confirmed by isolating a bacterial pathogen from a 
specimen obtained by maxillary sinus puncture at baseline.  If  sinus puncture and aspiration is 
performed in the trial, Gram  stain of the aspirate material with examination for white blood cells 
(WBCs) should be performed, as well as in vitro antimicrobial susceptibility  testing of bacterial 
isolates.   
 
Sponsors considering endoscopic cultures at baseline should discuss this with the FDA in 
advance of  trial initiation. 
 
Other techniques, such as the placement of a small-bore indwelling catheter during treatment, if 
feasible to perform, can be useful for examining the microbiological response to treatment across 
treatment arms over time in phase 2 trials.   
 
If baseline sinus puncture or endoscopy is performed, the trial should be conducted at sites with 
expertise in the procedure.  The protocol should describe the specific methods to be used for 
obtaining, transporting, and processing specimens and should describe specific culture 
techniques to be used on specimens.  
 
6.  Randomization, Stratification, and Blinding 
 
Patients should be randomized for treatment assignment at enrollment.  All trials should be 
double-blinded for therapy and assessment of outcome.  
 
When microbiological sampling is performed, investigators should be blinded to the 
microbiological data obtained at entry.  If patients fail therapy and require rescue therapy, the 
results of baseline and any subsequent microbiological data should be made available promptly 
to the treating clinician. 
 
8 
 Contains Nonbinding Recommendations 
7.   Special Populations 
 
Sponsors will likely be required to conduct trials  to support labeling for use in the pediatric 
population.8   Pediatric patients 1 year old and older can be included along with adults in ABS 
trials if a dose, regimen, and formulation for these patients has been identified that yields drug 
exposure similar to that in adults; pediatric patients over 12 years of age often receive the same  
dose and formulation as adults and usually can be enrolled in these trials.  Sinus puncture may 
not be appropriate for pediatric patients in certain situations.  Sponsors should discuss with the 
FDA when sinus puncture in pediatric patients is planned, before trial initiation, to ensure 
compliance with 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical 
Investigations.  Other considerations  for compliance with subpart D include whether there are 
sufficient safety data to allow study of pediatric patients, and the acceptability of both the trial 
design and diagnostic procedures in pediatric patients.  Sponsors pursuing an indication for ABS 
are strongly encouraged to discuss the requirements for pediatric studies in their overall drug 
development program  with the FDA early in  development, including the potential for 
extrapolation of adult efficacy data, appropriate pharmacokinetic studies  in pediatric patients to 
support the selection of the dose, and preapproval of a safety database in children.   
 
Drug development programs should include a sufficient number of geriatric patients to 
characterize safety and efficacy in this population.  Patients with renal or  hepatic impairment can 
be enrolled provided pharmacokinetics of the drug have been evaluated in these patients and 
appropriate dosing regimens have been defined. 
 
8.   Dose Selection 
 
Selection of an appropriate dose and duration of therapy for phase 3 clinical trials should use 
information gathered in earlier clinical development; for example, data from  pharmacokinetic 
and pharmacodynamic studies (including information regarding sinus penetration of the drug) 
and data from phase 2 dose-ranging trials. 
 
9.  Concomitant Medications 
 
ABS clinical trials should determine the additional contribution of the antimicrobial drug to 
clinical outcome beyond nonantimicrobial therapies.  Lack of standardization of concomitant 
medications can introduce an important source of  confounding in clinical trials if there are 
imbalances in receipt of nonantimicrobial therapies between trial groups.  Such confounding may 
occur even if the number  of patients receiving concomitant medications is similar between 
treatment groups but the reasons for administering concomitant medications differ.  Confounding 
also may occur when the patients in one group who receive concomitant medications differ in 
baseline characteristics from those patients who do not receive concomitant medications.  
                                                 
8  The  Pediatric Research Equity  Act (Public Law 108-155) requires the conduct of  pediatric studies for certain  drug  
and biological  products  (see section 505B(b) of the Federal  Food, Drug, and Cosmetic Act).  See the draft guidance  
for industry  How to Comply With the Pediatric Research  Equity Act.  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. 
9 
 Contains Nonbinding Recommendations 
Therefore, sponsors should make every attempt to control for potential confounders such as 
concomitant medications.   
 
