Complicated Urinary 

Tract Infections: 

Developing Drugs for 

Treatment 

Guidance for Industry 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
June 2018 

Clinical/Antimicrobial 
 
 
Revision 1 

   
Complicated Urinary 

Tract Infections: 

Developing Drugs for 

Treatment 

Guidance for Industry 

 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
 
Silver Spring, MD  20993-0002  

Phone: 855-543-3784 or 301-796-3400;  Fax: 301-431-6353;  Email: druginfo@fda.hhs.gov 
 
https://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)
  
 
June 2018 

Clinical/Antimicrobial 
 
 
Revision 1 

 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Considerations .................................................................................................................2
  
1.  Drug Development Population .........................................................................................................2
  
2.  Efficacy Considerations ...................................................................................................................2
  
3.  Safety Considerations.......................................................................................................................3
  
4.  Pharmacokinetic/Pharmacodynamic Considerations ......................................................................3
  
B.   Specific Efficacy Trial Considerations .........................................................................................3
  
1.  Clinical Trial Designs, Populations, and Enrollment Criteria  ........................................................3 
 
2.  Clinical Microbiology Considerations.............................................................................................5
  
3.  Randomization and Blinding ............................................................................................................6
  
4.  Specific Populations .........................................................................................................................6 
 
5.  Dose Selection and Formulations  ....................................................................................................7 
 
6.  Choice of Comparators ....................................................................................................................7
  
7.  Prior Nontrial Antibacterial Drug Therapy .....................................................................................7 
 
8.  Efficacy Endpoints ............................................................................................................................8 
 
a.   Primary efficacy endpoint .........................................................................................................8 
 
b.   Secondary endpoints ..................................................................................................................9 
 
9.  Trial Procedures and Timing of Assessments ..................................................................................9 
 
a.   Entry visit  ..................................................................................................................................9 
 
b.   On-therapy and end-of-therapy  visits ......................................................................................10 
 
c.   Post-treatment visits ................................................................................................................ 10 
 
10.   Statistical Considerations .......................................................................................................... 10 
 
a.   Analysis populations ................................................................................................................ 10 
 
b.   Noninferiority margins ............................................................................................................ 11 
 
c.   Sample size .............................................................................................................................. 11 
 
C.   Other Considerations ................................................................................................................... 11 
 
1.  Relevant Nonclinical Considerations............................................................................................. 11 
 
2.  Labeling Considerations ................................................................................................................ 11 
 
APPENDIX: JUSTIFICATION FOR NONINFERIORITY MARGIN FOR 

COMPLICATED URINARY TRACT INFECTIONS ........................................................... 12 
 
 
 
  Contains Nonbinding Recommendations 
Complicated Urinary Tract Infections:   

Developing Drugs for Treatment 

Guidance for Industry1
  
 
 
 
 
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 office responsible for this guidance as listed on the 
title page.  
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
treatment of complicated urinary tract infections (cUTIs).2  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 the treatment of cUTIs. 
 
We consider the treatment of cUTIs to be an indication distinct from the treatment of 
uncomplicated urinary tract infections.  This guidance addresses cUTI only.  Sponsors interested 
in pursuing an indication for the treatment of uncomplicated urinary tract infections should 
discuss clinical development plans with the FDA. 
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical  
trial design. 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    
 
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 
                                                 
1 This  guidance has been  prepared by the Division of  Anti-Infective Products in the Center  for Drug Evaluation and  
Research at the Food and Drug  Administration.  You may submit comments on this guidance at any time.  Submit  
comments to Docket No. FDA-2012-D-0148 (available at https://www.regulations.gov/docket?D=FDA-2012-D-
0148) (see the instructions for submitting comments in the docket). 
 
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.  For the most recent version of a guidance, check the FDA guidance web page  
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
1 
 Contains Nonbinding Recommendations 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
Complicated urinary tract infections are defined as a clinical syndrome characterized by pyuria 
and a documented microbial pathogen on culture of urine or blood, accompanied by local and 
systemic signs and symptoms, including fever (i.e., oral or tympanic temperature greater than 
38 degrees Celsius), chills, malaise, flank pain, back pain, and/or costo-vertebral angle pain or 
tenderness, that occur in the presence of a functional or anatomical abnormality of the urinary 
tract or in the presence of catheterization.  Patients with pyelonephritis, regardless of underlying 
abnormalities of the urinary tract, are considered a subset of patients with cUTIs.  Usually, one 
or more of the following conditions that increase the risk of developing a cUTI are present: 
 
   Indwelling urinary catheter 
   100 milliliters (mL) or more of residual urine after voiding (neurogenic bladder) 
   Obstructive uropathy (nephrolithiasis, fibrosis) 
   Azotemia caused by intrinsic renal disease  
   Urinary retention, including retention caused by benign prostatic hypertrophy  
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Drug Development Population  
 
The intended clinical trial population should be patients with all types of cUTIs.  Because 
pyelonephritis is an important subset of cUTI, approximately 30 percent or more of the clinical  
trial population should be patients with pyelonephritis for an indication for treatment of 
complicated urinary tract infections including pyelonephritis.   
 
2.  Efficacy Considerations  
 
Noninferiority trials are interpretable and acceptable for the indication of treatment of cUTI.  A 
showing of superiority is also readily interpretable.   
 
