Uncomplicated 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) 
 
August 2019 
Clinical/Antimicrobial 
 
   
Uncomplicated 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/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2019 
Clinical/Antimicrobial 
 
  Contains Nonbinding Recommendations 
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 and Dose Selection Considerations .....................................................................3 
B.  Specific Efficacy Trial Considerations .........................................................................................3 
1. Clinical Trial Designs, Populations, and Enrollment Criteria ........................................................3 
2. Clinical Microbiology Considerations .............................................................................................4 
3. Specific Populations .........................................................................................................................4 
4. Choice of Comparators ....................................................................................................................5 
5. Efficacy Endpoints ............................................................................................................................5 
a.  Primary efficacy endpoint .........................................................................................................5 
b.  Efficacy endpoints for a finding of superiority .........................................................................6 
c.  Secondary endpoints ..................................................................................................................6 
6. Trial Procedures and Timing of Assessments ..................................................................................6 
a.  Entry visit ..................................................................................................................................6 
b.  On-therapy and end-of-therapy visits ........................................................................................6 
c.  Post-treatment visits ..................................................................................................................6 
7. Statistical Considerations .................................................................................................................6 
a.  Analysis populations ..................................................................................................................7 
b.  Noninferiority margins ..............................................................................................................7 
c.  Sample size ................................................................................................................................7 
8. Labeling Considerations ..................................................................................................................8 
REFERENCES .............................................................................................................................. 9 
APPENDIX: JUSTIFICATION FOR NONINFERIORITY MARGIN FOR  
UNCOMPLICATED URINARY TRACT INFECTIONS ...................................................... 10 
 
 
  Contains Nonbinding Recommendations 
Uncomplicated 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 uncomplicated urinary tract infections (uUTIs).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 uUTIs.   
 
We consider the treatment of uUTIs to be an indication distinct from the treatment of 
complicated urinary tract infections (cUTIs).  This guidance addresses uUTIs only.  The FDA 
issued a separate guidance on cUTIs.3  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 (September 1998) and E10 
Choice of Control Group and Related Issues in Clinical Trials (May 2001), respectively. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
                                                 
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.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 See the guidance for industry Complicated Urinary Tract Infections:  Developing Drugs for Treatment (June 
2018).  We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web 
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
1  Contains Nonbinding Recommendations 
 
 
II.  BACKGROUND 
 
uUTI is defined as a clinical syndrome characterized by pyuria and a documented microbial 
pathogen on urine culture, accompanied by local signs and symptoms such as lower abdominal 
discomfort and dysuria.  uUTIs, also referred to as acute cystitis, occur in females with normal 
anatomy of the urinary tract and are not accompanied by systemic signs or symptoms, such as 
fever greater than 38 degrees Celsius or costovertebral angle pain.  Urinary tract infections in 
males are characterized as cUTIs because these infections occur in association with urologic 
abnormalities such as instrumentation or bladder outlet obstruction (e.g., benign prostatic 
hyperplasia).   
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Drug Development Population 
 
The intended clinical trial population should be female patients with uUTIs.   
 
2.  Efficacy Considerations 
 
Active-controlled trials designed for findings of superiority or noninferiority are potential 
options to evaluate antibacterial drugs for the treatment of uUTI.  A treatment effect of 
antibacterial drug therapy for uUTI has been established (see the Appendix).  Therefore, the 
noninferiority trial design is acceptable for demonstration of efficacy. 
 
The treatment-delay, placebo-controlled trial design allows for a finding of superiority of the 
investigational drug compared to placebo at a time point early in therapy, after which patients 
randomized to treatment delay receive antibacterial drug treatment.  Sponsors interested in 
conducting a placebo-controlled trial should discuss trial design and safety issues with the FDA.  
All trial designs should provide appropriate provisions for patient safety.4 
 
If a sponsor seeks only a uUTI indication for an investigational drug, we recommend two 
adequate and well-controlled trials.  A single adequate and well-controlled trial supported by 
other confirmatory evidence, such as a trial in another infectious disease indication, can provide 
evidence of effectiveness.5  Sponsors should discuss with the FDA the other independent 
evidence that would be used to support the findings from a single trial in uUTI. 
                                                 
4 For examples, see the References section of this guidance for references that include placebo-controlled or 
nonantibacterial-controlled trials in uUTI patients. 
 