Treatment groups should be well-balanced with the use of nonantimicrobial  therapies to ensure 
that the treatment effect on an outcome  measure would be attributed to the investigational 
antibacterial drug.  This can be accomplished through a protocol-specified nonantimicrobial 
background regimen with the dose and frequency of  use similar for all patients in the trial; 
however, the use of standardized, nonantimicrobial therapy in the protocol should be based on 
experimental evidence that the treatment is effective.  At a minimum, the protocol should specify 
appropriate options for nonantimicrobial therapies during the trial.    
 
Concomitant medication use should be captured in all patients using a daily medication log.  Use 
of concomitant medications alone should not be an efficacy endpoint but should be analyzed in 
combination with a symptom  assessment using a patient-reported outcome (PRO) or caregiver-
reported instrument.  For example, the endpoint can be defined to evaluate whether symptoms  
persist after concomitant medication administration.   
 
10.  Efficacy Endpoints 
 
The primary emphasis of the trial should be the effect of the antimicrobial drug on outcomes that 
are clinically important to patients.  A well-defined and reliable PRO measure designed to 
capture the important symptoms of ABS can be considered a direct measure of treatment benefit 
and can be used in a trial to support labeling claims for efficacy.  Patient outcome  should be 
based on symptom response per patient rather than per sinus (i.e., outcome is measured 
identically regardless of whether unilateral or bilateral disease is present).  The primary outcome  
assessment can be characterized as a success  or  failure  as follows: 
 
 	  Clinical success.  Clinical success can be documented when a patient reports 
improvement or resolution of clinically meaningful symptoms  present at enrollment and  
the absence of new symptoms  or complications attributable to sinusitis. 
 
 	  Clinical failure.   Clinical failure can be documented as follows: 
 
 	  Protocol-defined worsening of symptoms or failure to improve at certain time points 
(e.g., failure to have symptomatic improvement 72 hours after treatment onset) 
 
 	  Development of a new symptom  of ABS during treatment 
 
 	  Development of complications of ABS such as meningitis and/or brain abscess, 
subdural empyema, cortical or sinus vein thrombosis, or extension of disease to the 
orbit of the eye 
 
 	  Treatment with nontrial antibacterial drugs for another related infectious disease (e.g., 
for treatment of  CABP)   
 
10 
 Contains Nonbinding Recommendations 
A PRO instrument can measure responses based on a scale score, and then the score should be 
used as the outcome  variable.  For patients who cannot report for themselves (e.g., young 
children), a caregiver assessment can be developed that reports on behaviors and signs that are 
probably related to the patients symptoms.  Development of a new PRO or caregiver-reported 
instrument should begin well in advance of phase 3 clinical trials so that the instrument can be 
ready for incorporation into the phase 3 protocol.9  For example, after content validity is 
established, sponsors can evaluate construct validity, reliability, and responsiveness of the 
instrument during phase 2 trials.  Evaluation of the patient responses using the instrument in 
phase 2 could be used to inform  sample size calculations for phase 3 trials.  
 
We recommend that the primary efficacy endpoint should be the time  to clinical success, defined 
as the period  from  the start of  trial drug therapy to clinically meaningful symptomatic 
improvement or resolution.  Sponsors who choose to  use response at a fixed time point as the 
primary outcome (i.e., as the test-of-cure assessment) should provide  evidence to support the 
selection of that specific time point. 
 
Patients who experience improvement of symptoms but then worsen during clinical trial 
participation should be considered clinical failures on the primary efficacy analysis.  Sinus 
puncture in patients who experience additional symptoms may be valuable for secondary 
analyses, because the results would allow a differentiation between patients who may still harbor 
the initial pathogen (relapse) compared with those patients who have acquired a new pathogen or 
have a noninfectious etiology for symptoms (recurrence).  Bacterial isolates obtained from 
clinical relapse or recurrences should be subjected to an  appropriate in vitro method (e.g., pulse 
field electrophoresis gel) to determine if the original isolate and the subsequent isolate are 
indistinguishable (relapse) or different (recurrence).  The susceptibility profile should be 
performed for any pathogens isolated.   
 