A single adequate and well-controlled trial supported by other independent evidence, such as a 
trial in another infectious disease indication, can provide evidence of effectiveness.4  Sponsors 
should discuss with the FDA the other independent evidence that would be used to support the 
findings from a single trial in cUTI. 
 
                                                 
4 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human  Drug and Biological 
Products. 
2 
 Contains Nonbinding Recommendations 
3.   Safety Considerations 
 
In general, we recommend a preapproval safety database of 700 patients or more.  If the same  
dose and duration of therapy for treatment of cUTI were used in clinical trials for other infectious 
disease indications, the safety information from those clinical trials can be part of the overall 
preapproval safety database. For new drugs that have an important clinical benefit compared to 
existing therapies, a smaller preapproval safety database may be appropriate.  Sponsors should 
discuss the appropriate size of the preapproval safety database with the FDA during clinical 
development. 
 
4.  Pharmacokinetic/Pharmacodynamic Considerations  
 
The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the drug should be evaluated 
using in vitro models or animal models of infection, if not previously performed.  Achieving 
adequate urine drug concentrations to evaluate antibacterial activity in the urine is an important 
consideration in patients with cUTI.  Serum concentration of the drug is also an important 
consideration because patients with cUTI can have bacteremia and renal parenchymal 
involvement.  The PK/PD characteristics of the drug can be used to guide selection of the dose 
and dosing interval based on serum and urine concentrations in relation to the minimum  
inhibitory concentration.  Because concentrations can be influenced by renal impairment, 
sponsors should evaluate the effect of renal impairment on serum and urine concentrations early 
in clinical development.  We recommend that blood and urine drug concentrations be evaluated 
in phase 1 and phase 2. 
 
The PK/PD characteristics of the drug (including the relationships to the minimum inhibitory 
concentrations noted above) should be integrated with the findings from phase 1 PK clinical 
trials to help identify appropriate dosing regimens for evaluation in phase 2 and phase 3 clinical 
trials. A dose-response trial design can be considered as an option for clinical trials early in 
development to weigh the benefits and risks of various doses and to ensure that suboptimal doses 
or excessive doses (beyond those that add to efficacy) are not used in a phase 3 trial.  
 
Collection of PK data in phase 2 clinical trials can be used to explore the exposure-response 
relationships and to confirm that the proper doses and regimens are selected for further 
evaluation in phase 3 clinical trials.  Collection of PK data in phase 3 clinical trials may help to 
explain potential questions regarding efficacy or safety that might arise from the clinical trials.  
Sponsors should consider a sparse sampling strategy to include all patients in clinical trials with 
cUTIs to allow for the estimation of drug exposure in each patient.  
 
B.  Specific Efficacy Trial Considerations 
 
1.  Clinical Trial Designs, Populations, and Enrollment Criteria 
 
Sponsors should conduct randomized, double-blind, and active-controlled cUTI trials, using a 
noninferiority or superiority design.  Placebo-controlled trials are not appropriate for this 
indication except when they are add-on superiority trials in which patients receive either placebo 
or investigational drug added to standard-of-care antibacterial drug treatment.   
 
3 
 Contains Nonbinding Recommendations 
The patient population should include patients with cUTI, and at least 30 percent of the patient 
population should have pyelonephritis for the indication for treatment of cUTI and 
pyelonephritis. 
 
We recommend the following inclusion and exclusion criteria: 
 
 	  Recommended inclusion criteria: 
 
	   At least two of the following signs or symptoms: 
 
  Chills or rigors or warmth associated with fever (e.g., oral temperature greater 
than 38 degrees Celsius) 
 
  Flank pain (pyelonephritis) or pelvic pain (cUTI)  
 
  Nausea or vomiting  
 
  Dysuria, urinary frequency, or urinary urgency 
 
  Costo-vertebral angle tenderness on physical examination 
 
and 
 
	   Urine specimen with evidence of pyuria: 
 
  Dipstick analysis positive for leukocyte esterase 
 
or 
 
  At least 10 white blood cells per cubic millimeter 
 
   Recommended exclusion criteria: 
 
   Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of 
more than 24 hours during the previous 72 hours5  
 
   Concurrent use of nonstudy antibacterial drug therapy that would have a potential 
effect on outcome evaluations in patients with cUTI  

 
   Patients with suspected or confirmed prostatitis 

 
   Patients with renal transplantation 
 
 
                                                 
5 Patients who have objective documentation of clinical progression  of cUTI while  on antibacterial drug therapy,  or  
patients who  received antibacterial drugs for  surgical prophylaxis and then develop cUTI, may be appropriate for  
enrollment.  
4 
 Contains Nonbinding Recommendations 
	   Patients with ileal loops 
 
	   Patients who are likely to receive ongoing antibacterial drug prophylaxis after 
treatment of cUTI (e.g., patients with vesico-ureteral reflux) 
 
	   Any recent history of trauma to the pelvis or urinary tract 
 
	   Patients with uncomplicated urinary tract infections (generally female patients with 
urinary frequency, urgency, or pain or discomfort without systemic symptoms or 
signs of infection) 
 
2.  Clinical Microbiology Considerations 
 
Before receipt of clinical trial drug therapy, all patients should submit a urine specimen for 
culture and in vitro antimicrobial susceptibility testing.6  Patients with an indwelling catheter 
should have urine samples collected following the placement of a new catheter, or aseptic 
techniques through a properly disinfected collection port if the indwelling catheter cannot be 
removed.  
 