5 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998). 
2  Contains Nonbinding Recommendations 
 
3.  Safety Considerations 
 
In general, we recommend a preapproval safety database of at least 800 patients at the proposed 
dose and duration for treatment.  If the dose and duration of therapy used in clinical trials for 
other infectious disease indications are the same or greater than the dose and duration proposed 
for treatment of uUTI, the safety information from those clinical trials can be part of the overall 
preapproval safety database.  Sponsors should discuss the appropriate size of the preapproval 
safety database with the FDA during clinical development. 
 
4.  Pharmacokinetic and Dose Selection Considerations 
 
The pharmacokinetics of the drug should be determined, including its excretion in urine.  Urinary 
concentrations of the drug are important when bacterial infection is limited to the lower urinary 
tract (i.e., uUTI).  Drug concentrations in urine over time should be assessed during early stages 
of a clinical development program.  
 
Phase 2 dose-ranging studies are recommended.  Phase 2 studies should include assessment of 
blood and urine drug concentrations to explore exposure-response relationships for safety and 
efficacy.  Sponsors can consider sparse blood sampling for drug exposure estimates in phase 3 
trials.  
 
B.  Specific Efficacy Trial Considerations 
 
1.  Clinical Trial Designs, Populations, and Enrollment Criteria 
 
Sponsors should conduct randomized, double-blind, controlled trials in female patients with 
uUTI, using a superiority or noninferiority design.  
 
We recommend the following inclusion and exclusion criteria: 
 
  Patients should be adult females and, if appropriate, adolescent females with evidence of 
pyuria (see section III.B.2., Clinical Microbiology Considerations) and at least two of the 
following signs or symptoms of uUTI: 
 
  Dysuria 
  Urinary frequency 
  Urinary urgency 
  Suprapubic pain 
 
  Patients should not have the following: 
 
  Signs or symptoms of systemic illness such as fever greater than 38 degrees Celsius, 
shaking chills, or other clinical manifestations suggestive of cUTI 
 
3  Contains Nonbinding Recommendations 
  Treatment with other antibacterial drugs that are effective for treatment of the current 
uUTI  
 
2.  Clinical Microbiology Considerations 
 
Before receipt of drug therapy, all patients should submit a urine specimen for culture and 
antimicrobial susceptibility testing.6  A microscopic evaluation for pyuria or dipstick analysis for 
leukocytes, nitrites, or a catalase test of the urine specimen should be performed.  The urine 
specimen should be cultured using standard microbiology laboratory procedures.  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 microbiologic 
success for a mid-stream clean-catch urine specimen (see section III.B.5., Efficacy Endpoints).  
Antimicrobial susceptibility testing of the isolates to the investigational drug and to other 
recommended antimicrobial drugs that may be used to treat uUTIs should be performed using 
standardized methods unless other in vitro susceptibility testing is justified.8   
 
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 an investigational antibacterial drug for treatment of uUTI 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.  Specific Populations 
 
Sponsors should enroll in the trials patients from across a wide age range, including geriatric 
patients.9  Sponsors can enroll patients with hepatic impairment in phase 3 trials provided the 
sponsor has evaluated the pharmacokinetics of the drug in these patients and has defined 
appropriate dosing regimens. 
 
We encourage sponsors to begin discussions about their pediatric clinical development plans as 
early as is feasible because pediatric studies under section 505B of the Federal Food, Drug, and 
Cosmetic Act (FD&C Act), if applicable, 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 
                                                 
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 the Clinical 
Microbiology Procedures Handbook, 3rd Edition, 2010, or a more recent edition; and the Cumitech 2C:  Laboratory 
Diagnosis of Urinary Tract Infections, 2009, 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. 
 
9 See the ICH guidances for industry E7 Studies in Support of Special Populations:  Geriatrics (August 1994) and 
E7 Studies in Support of Special Populations:  Geriatrics; Questions and Answers (February 2012). 
4  Contains Nonbinding Recommendations 
end-of-phase 2 meeting or such other time as may be agreed upon by the FDA and the sponsor.10  
Sponsors can include adolescent patients in phase 3 safety and efficacy trials, if appropriate. 
 
Given the different clinical considerations regarding urinary tract infections in pregnant patients 
(Gupta et al. 2011), sponsors should discuss with the FDA if the investigational drug is being 
considered for use in pregnant patients who may have the potential to benefit from the 
investigational drug. 
 
4.  Choice of Comparators 
 
In general, sponsors should use an active comparator that is considered standard of care for 
treatment of uUTI in the United States for this indication.  The active comparator generally 
should be approved by the FDA for treatment of uUTI.  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.  For a noninferiority trial, it is important that the analysis population 
includes only patients for whom the bacterial pathogen is fully susceptible to the active control 
drug on in vitro susceptibility testing. 
 