Patients who discontinue therapy because of an adverse event should be evaluated at the time  of 
discontinuation of the trial drug therapy. These patients should not be considered withdrawn 
from the trial in terms of overall evaluation; investigators should continue to follow all such 
patients at trial visits as scheduled and continue to record information on both safety and efficacy 
outcomes.  If at the time the trial drug therapy is discontinued the patient is alive, without 
complications, and does not receive additional antimicrobial therapy, then the patient should be 
evaluated following the protocol criteria; discontinuation of therapy because of an adverse event 
should not automatically be considered a clinical failure.  
 
Sponsors can present secondary analyses on variables such as: 
 
 	  Clinical response based on the number of sinuses involved (e.g., isolated maxillary 
disease compared to maxillary disease with other sinuses involved) 
 
 	  Clinical  response in unilateral versus bilateral disease 
 
 	  Investigator  assessment of  the patients clinical signs 
                                                 
9 For more information regarding the development of PRO  measures, see the guidance for industry  Patient-Reported  
Outcome Measures: Use in  Medical Product Development to Support Labeling Claims. 
11 
 Contains Nonbinding Recommendations 
 
   Subgroup analyses based on patient demographics 
 
Analyses of secondary and additional endpoints usually should be considered exploratory 
because a trial usually is not designed  to address the questions  raised by these analyses, either 
because of multiple comparisons and/or concerns with subgroup analyses (see section III.B.12., 
Statistical Considerations).  However, the conclusions of such analyses can be strengthened if 
hypotheses related to these endpoints  are prespecified  in the protocol, if adjustments for multiple 
comparisons (maintenance of  type I error)  are outlined in the protocol, and if  the trial is 
appropriately powered to determine differences between groups related to these variables.  
Analyses of secondary and additional endpoints can be most helpful for identifying areas for 
study in future trials. 
 
11.  Trial Visits and Timing of Assessments 
 
a.  Entry visit 
 
At entry, the investigator should evaluate the patient by performing an appropriate history and 
physical examination.  Information recorded  on the case report form  during the entry 
examination should include the following: 
 
   History and demographic characteristics 
 
   Date of visit 
   Age and sex 
   Underlying medical conditions, if any 
   History of  previous episodes of  acute sinusitis  and history of  allergic rhinitis 
   History of tobacco use 
   History of smoking 
   Previous or current use of antibacterial drugs, and the indication or reason  for use 
   Recent and/or current use of nonantibacterial concomitant medications 
 
   Symptoms 
 
The presence of each symptom,  as discussed in section III.B.2., Trial Population, and 
section III.B.3., Inclusion Criteria, should be documented directly as reported by the 
patient (or caregiver).  Baseline symptoms also can be recorded by patients or caregivers 
in a PRO or caregiver-reported instrument that is well-defined and reliable in the 
population to be studied. 
 
   Signs 
 
   Vital signs including body temperature measurement 
   Presence of  unilateral or bilateral disease 
   Findings on transillumination of sinuses 
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   Findings on nasal speculum  examination 
   Presence of purulent secretions 
   Radiographic testing by plain radiographs, computed tomography, or ultrasound 
   Other laboratory tests (e.g., peripheral WBC count) 
 
 	  Sample collection 
 
At clinical trial sites where sinus puncture and aspiration will be performed, baseline 
sinus puncture with aspirate should be sent for culture and identification and in vitro 
susceptibility testing of bacterial isolates.  All isolates considered to be possible 
pathogens should be saved in the event that additional testing of the isolate is needed.  
For microbiological assessment, the investigator should collect the following 
information:10  
 
	   Identification of the affected sinuses sampled (right and/or left).  
 
	   A description of how the sample was obtained, processed, and transported to the 
laboratory. 
 