A microscopic evaluation (e.g., Gram stain) or dipstick analysis for leukocytes, nitrates, or a 
catalase test of the urine specimen should be performed.  The urine specimen should be cultured 
by following established standard microbiology laboratory procedures.  Sponsors should 
describe the urine collection and culture methods, and provide a standardized algorithm in the 
clinical trial site microbiology laboratories for final reporting of the culture results.  In general, a 
single species of bacteria on pure culture identified at 105 colony forming units per milliliter 
(CFU/mL) or greater should be considered a true bacterial pathogen,7 and no growth of bacteria 
(or growth at a quantitation of less than 103 CFU/mL) should be considered a microbiological 
success for a mid-stream clean-catch urine specimen (see section III.B.8., Efficacy Endpoints).  
In vitro antimicrobial susceptibility testing of the isolates to the investigational drug and to other 
recommended antimicrobial drugs that may be used to treat cUTIs should be performed using 
standardized methods unless otherwise justified.8    
 
We recommend blood cultures taken at two separate sterile venipuncture sites before initiation of 
clinical trial drug therapy.  
 
                                                 
6 Proper methods of urine specimen collection for analysis and culture are important enrollment considerations for 
clinical trials; see, for example, publications  from the American Society for Microbiology, such as American 
Society for Microbiology, 2010, Clinical Microbiology  Procedures Handbook, 3rd Edition,  or a more recent edition;  
and American Society for Microbiology, 2009, Cumitech 2C:  Laboratory  Diagnosis of  Urinary Tract Infections, 
coordinating editor SE Sharp, or a more recent edition.  
 
7 Sponsors  should prespecify in the protocol  how  patients who have more than one bacterial species (isolated on a 
baseline urine culture) will be handled in the efficacy analysis. 
 
8 Standard methods for in vitro susceptibility testing are developed by organizations such as the Clinical and 
Laboratory Standards Institute, Wayne, PA. 
5 
 Contains Nonbinding Recommendations 
All isolated bacteria considered to be possible pathogens should be saved in the event that 
additional testing of an isolate is needed (e.g., determination of genetic relatedness among strains 
by pulse-field gel electrophoresis or other molecular fingerprinting methods).  
 
Development of new rapid diagnostic tests may facilitate future clinical trial design and 
potentially benefit patients by providing earlier diagnosis of causative organisms.  Clinical trials 
of a new antibacterial drug for treatment of cUTI may provide an opportunity to contribute to the 
evaluation of a new diagnostic test.  Sponsors interested in the development of a new rapid 
diagnostic test should discuss this opportunity with the FDA. 
 
3.  Randomization and Blinding 
 
Patients should be randomized at enrollment to the treatments studied in the trial.  All trials 
should be multicenter and double-blinded unless there is a compelling reason for single-blind or 
open-label trials. If trials are single-blind or open-label, sponsors should discuss potential biases 
with the FDA and how these biases will be addressed.  
 
4.  Specific Populations 
 
The trials should include patients of both sexes and all races, as well as geriatric patients.9   
Patients with renal or hepatic impairment can be enrolled, provided the pharmacokinetics of the 
drug have been evaluated in these patients and appropriate dosing regimens have been defined.   
 
Sponsors are encouraged to begin discussions about their pediatric clinical development plan as 
early as is feasible because pediatric studies are a required part of the overall drug development 
program and sponsors are required to submit pediatric study plans no later than 60 days after an 
end-of-phase 2 meeting or such other time as may be agreed upon by the FDA and the sponsor.10  
 
In general, safe and effective treatments are available for pregnant patients with cUTIs.  
Therefore, it is generally appropriate to complete phase 3 clinical trials that establish safety and 
efficacy in nonpregnant patients before trials in pregnant patients are initiated.  However, if 
treatment options are not available for pregnant patients with cUTIs (e.g., pregnant patients with 
bacterial pathogens resistant to all available antibacterial drugs), it may be appropriate to 
characterize safety and pharmacokinetics in pregnant patients with cUTIs who have the potential 
to benefit from the investigational drug.  Before sponsors consider clinical evaluations of an 
investigational drug in pregnant women, they should complete nonclinical toxicology studies, 
reproductive toxicology studies, and phase 1 and phase 2 clinical trials.  Infants born to mothers 
who received the investigational drug should be followed by the trials investigators until at least 
12 months of age. 
                                                 
9 See the ICH guidances for industry E7 Studies in Support of  Special Populations:  Geriatrics and E7 Studies in  
Support of  Special Populations:  Geriatrics; Questions and Answers. 
 
10 See the Pediatric Research Equity Act (Public Law 108-155; section 505B of the Federal Food, Drug, and  
Cosmetic Act; 21 U.S.C. 355c), as amended by the Food and Drug Administration Safety  and Innovation Act  
(Public Law  112-144), and the draft guidance for industry  Pediatric Study Plans:  Content of  and Process for  
Submitting Initial Pediatric Study  Plans and Amended Initial Pediatric Study Plans. When  final, this guidance will 
represent the  FDAs current thinking  on this topic. 
6 
 Contains Nonbinding Recommendations 
 
5.  Dose Selection and Formulations 
 
To choose the dose or doses to be evaluated in phase 3 clinical trials, sponsors should integrate 
the findings from nonclinical toxicology studies, other in vitro animal studies, animal models of 
infection, pharmacokinetics, safety and tolerability information from phase 1 clinical trials, and 
safety and efficacy information from phase 2 dose-ranging clinical trials.  An assessment of 
tissue penetration from animal studies as well as sufficient blood and urine concentrations in 
phase 1 and phase 2 trials can be used as supportive evidence that the selected dose is likely to 
achieve drug concentrations sufficient to exert an antimicrobial and clinical effect (see section 
III.A.4., Pharmacokinetic/Pharmacodynamic Considerations).  In addition, pharmacokinetics of 
the drug in specific populations (e.g., patients with hepatic impairment) should be evaluated 
before initiation of phase 3 trials to determine whether dose adjustments are necessary.  This 
evaluation may help avoid the exclusion of such patients from phase 3 clinical trials. 
 