5.  Efficacy Endpoints 
 
The following subsections describe the FDAs recommended primary efficacy endpoint and 
secondary endpoints. 
 
a.  Primary efficacy endpoint 
 
The primary efficacy endpoint should be based on a responder outcome of clinical and 
microbiologic response. 
 
  Clinical and microbiologic response:  Resolution of the symptoms of uUTI (see section 
III.B.1., Clinical Trial Designs, Populations, and Enrollment Criteria) 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 (microbiologic 
response) assessed at a fixed time point after randomization that is based on the duration 
of investigational antibacterial drug therapy and half-life of the investigational drug. 
 
  Clinical or microbiologic failure:  Patients who did not meet the definition of clinical 
and microbiologic response (see above) or who died during the trial.  
 
                                                 
10 See section 505B of the FD&C Act 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 (March 2016).  
When final, this guidance will represent the FDAs current thinking on this topic. 
5  Contains Nonbinding Recommendations 
b.  Efficacy endpoints for a finding of superiority 
 
Sponsors can use the primary efficacy endpoint discussed in section III.B.5.a., Primary efficacy 
endpoint, or discuss with the FDA other endpoints and clinical trial designs for superiority, 
including designs that incorporate a delayed treatment group with standard or approved therapies 
(see section III.B.4., Choice of Comparators). 
 
c.  Secondary endpoints 
 
Patients should be evaluated for continued resolution of symptoms and microbiologic success at 
a fixed time point approximately 21 to 28 days following randomization.  This assessment helps 
to evaluate sustained microbiologic success and resolution of all clinical symptoms of uUTI (a 
responder outcome) as a secondary endpoint.  Sponsors also should evaluate the clinical and 
microbiologic responses separately at each fixed time point assessment as secondary endpoints.   
 
6.  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. 
 
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 the 
investigational drug needs to be continued beyond the protocol-specified duration, the protocol 
should prespecify objective criteria for extending the therapy.  
 
c.  Post-treatment visits 
 
The responder endpoint should be evaluated at a fixed time point after randomization that is 
based on the duration of investigational antibacterial drug therapy and half-life of the 
investigational drug.  Patients should be evaluated by history and physical examination for 
adverse reactions.  Symptoms of uUTI should be assessed at this visit and a urine specimen 
should be obtained for microscopic examination and culture.  An assessment for the maintenance 
of clinical and microbiologic response should occur at approximately 21 to 28 days after 
randomization. 
 
7.  Statistical Considerations 
 
In general, before trial initiation the sponsor should develop a detailed statistical analysis plan 
stating the trial hypotheses and the analysis methods.  The primary efficacy analysis is usually 
based on the difference in the proportions of patients achieving a successful response. 
 
6  Contains Nonbinding Recommendations 
a.  Analysis populations 
 
The following definitions apply to various analysis populations in uUTI clinical trials:   
 
  Intent-to-treat (ITT) population:  All patients who were randomized.  
 
  The microbiological intent-to-treat population (micro-ITT population):  Randomized 
patients who did not have growth of a bacterial pathogen on culture of urine at baseline 
should be excluded from this population.  For a noninferiority trial, the micro-ITT 
population should include patients who have growth of bacterial pathogens on culture of 
urine at baseline demonstrating susceptibility to the active control drug.  Patients should 
not be excluded from this population based on events that occurred after randomization 
(e.g., loss to follow-up). 
 
  Clinically evaluable population: Patients who meet the definition of the ITT population 
and who follow important components of the trial as specified in the protocol.  
 
  Microbiologically evaluable population:  Patients who meet the definition for the 
micro-ITT population and who follow important components of the trial as specified in 
the protocol.  
 
  Safety population:  All patients who received at least one dose of the drug during the 
trial. 
 
The sponsor should consider the micro-ITT population as the primary analysis population for a 
noninferiority trial.  The sponsor should evaluate the consistency of the results in all populations, 
explore any inconsistencies in the results of these analyses, and provide explanations 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.11  For a uUTI trial, a noninferiority 
margin of 10 percent is supported by historical evidence (see the Appendix).   
 
c.  Sample size 
 
An estimate of the sample size for a noninferiority trial with 1:1 randomization is approximately 
310 patients per group in the micro-ITT population.  This sample size is based on a 
noninferiority margin of 10 percent, a clinical success rate in the micro-ITT population of 80 
percent in the treatment and control groups, a two-sided  = 0.05 statistical significance level, 
and 90 percent power.  Approximately 80 percent of patients should have a bacterial pathogen 
                                                 
11 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).   
7  Contains Nonbinding Recommendations 
identified by baseline culture and belong to the micro-ITT population, and thus approximately 
388 patients per group may need to be included in the ITT population.   
 