	   Identification of the bacterial isolate (this information should  remain blinded while 
the patient is  receiving trial drug therapy). 
 
	   In vitro susceptibility (preferably minimum inhibitory concentration) testing of the 
isolates to both the trial and control drugs.  This information should remain blinded 
while the patient is receiving trial drug therapy.  In vitro susceptibility testing should 
be performed by using standardized methods, such as the Clinical and Laboratory 
Standards Institute methods, unless otherwise justified. 
 
Quantification of the bacterial load at baseline may be helpful for analysis but is not 
required.  If bacterial quantification will be used,  the protocol  for quantification should be 
provided to the FDA for review before initiating clinical trials.  
 
b.  On-therapy visits 
 
Each patient should have daily on-therapy assessments of symptoms using a well-defined and 
reliable PRO or caregiver-reported instrument that ensures that any potential biases in  the 
method of questioning do not affect trial outcome.  The ability to detect differences between 
therapies for a time-to-resolution endpoint may be  increased if assessments are done more often 
(e.g., twice daily).  Therapy should be continued as described in the protocol regardless of 
whether symptoms have resolved; however, patients with resolution of symptoms  can be 
considered as having achieved clinical success if this is a trial-defined outcome  (i.e., patients 
with continuing symptoms should be classified as not having achieved clinical success at the 
measured time point).  Investigators should attempt to allow  a minimum of 72 hours on trial drug 
therapy before classifying a patient as a clinical  failure.  
                                                 
10 Similar procedures should be followed if endoscopy is performed as part of the protocol. 
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Assigning clinical failure and permitting use of rescue antibacterial therapy should be reserved 
for patients who are worsening on their assigned treatment arm;  specific criteria to identify these 
patients should be included in the protocol.  It is  important that investigators distinguish patients 
who are worsening (i.e., where rescue therapy is  appropriate) from  patients who are slow to 
improve but may still remain on assigned therapy and thereby achieve clinical success at a later 
time point.11  Sinus puncture can be performed in patients whose therapy has failed and the 
sample sent for culture and identification and in vitro susceptibility testing  of  isolates.  In the 
case of clinical failure, therapy should then  be changed to an appropriate alternative 
antimicrobial treatment for ABS, with other therapeutic modifications as necessary; results from  
baseline cultures (if available) can  be released to the investigator  at this time to guide treatment, 
although blinding to original treatment arm  should still be maintained.  
 
Consideration should be given to obtaining blood sample for the measurement of drug 
concentration (e.g., a sparse sampling strategy).  An assessment of drug exposure in phase 3 
could help explain trial outcomes related to efficacy and/or safety.  It could also be used to assess 
the relationship between the pharmacokinetic/pharmacodynamic indices and observed clinical 
outcomes.  The protocol should provide a description of the sampling strategy and the proposed 
analysis plan. 
 
c.  Early follow-up visit 
 
The early follow-up visit should occur after completion of all trial drug therapy at a time when 
the investigational drug is expected to clear from the infection site.  For example, if the 
investigational drug with a short half-life is administered for 10 days, this visit can occur on day 
11 to 14 after therapy initiation.  At this visit the investigator should perform  a directed medical 
history and physical examination, as well as appropriate laboratory measurements.  The 
investigator also should inquire about adverse events.  If clinical relapse or recurrence is 
suspected, a specimen should be obtained for bacterial culture by sinus puncture and aspiration. 
 
d.  Late follow-up assessment 
 
The late follow-up assessment should occur 10 to  14 days after the completion of all therapy 
(e.g., if trial drug therapy is administered for 10 days, this assessment can occur on days 20 to 24 
after therapy  initiation).  For patients who have  no adverse events noted at the early follow-up 
assessment and who are clinical successes (i.e., previous resolution of  all symptoms), this 
assessment can be performed by a telephone contact or other interactive technology.  For patients 
with adverse events occurring at  or after the early follow-up assessment, investigators should 
perform an assessment that includes a medical history, a physical examination, appropriate 
laboratory evaluations, identification of any new adverse events, and follow-up on unresolved 
adverse events.  The follow-up assessment should include questions regarding any symptoms of 
                                                 