Antibacterial drug therapy for cUTI is generally initiated with an intravenous (IV) drug 
administered for several days followed by a switch to an oral drug to complete an overall course 
of antibacterial drug therapy for at least 7 days.  For drugs that have both an IV and oral 
formulation, patients can switch from IV to oral drug during the trial provided that the 
pharmacokinetics of the IV and oral formulations have been adequately evaluated to determine 
appropriate dosing regimens.  
 
For drugs that have only an IV formulation, the switch from the IV investigational drug to a 
different oral drug should allow enough time for  proper assessment of the IV drugs safety and 
efficacy for treatment of cUTI (e.g., IV investigational drug for 5 days followed by a different 
oral antibacterial drug for 2 days to complete an overall course of treatment for 7 days).  
Approximately 5 days of IV therapy (i.e., 4 to 6 days of therapy) is generally recommended for 
this assessment and should be specified in the protocol.  This time period is supported by 
recently conducted trials that defined a switch from IV to oral therapy (see the Appendix).  The 
duration of the oral drug therapy, to complete at least a 7-day course of antibacterial drug 
therapy, also should be specified in the protocol.  
 
6.  Choice of Comparators 
 
In general, the active comparator to be used in clinical trials should be one that is considered 
standard of care in the United States for this indication.  When evaluating the current standard of 
care, we consider recommendations by authoritative scientific bodies (e.g., Infectious Diseases 
Society of America) based on clinical evidence and other reliable information that reflects 
current clinical practice.  
 
7.  Prior Nontrial Antibacterial Drug Therapy 
 
Ideally, patients enrolled in a cUTI clinical trial should not have received prior antibacterial drug 
therapy because such therapy may obscure true treatment differences between an investigational 
drug and the control drug, thereby introducing bias toward a finding of no difference between 
treatment groups (i.e., a bias toward noninferiority).  However, exclusion of all patients who 
have received prior antibacterial therapy could result in a patient population with lesser severity 
7 
 Contains Nonbinding Recommendations 
of illness and greater potential for spontaneous recovery; this also could bias trial results toward 
a finding of no difference between treatment groups (i.e., a bias toward noninferiority). 
 
A pragmatic approach to these concerns is to:  (1) encourage prompt enrollment procedures so 
that patients can receive the clinical trial treatment initially, with no need for other antibacterial 
drug therapy; and (2) allow enrollment of some patients who have received up to 24 hours of 
antibacterial drug therapy (ideally there would be few such patients but up to approximately 25 
percent of the patient population may be appropriate).  This would permit patients in the trial to 
receive prompt antibacterial drug therapy as clinically necessary, consistent with the standard of 
care. The total duration of the prior effective therapy should be less than 24 hours and ideally 
limited to one dose of an antibacterial drug with a short half-life.  It would be important to 
evaluate the results in the subgroup of patients (i.e., the majority of patients) who did not receive 
prior effective antibacterial drug therapy.   
 
8.  Efficacy Endpoints  
 
The following subsections describe the recommended primary efficacy endpoint and secondary 
endpoints. 
 
a.  Primary efficacy endpoint 
 
The primary efficacy endpoint should be a responder outcome.  
 
 	  Clinical and microbiologic response:  Resolution of the symptoms of cUTI present at 
trial entry (and no new symptoms) and the demonstration that the bacterial pathogen 
found at trial entry is reduced to fewer than 103 CFU/mL on urine culture 
(microbiological success).11    
 
	   Clinical or microbiologic failure:  Symptoms of cUTI present at trial entry have not 
resolved or new symptoms have developed, the patient has died, or the urine culture 
taken at any time during or after completion of therapy grows greater than or equal to 103  
CFU/mL of the original pathogen identified at trial entry. 
 
In general, the efficacy evaluation (test of cure) for an investigational drug administered for the 
entire duration of therapy for cUTI should occur at a fixed time point after randomization.  The 
fixed time point should include a period of observation after the completion of antibacterial drug 
therapy; the period of observation should be at least 5 days.12  Symptom resolution should 
                                                 
11 Microbiological success is an important component of the responder endpoint because the ascending route of 
infection is the most common pathophysiological mechanism for cUTI.  Continued bacteriuria at greater than 104  
CFU/mL in patients recently completing treatment for cUTI  represents a known risk for enhanced  rate  of  relapse of  
cUTIs.  Hence, microbiological success, along with resolution of symptoms, is the evidence needed to support a 
conclusion  of treatment benefit (i.e., how a patient feels, functions, and survives).   (See, for example, JD Sobel and  
D Kaye, 2010, Urinary Tract Infections, in GL Mandel, JE Bennett, R Dolin, eds., Principles and Practice of 
Infectious Diseases, 7th  edition, Philadelphia, PA, Churchill Livingstone Elsevier, 957985.)   
 