The sample size estimate for a treatment delay superiority trial with 1:1 randomization is 
approximately 181 patients per group based on assumed success rates of 80 percent in the 
investigational group and 65 percent in the control group (e.g., placebo treatment delay), a two-
sided  = 0.05 statistical significance level, and 90 percent power. 
 
8.  Labeling Considerations 
 
Generally, the labeled indication should be the treatment of uUTI caused by the specific bacteria 
identified in a sufficient number of patients in the clinical trials.  
 
8  Contains Nonbinding Recommendations 
REFERENCES 
 
Asbach HW, 1991, Single Dose Oral Administration of Cefixime 400mg in the Treatment of 
Acute Uncomplicated Cystitis and Gonorrhoea, Drugs, 42 Suppl 4:1013. 
 
Bleidorn J, I Gagyor, MM Kochen, K Wegscheider, and E Hummers-Pradier, 2010, 
Symptomatic Treatment (Ibuprofen) or Antibiotics (Ciprofloxacin) for Uncomplicated Urinary 
Tract Infection?  Results of a Randomized Controlled Pilot Trial, BMC Med, 8:30. 
 
Christiaens TC, M De Meyere, G Verschraegan, W Peersman, S Heytens, and JM De Maeseneer, 
2002, Randomised Controlled Trial of Nitrofurantoin Versus Placebo in the Treatment of 
Uncomplicated Urinary Tract Infection in Adult Women, Br J Gen Pract, 52(482):729734. 
 
Dubi J, P Chappuis, and R Darioli, 1982, Treatment of Urinary Infection With a Single Dose of 
Co-Trimoxazole Compared With a Single Dose of Amoxicillin and a Placebo, Schweiz Med 
Wochenschr, 112(3):9092. 
 
Ferry SA, SE Holm, H Stenlund, R Lundholm, and TJ Monsen, 2007, Clinical and 
Bacteriological Outcome of Different Doses and Duration of Pivmecillinam Compared With 
Placebo Therapy of Uncomplicated Lower Urinary Tract Infection in Women:  The LUTIW 
Project, Scand J Prim Health Care, 25(1):4957. 
 
Gagyor I, J Bleidorn, MM Kochen G Schmiemann, K Wegscheider, and E Hummers-Pradier, 
2015, Ibuprofen Versus Fosfomycin for Complicated Urinary Tract Infection in Women:  
Randomized Controlled Trial, BMJ, 351:h6544. 
 
Gupta K, TM Hooton, KG Naber, B Wullt, R Colgan, LG Miller, GJ Moran, LE Nicolle, R Raz, 
AJ Schaeffer, and DE Soper, 2011, International Clinical Practice Guidelines for the Treatment 
of Acute Uncomplicated Cystitis and Pyelonephritis in Women:  A 2010 Update by the 
Infectious Diseases Society of America and the European Society for Microbiology and 
Infectious Diseases, Clin Infect Dis, 52(5):e103e120. 
 
Vik I, M Bollestad, N Grude, A Brheim, E Damsgaard, T Neumark, L Bjerrum, G Cordoba, IC 
Olsen, and M Lindbk, 2018, Ibuprofen Versus Pivmecillinam for Uncomplicated Urinary Tract 
Infection in Women  A Double-Blind, Randomized Non-inferiority Trial, PLOS Medicine, 
15(5): e1002569. 
 
9  Contains Nonbinding Recommendations 
APPENDIX: 
JUSTIFICATION FOR NONINFERIORITY MARGIN FOR  
UNCOMPLICATED URINARY TRACT INFECTIONS 
 
We identified two trials of uncomplicated urinary tract infection (uUTI) that used a placebo 
control, assessed a combined clinical and microbiological eradication outcome, and were 
published in the English language (Asbach 1991; Ferry et al. 2007).  Young adult females with 
symptoms such as dysuria and urinary frequency and/or urgency and a baseline urine culture 
positive for a bacterial pathogen (e.g., growth of bacteria at a quantitation of greater than 105 
colony forming units per milliliter (CFU/mL)) were enrolled in these trials.  The responder 
efficacy endpoint of both resolution of symptoms (clinical resolution) and microbiological 
eradication of the bacterial pathogen from urine (bacterial pathogen found at trial entry is 
reduced to fewer than 103 CFU/mL on follow-up urine culture) was evaluated in these two trials 
(Table 1). 
 