11  In a time-to-resolution analysis, a patient should be classified as  a success  at the time of complete resolution of 
symptoms.  Although the patients that remain are failures at  each time point, failure is  not carried forward unless a  
patient has reached a specific failure endpoint (e.g., the development of a bacterial complication of ABS and the 
need to  administer rescue therapy).  Criteria for failure or the need  for rescue  therapy should  be  explicitly outlined  in  
the clinical protocol.   
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ABS to ascertain if clinical relapse or  recurrence has occurred; if  clinical  relapse or  recurrence is 
suspected, a specimen should be obtained for bacterial culture. 
 
e.  Safety evaluations 
 
The protocol should specify the methods to be used  to obtain safety data during the course of the 
trial.  Both adverse event information and safety laboratory data should be  collected.  Age- and 
sex-appropriate normal laboratory values should be included with  clinical measurements when 
reporting laboratory data.  Additional safety evaluations also  may be needed because of the 
nonclinical and clinical profile of the specific drug under study.  Longer  term assessment of 
adverse events after discontinuation or completion of the antimicrobial also can be considered 
depending on the specific drug being studied. 
 
All patients should be evaluated for safety at the time of each trial visit or  assessment, regardless 
of whether the test drug has been discontinued.  Although serious and unexpected adverse events 
and follow-up information about these events  are required to be reported (21 CFR 312.32 
(c)(1)(i)(A) and 21 CFR 312.32(d)(1) and (2)), we recommend that  in general all adverse events 
should be followed until resolution, even if time on trial would otherwise have been completed.  
 
12.  Statistical Considerations 
 
Sponsors should designate the hypotheses to be tested before trial initiation.  These hypotheses 
should be stated in the statistical analysis plan and the trial should be powered to detect 
differences between trial arms.  If sponsors choose to test multiple hypotheses, they should 
address issues related to the potential increase in obtaining false positive results (type I error) 
because of multiple comparisons, either  by adjusting the type I error or using a stepwise, closed 
testing strategy for hypothesis testing. If sponsors use a closed testing hypothesis strategy, they 
should justify the order of hypothesis testing before trial initiation.  These issues should be 
discussed with the FDA in advance of trial enrollment.  
 
a.  Analysis populations 
 
The following definitions apply to various populations for analyses in ABS clinical  trials:  
 
	   Safety population    All patients who receive at least one dose of assigned therapy 
during the trial. 
 
	   Intent-to-treat (ITT) population   All patients who are randomized. 
 
	   Microbiological intent-to-treat (micro-ITT) population   When sinus aspiration or 
endoscopy is performed as defined in the protocol, patients who are randomized and who 
have a pathogen known to cause ABS isolated at baseline.  Patients should not be 
excluded from this population based upon events  that are measured after randomization 
(e.g., loss to follow-up). 
 
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	   Per-protocol populations (also referred to as the clinically evaluable or  
microbiologically evaluable populations)   The population of patients who meet the 
definition for the primary analysis population (ITT or micro-ITT population) and who 
follow important components of the protocol as specified (e.g., administration of a 
specified minimum amount of trial drug therapy).  Traditionally, adequacy of therapy for 
a per-protocol analysis population has been defined as patients who have received greater 
than 80 percent (or within 80 to 120 percent) of the prescribed dose amount and/or dosing 
regimen.  Sponsors should document compliance with dosing (e.g., daily assessment, 
patient or caregiver diary, urine testing, or MEMS caps).   
 