12  The period of  observation after completion of antibacterial drug therapy depends on the PK characteristics and  
half-life of the drug, but in  general should be a fixed time point specified in the protocol.  
8 
 Contains Nonbinding Recommendations 
include all the core symptoms of cUTI (i.e., resolution of dysuria, urinary frequency, urinary 
urgency, suprapubic pain, and flank pain). Baseline symptoms associated with anatomic 
abnormalities that predispose to cUTI (e.g., symptoms associated with the presence of an 
indwelling urinary catheter) do not need to be resolved for a consideration of successful 
responder. 
 
For an investigational drug that has only an IV formulation, the IV investigational drug should be 
maintained for approximately 5 days (i.e., 4 to 6 days of IV therapy) before a switch to an oral 
drug to provide a proper assessment of safety and efficacy of the IV drug. In addition to the 
primary efficacy endpoint at approximately day 5 of IV therapy, the maintenance of resolution of  
the core symptoms of cUTI and microbiological success at a fixed time point after randomization 
should be evaluated. For example, a trial in which patients receive 5 days of IV investigational 
drug therapy plus 2 days of oral therapy with another drug (for a total of 7 days of antibacterial 
drug therapy) should evaluate the responder outcome at approximately 14 days after 
randomization, allowing for a period of observation of approximately 7 days after completion of 
therapy. An IV investigational drug should demonstrate successful noninferiority (or 
superiority) at both endpoints:  (1) at approximately day 5 of IV therapy as the primary efficacy 
endpoint; and (2) at a fixed time point after randomization that accounts for the total duration of 
antibacterial therapy plus a period of observation after completion of antibacterial drug therapy. 
 
A symptom outcome assessment should use a structured assessment of responses given by the 
patient.13  Sponsors should specify the methods that patients will use to record the core 
symptoms of cUTI for discussion with the FDA.  The patients assessment tool should include 
each of the core symptoms of cUTI at baseline and at the trial endpoint and should be 
noncomparative (i.e., it should not require patients to compare their current state with an earlier 
period). 
 
b.  Secondary endpoints 
 
Patients should be evaluated for continued resolution of symptoms and microbiological success 
at a fixed time point approximately 21 to 28 days following randomization.  This assessment 
helps to evaluate sustained microbiological success and resolution of all clinical symptoms of  
cUTI (a responder outcome) as a secondary endpoint.  Sponsors also should evaluate the clinical 
outcome responses and microbiologic outcome responses separately at each fixed time point 
assessment as secondary endpoints. 
 
9.  Trial Procedures and Timing of Assessments 
 
a.  Entry visit 
 
Sponsors should collect baseline demographic and clinical information at the entry visit and 
include clinical signs and symptoms, microbiologic specimens (Gram stain and culture of urine; 
blood culture), and laboratory tests, as appropriate. 
 
                                                 
13 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims. 
9 
 Contains Nonbinding Recommendations 
b.  On-therapy and end-of-therapy visits 
 
Patients should be evaluated at least once during therapy or at the end of prescribed therapy.  
Clinical and laboratory assessments for safety should be performed as appropriate.  If it is 
possible that the investigational drug would need to be continued beyond the protocol-specified 
duration, objective criteria for extending the therapy should be prespecified in the protocol.  An 
on-therapy visit at the time of IV-to-oral switch should have a urine specimen obtained for 
microscopic examination and culture as well as clinical observations and patient symptoms.   
 
c.  Post-treatment visits 
 
The responder endpoint should be evaluated at a fixed time point following randomization that 
accounts for the total duration of antibacterial drug therapy plus a period of observation of at 
least 5 days after completion of antibacterial drug therapy (e.g., a fixed time point at 14 days 
after randomization).  Patients should be evaluated by history and physical examination for 
clinical signs, including vital signs, at this visit.  Patients should be assessed at this visit for 
symptom resolution and a urine specimen should be obtained for microscopic examination and 
culture. An assessment for the maintenance of clinical response should occur at approximately 
21 to 28 days after randomization.   
 
10.  Statistical Considerations 
 
In general, sponsors should provide a detailed statistical analysis plan stating the trial hypotheses 
and the analysis methods before trial initiation.  The primary efficacy analysis is usually based 
on the difference in the proportions of patients achieving a successful clinical and 
microbiological response. 
 
a.  Analysis populations 
 
The following definitions apply to various analysis populations in cUTI clinical trials:   
 
 	  Intent-to-treat (ITT) population:  All patients who were randomized.  
 
 	  The microbiological intent-to-treat population (micro-ITT population):  All 
randomized patients who have a baseline bacterial pathogen on culture of urine or blood 
that causes cUTI against which the investigational drug and control drug have 
antibacterial activity. Patients should not be excluded from this population based upon 
events that occurred post-randomization (e.g., loss to follow-up). 
 
 	  Clinically evaluable or per-protocol populations:  Patients who meet the definition for 
the ITT population and who follow important components of the trial as specified in the 
protocol. 
 
 	  Microbiologically evaluable populations:  Patients who meet the definition for the 
micro-ITT population and who follow important components of the trial as specified in 
the protocol. 
 
10 
  Contains Nonbinding Recommendations 
   Safety population:  All patients who received at least one dose of drug during the trial.  
 