Table 1:  Clinical Resolution Plus Microbiological Eradication Outcome Assessment 
 
Control 
Timing of  Antibacterial 
Study Name  Group 
Outcome  Group Responder  Difference  95% CI* 
(first author)  Responder 
Assessment  Rate 
Rate  
Oral cefixime (400 
Days 1417  Placebo 
Asbach  mg single dose)   61.4%  36.3% to 86.5% 
post therapy  5/19 (26%) 
50/57 (88%) 
Oral pivmecillinam 
(pooled groups 
given 200 mg TID* 
x7 days, 200 mg  Placebo 
Ferry  Days 810  43.7%  37.5% to 49.2% 
BID* x7 days, or  30/227 (13%) 
400 mg BID* x3 
days)  
374/657 (57%)  
           
Random effects meta-analysis  49.4%  33.2% to 65.6% 
* CI = confidence interval; TID = ter in die or three times per day; BID = bis in die or two times per day 
 
An estimate for the treatment difference for the responder efficacy endpoint of clinical resolution 
plus microbiological eradication is approximately 33 percent (the lower bound of the two-sided 
95 percent confidence interval from Table 1).  Because of the differences between the point 
estimate antibacterial group responder rates and what might be expected in prospective 
noninferiority trials, we discounted 50 percent of the treatment effect to account for uncertainties 
and generalizability issues when translating the historical treatment effect to the effect of a 
current active control, as recommended in the guidance for industry Non-Inferiority Clinical 
Trials to Establish Effectiveness (November 2016).1  Therefore, an estimated treatment 
difference (M ) is approximately 16 percent.  Considering preservation of the treatment effect, 
1
we recommend a clinically acceptable noninferiority margin (M ) of 10 percent.  
2
                                                 
1 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
10  Contains Nonbinding Recommendations 
 
Below, we identify five additional published prospective and controlled trials of uUTI and 
describe results that are supportive of the treatment effect of an antibacterial drug for uUTI.  
These five trials were not included in the meta-analysis above for the responder endpoint for the 
following reasons.  
 
1.  One trial (Bleidorn et al. 2010) compared antibacterial drug treatment to ibuprofen.  
Ibuprofen appeared to influence symptom resolution as compared to ciprofloxacin, thus 
the trial did not show a significant difference between treatment groups for symptom 
resolution at Days 4 and 7.  There appeared to be an advantage for the antibacterial group 
for the microbiological eradication endpoint on Day 7 (72 percent eradication in the 
ciprofloxacin group compared to 49 percent in the ibuprofen group), but this difference 
was not statistically significant.  
 
2.  A second trial (Christiaens et al. 2002) evaluated clinical and microbiologic response 
separately, which showed significant differences in favor of the antibacterial drug group 
over placebo on Days 3 and 7 for both endpoints.  However, this trial was not included in 
the analysis because patient level data were not available to assess an individual patients 
outcome on the combined responder endpoint.  
 
3.  A third trial (Gagyor et al. 2015) enrolled patients that presented to an outpatient clinic 
with signs and symptoms of uUTI, regardless of whether a baseline urine culture 
demonstrated a bacterial pathogen.  Furthermore, there were no outcome data on 
microbiological eradication because the trial did not evaluate urine cultures at a follow-up 
visit.  A statistically significantly greater proportion of females achieved resolution of 
symptoms at Day 7 in the fosfomycin group compared to the ibuprofen group (82 percent 
for fosfomycin group and 70 percent for the ibuprofen group).  
 
4.  A fourth trial (Dubi et al. 1982) was not published in the English language and 
approximately 25 percent of the patients enrolled in this trial had only a positive urine 
culture with no symptoms of uUTI (i.e., females with asymptomatic bacteriuria).  This 
trial showed a statistically significant difference in favor of the antibacterial drug on the 
responder endpoint compared to placebo (70 percent versus 44 percent, respectively), 
although these results were likely driven by the microbiological eradication outcome 
measure caused by some patients not having symptoms at baseline.  
 
5.  A fifth trial (Vik 2018) enrolling females with uUTI, randomized to receive an 
antibacterial drug or ibuprofen, included the evaluation of women who did not have a 
positive urine culture at baseline.  The results showed that ibuprofen was inferior to the 
antibacterial drug (74 percent of patients in the antibacterial drug group were free of 
symptoms at Day 4 compared to 39 percent of patients in the ibuprofen group).   
 
11