In general, the ITT population should be considered the primary analysis population.  Trials that 
enroll patients with baseline sinus aspiration can chose to evaluate the micro-ITT population as 
the primary analysis population.  The micro-ITT population is the population most likely to show 
the largest treatment effect of  antibacterial treatment.12   Other analysis populations in the trial 
should be evaluated as well to ensure consistency of  results.  It is important to note that the per-
protocol  population analyses are subgroup analyses because they exclude patients based upon 
events that occur after randomization.  Patients in such  subgroup analyses may differ by 
important factors (both measured and unmeasured) other than the drug received.   
 
b.  Noninferiority margins 
 
FDA review of previous ABS trials has not been able to establish a reliable estimate of the 
magnitude of benefit for treatment of ABS by antimicrobial drugs.  Therefore, we do not 
recommend the use of noninferiority  trials to establish evidence of effectiveness for regulatory 
approval of a new indication for ABS.  See also the draft guidance for industry Non-Inferiority 
Clinical Trials13 and the guidance for industry Antibacterial Drug Products: Use of 
Noninferiority Trials to Support Approval. 
 
c.  Sample size  
 
The appropriate sample size for a clinical trial should be based upon the number of patients 
needed to answer the research question posed by the trial.  The sample size is influenced by 
several factors including the prespecified type I and type II error rates, the expected success rate, 
and the amount by which the investigational drug is expected to be superior  to the control (effect 
size).  Sample size should be based upon the number of patients needed to draw conclusions 
based on the analysis population.  For example, the effect size for an antibacterial drug is likely 
to be larger among patients in a micro-ITT analysis population with confirmed bacterial 
pathogens.  There may be circumstances where a sample size estimate for an efficacy analysis in 
ABS trials may not include a sufficient number of patients for an adequate evaluation of safety, 
                                                 
12 The culture results (i.e., the specific bacterial organisms) that define whether a patient should be included in the 
micro-ITT population should  be stated in the protocol.  For example, a trial design  with  all isolates obtained by  
endoscopy may wish  to  include only patients with S. pneumonia  or  H. influenzae  isolates in the micro-ITT analysis 
to  improve  specificity.   
 
13  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.  
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in which case there are several choices to enhance the number of patients in an overall 
preapproval safety database (see section III.A.4., Safety Considerations).  
 
d.  Missing data 
 
There is no single optimal way to deal with missing data from clinical trials.  Sponsors should 
make every attempt to limit loss of  patients from  the trial.  Analyses that exclude patients are 
subgroup analyses, and patients who do not complete the trial may differ substantially from  those 
patients who remain in the trial in both measured and unmeasured ways.  Therefore, sponsors 
should prespecify in the protocol the method of how missing data will be included in the analysis 
of trial results.  Sponsors  also should present sensitivity analyses in the final report such as 
including all missing patients as failures, including all missing patients as successes, and 
including all missing data as successes or failures in each treatment group respectively.  
 
Different rates of missing data or differences in the reasons for missing data across treatment 
arms can be a cause for concern in the interpretation of  a clinical trial.  If  this situation occurs, it 
should be addressed in the report. 
 
e.  Statistical analysis plan  
 
The sponsor should submit to the FDA before trial initiation the statistical analysis plan for any 
phase 3 ABS trial. 
 
13.  Ethical Considerations 
 
Review of previous placebo-controlled trials of the treatment of ABS has shown variable results, 
with several placebo-controlled trials showing no effect of antimicrobial treatment for ABS.  
Accordingly,  trials have  not shown a risk to placebo-treated patients that make future placebo-
controlled trials unethical; the risk  from  placebo treatment may be similar to that associated with 
antibacterial therapy because low-frequency severe events (e.g., pseudomembranous colitis or 
serious allergic reactions) have  been observed with almost all antibacterial drugs.  The 
occurrence of common but less-severe adverse events (e.g., diarrhea) from antibacterial drugs 
also can be  relevant  in assessing the risk-benefit  to patients in  a placebo-controlled trial where 
the expected treatment effect may be small.  Rescue antibacterial therapy can be incorporated 
into the trial design so that individual patients are treated at  the time a failure outcome is 
assigned;  this may serve to mitigate concerns regarding inclusion of a placebo group in an ABS 
trial.  All trial designs should provide appropriate provisions for patient safety.  
 
14.  Labeling Considerations 
 
The following is an example of a labeled indication for the treatment of ABS. 
 
Drug X is indicated in the treatment of acute bacterial sinusitis due to susceptible isolates of 
(Genus and species of the relevant bacterial pathogens). 
 
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