The micro-ITT population should be considered the primary analysis population.  Consistency of 
the results should be evaluated in all populations and any inconsistencies in the results of these 
analyses should be explored and explanations provided in the final report.  
 
b.  Noninferiority margins 
 
Noninferiority trials can be an appropriate trial design if there is reliable and reproducible 
evidence of a treatment effect for the comparator drug.14  For a cUTI trial, a noninferiority 
margin of 10 percent is supported by the historical evidence (see the Appendix).  Sponsors 
should discuss with the FDA the selection of a proposed margin greater than 10 percent. 
 
c.  Sample size 
 
An estimate of the sample size for a noninferiority trial with 1:1 randomization is approximately 
425 patients per group based on a noninferiority margin of 10 percent and a clinical success rate 
in the micro-ITT population of 80 percent in the control group.  Approximately 80 percent of 
patients should have a bacterial pathogen identified by culture (the micro-ITT primary efficacy 
analysis population would consist of approximately 337 patients per group).  The trial should 
have enough statistical power to rule out a greater than 10 percent inferiority of the 
investigational drug to control drug (upper bound of the two-sided 95 percent confidence interval 
for the clinical success rate of control drug minus investigational drug).  
 
C.  Other Considerations 
 
1.  Relevant Nonclinical Considerations 
 
New antibacterial drugs being studied for cUTIs should have nonclinical data documenting 
activity against commonly implicated pathogens for cUTI.15  Animal models of cUTIs may 
contribute to demonstrating proof of concept for the treatment of cUTIs and for evaluating 
antibacterial activity. Animal studies should not be considered a substitute for clinical trials in 
patients with cUTIs that must be conducted to evaluate safety and efficacy of the drug (21 CFR 
314.600). 
 
2.  Labeling Considerations 
 
The labeled indication under the INDICATIONS AND USAGE section should reflect the patient 
population enrolled in the clinical trials. Approximately 30 percent of the patient population in 
the cUTI clinical trials should have a diagnosis of pyelonephritis for the indication to include 
treatment of both complicated urinary tract infections and pyelonephritis. 
 
                                                 
14 See the guidance for industry Non-Inferiority Clinical Trials.  
 
15 See the guidance for industry Microbiology Data  for Systemic Antibacterial Drugs  Development, Analysis, and 
Presentation.  
11 
  Contains Nonbinding Recommendations 
APPENDIX: JUSTIFICATION FOR NONINFERIORITY MARGIN FOR 

COMPLICATED URINARY TRACT INFECTIONS 
 
 
A literature search found four articles published before the availability of antibacterial drug 
therapy that are case series of patients in which the clinical  courses of patients with complicated 
urinary tract infections (cUTIs), in the absence of antibacterial drug treatment, were described.  
 
A total of seven recently conducted clinical trials were identified that evaluated drugs approved 
for treatment of cUTI that had sufficient data to assess clinical and microbiologic outcomes of 
individual patients after a period of observation following completion of antibacterial drug 
treatment (end of all therapy).  Four of the seven clinical trials that evaluated intravenous (IV) 
antibacterial drugs included an oral switch and had sufficient data to assess outcomes on 
individual patients at the time of the IV-to-oral switch (end of IV therapy).  
 
Case Series of Patients With cUTI Before the Availability of Antibacterial Drugs  
 
The results of the four case series that describe the natural history of cUTIs without the use of 
antibacterial drugs are shown in Table 1.  One article described the responder endpoint, while 
three articles described either microbiological success or clinical response.  We chose to consider 
microbiological success + clinical response as representing the greatest proportion that could 
have achieved both microbiological success and resolution of clinical symptoms.  Overall 
clinical and microbiological success in these pre-antibacterial studies was no higher than 30 
percent.  As noted in Table 1, an upper bound for meta-analysis of the results is about 33 percent. 
12 
  Contains Nonbinding Recommendations 
Table 1. Summary of Studies of cUTI Before Antibacterial Drug Therapies  
Microbio-
Endpoint 
Timing of  Microbiolog- Clinical   logical Success 
Study  Population   Specified in 
Evaluation   ical Success   Response   + Clinical  
the Paper  
Response  
Relief of  
83% completed  
symptoms  
the 
Culver  Adults with   Not  and two 
nonantibacterial   Not provided  30/116 (25.9%)  
19181,2,3   cUTI  provided   successive 
therapy within  1  
negative  
month 
cultures  
Nonantibacterial 
Negative  
therapy 
Henline  Adults with   Not  Not provided  urine cultures 
administered  7/31 (22.6%)  
19253,4   cUTI  provided    7/31  (22.6%)   obtained by  
until negative 
cystoscopy 
cultures 
Nonantibacterial 
therapy 
Koll  Adults with   Not  Not provided  Sterile urine 
administered  4/15 (26.7%)  
19113,5   cUTI  provided    4/15  (26.7%)   cultures 
until sterile urine 
obtained  
Supportive  Not specified, 
Todd  Adults with   therapy or   Not provided  in general  
Not provided  3/10 (30%) 
18576,7   cUTI  surgical   3/10  (30.0%)   relief of  
intervention    symptoms  
DerSimonian and Laird random effects meta-analysis for the microbiological success + clinical response:  
25.6% (95% CI:   19.6%,  32.7%)8,9  
1 Culver, H, RD Herrold, and FM Phifer, 1918, Renal Infections:  A Clinical and Bacteriologic Study, Journal of the American Medical 

Association, 70:14441448. 
 
2 This paper provides the best estimate of an endpoint of both clinical and microbiological cure for patients with cUTI treated without 

antibacterial drug therapy.
  
3 Therapies at this time consisted of altering the urinary pH or altering surface tension that may have resulted in an indirect antibacterial effect. 
 
Patients had symptoms of cUTI for  months or in some  cases years before presenting for treatment. 

4 Henline, RB, 1925, Hexyl Resorcinol in the Treatment of 50 Cases of Infections of the Urinary Tract, J Urol, 14:119133.
  
5 Koll, IS, 1911, An Experimental and Clinical Study of the Colon Bacillus Infections of the Urinary Tract, J Urol, VII(11):417428. 
 
6 Todd, R, 1857, Clinical Lectures on Certain Diseases of the Urinary Organs and on Dropsies, Philadelphia:  Blanchard and Lea,  243261. 
 
7 Later in the 1800s, the germ theory  of disease was described by  Louis Pasteur and Robert Koch. 
 
8 DerSimonian, R and N Laird, 1986, Meta-Analysis in Clinical Trials, Control Clin Trials, 7:177187. 
  
9 CI = confidence interval 

 
Evaluation of Recently Conducted Phase 3 Trials of cUTI for End of Therapy  
 
Table 2 includes the results of active-controlled trials of drugs approved for treatment of cUTI at 
the time of the trial or drugs subsequently approved for treatment of cUTI based on these 
successful trial results.  The trials reported microbiological success and investigator-assessed 
clinical responses for individual patients at time points ranging between 3 to 10 days after 
completion of antibacterial drug therapy.  In general, antibacterial drug therapy was administered 
for approximately 2 weeks.  Microbiological success for all of these trials was defined as having 
fewer than 104 colony forming units per milliliter (CFU/mL) on quantitative urine cultures.  
Clinical response was defined, in general, as complete resolution of symptoms or improvement 
13 
  Contains Nonbinding Recommendations 
in symptoms such that no additional antibacterial drugs were required.  Some trials in Table 2 
have two treatment groups and each group is displayed separately.  The analyses are based on the 
microbiological intent-to-treat (micro-ITT) population (i.e., all patients with a documented 
bacterial infection).  
 
Table 2. Summary of Phase 3 Trials in Patients With cUTI; Micro-ITT Populations 
Microbiological  
Day of   Microbio- Clinical   Success +  
Study  Source  
Evaluation   logical Success*  Response   Clinical  
Response  
188/208   Trial 
1   7-10 d post-Rx   171/208 (82.2%)   164/208 (78.8%)  
(90.4%)   datasets 
166/192   Trial 
2   7-10 d post-Rx   149/192 (77.6%)   139/192 (72.4%)  
(86.5%)   datasets 
185/227   Trial 
5-9 d post-Rx   197/227 (86.8%)   180/227 (79.3%)  
(81.5%)  datasets 
3 
206/248   Trial 
5-9 d post-Rx   209/248 (84.3%)   197/248 (79.4%)  
(83.1%)  datasets 
112/139   Trial 
5-9 d post-Rx   106/139 (76.3%)   104/139 (74.8%)  
(80.6%)  datasets 
4 
55/73    Trial 
5-9 d post-Rx   54/73  (74.0%)   51/73 (69.9%)  
(75.3%)  datasets 
291/325   Trial 
6-9 d post-Rx   257/325 (79.1%)   241/325 (74.2%)  
(90.0%)   datasets 
5 
260/323   Trial 
6-9 d post-Rx   253/323 (78.3%)   233/323 (72.1%)  
(80.5%)  datasets 
294/337   Trial 
6   6-9 d post-Rx   278/337 (82.5%)   255/337 (75.7%)  
(87.2%)   datasets 
224/317   Trial 
3-9 d post-Rx   240/317 (75.7%)   201/317 (63.4%)  
(70.7%)  datasets 
7 
205/302   Trial 
3-9 d post-Rx   229/302 (75.8%)   193/302 (63.9%)  
(67.9%)  datasets 
DerSimonian and Laird random effects meta-analysis for the microbiological success + clinical response:  
73.2% (95% CI: 69.6%, 76.6%) 
(See notes 8 and 9 at the bottom of Table 1.)  
 
* Criteria for  microbiological success was evaluated using fewer than 104 CFU/mL. 
 
Overall, the rate of microbiologic and clinical success was not lower than 63 percent and the 
mean response in the meta-analysis was 73 percent with a lower bound of the 95 percent 
confidence interval at almost 70 percent. Analyses of recently conducted clinical trials in cUTI 
that evaluated both fewer than 104 CFU/mL and fewer than 103 CFU/mL as the microbiological 
success criteria found that the two criteria performed similarly.  Hence, the treatment effects are 
applicable using either fewer than 104 CFU/mL or fewer than 103 CFU/mL as the 
microbiological response criteria.  We recommend that the microbiological success component 
of the responder outcome is fewer than 103 CFU/mL (see section III.B.8., Efficacy Endpoints, of 
the guidance).  
 
14 
  Contains Nonbinding Recommendations 
Treatment Effect and Support for Noninferiority Margin for End of Therapy 
 
An estimate of the treatment difference can be derived from comparing the upper bound of the 
rate of the microbiological success plus clinical resolution noted before antibacterial drug 
therapies were available (approximately 33 percent from Table 1), and the lower bound of the 
rate of the microbiological success plus clinical resolution from recently conducted clinical trials 
of antibacterial drugs (approximately 70 percent from Table 2).  There is thus clear evidence of 
an effect of the active control (i.e., historical evidence of sensitivity to drug effect) and the 
treatment difference is estimated to be 37 percent (70 percent minus 33 percent).  It may be 
reasonable to estimate the entire effect of the active control (M ) at 37 percent, but given the 
1
uncertainties with the data presented in the historical case series, the effect of the active control 
(M ) should be somewhat discounted.  Therefore, we choose M  of 30 percent. 
1 1
 
For the selection of a noninferiority margin, a proportion of M  should be preserved to maintain 
1
the important treatment effects of antibacterial drugs in the treatment of cUTI.  Thus, a 
noninferiority margin (M ) of 10 percent can be supported for active-controlled clinical trials of 
2
cUTI using a responder endpoint of microbiological success plus clinical resolution at a fixed 
time point after randomization that accounts for the total duration of antibacterial drug therapy 
plus a period of observation of at least 5 days after completion of antibacterial drug therapy, in 
the patient population with microbiologically documented cUTI.  Sponsors should discuss with 
the FDA the selection of a noninferiority margin greater than 10 percent. 
 
Treatment Effect and Support for Noninferiority Margin for End of IV Therapy  
 
We evaluated patient-level data from phase 3 IV-to-oral-switch trials in patients with cUTI that 
were submitted to support an application for approval of an IV drug.  The trials provided specific 
clinical and microbiological criteria for switching from IV to oral therapy.  In general, patients 
were required to have microbiological success on therapy and to have achieved improvement in 
clinical symptoms before switching to oral therapy.  We considered clinical response as having 
complete resolution of symptoms of cUTI at the timing of the IV-to-oral switch (i.e., resolution 
of dysuria, frequency, suprapubic pain, urgency, and flank pain, which were evaluated in all 
trials).  In addition, some trials also required that patients should not have nausea or vomiting 
upon switching to oral therapy.  The information on resolution of nausea or vomiting was not 
recorded on case report forms and therefore was not used as a specific symptom response or 
resolution in the trials electronic datasets.  Table 3 provides a summary of the trials that 
incorporated an IV-to-oral switch and evaluated symptom responses at the timing of the IV-to-
oral switch.  
 
15 
  Contains Nonbinding Recommendations 
Table 3. Summary of Phase 3 Trials Evaluating Responses at End of IV Therapy 
Mean   Microbiological Success  Clinical   Microbiological  
Study 
Duration of   During Treatment With  Response at End  Success + Clinical   Source  
Group 
IV Therapy  IV*  of IV Therapy#   Response  
106/216  106/216    Trial 
1  4.0 days   100%  
(49.1%)  (49.1%)   datasets 
113/230  113/230    Trial 
2  4.1 days   100%  
(49.1%)  (49.1%)   datasets 
87/130   87/130   Trial 
3  4.0 days   100%  
(66.9%)  (66.9%)   datasets 
47/67   47/67   Trial 
4  4.0 days   100%  
(70.1%)  (70.1%)   datasets 
230/317  230/317    Trial 
5  5.4 days   100%  
(72.5%)  (72.5%)   datasets 
224/311  224/311    Trial 
6  5.3 days   100%  
(72.0%)  (72.0%)   datasets 
230/329  230/329    Trial 
7  5.5 days   100%  
(69.9%)  (69.9%)   datasets 
DerSimonian and Laird random effects meta-analysis for the microbiological success + clinical response:  
64% (95% CI:  56%, 72%)  
(See notes 8 and  9 at the bottom of Table 1.) 
* Criteria for  microbiological success was evaluated using fewer than 104 CFU/mL. 

# The five symptoms that were evaluated as having complete resolution in this analysis were symptoms evaluated among all seven study groups:  

dysuria, frequency, suprapubic pain, urgency, and flank pain. 
 
 
Treatment Effect and Support for Noninferiority Margin for End of IV Therapy  
 
An estimate of the treatment difference of an IV antibacterial drug can be derived from 
comparing the upper bound of the rate of microbiological success plus clinical response noted 
before antibacterial drug therapies were available (approximately 33 percent from Table 1), and 
the lower bound of the rate of microbiological success plus clinical response from recently 
conducted clinical trials of antibacterial drugs using the time point of a switch from IV to oral 
therapy (approximately 56 percent from Table 3).  The treatment difference is estimated to be 23 
percent (56 percent minus 33 percent).  Given the uncertainties with the data presented in the 
historical case series, the effect of the active control (M ) should be somewhat discounted.  
1
Therefore, we choose M  of 20 percent. 
1
 
On clinical grounds, an M  of 10 percent can be supported for active-controlled clinical trials of 
2
cUTI using a responder endpoint of microbiological success plus clinical resolution at a fixed 
time point of approximately 5 days of IV investigational drug therapy at the time of IV-to-oral 
switch. Trials should continue to follow patients throughout the course of therapy and a period 
of observation of at least 5 days after completion of antibacterial drug therapy (e.g., a fixed time 
point at approximately 14 days after randomization) for overall evaluation of safety and efficacy 
of the IV investigational drug. Sponsors should discuss with the FDA the use of a noninferiority 
margin greater than 10 percent.  
16