Uncomplicated 

Gonorrhea:  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 2015 

Clinical/Antimicrobial 
 
 
   
Uncomplicated 

Gonorrhea:  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  

Tel: 855-543-3784 or 301-796-3400;  Fax: 301-431-6353; Email:  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)
  
 
August 2015 

Clinical/Antimicrobial 
 
 
     
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   DEVELOPMENT PROGRAM ....................................................................................... 2
  
A.   General Considerations .................................................................................................................2
  
1.  Early Phase Development Considerations.......................................................................................2 
 
2.  Drug Development Population .........................................................................................................2
  
3.  Efficacy Considerations ...................................................................................................................2
  
4.  Safety Considerations.......................................................................................................................3
  
B.   Specific Efficacy Trial Considerations .........................................................................................3
  
1.  Trial Design, Populations, and Entry Criteria .................................................................................3
  
2.  General Exclusion Criteria ..............................................................................................................3
  
3.  Clinical Microbiology Considerations.............................................................................................4
  
4.  Randomization, Stratification, and Blinding ....................................................................................4
  
5.  Specific Populations .........................................................................................................................4
  
6.  Dose Selection ..................................................................................................................................5
  
7.  Use of Active Comparators and Concomitant Therapy....................................................................5 
 
8.  Efficacy Endpoint  .............................................................................................................................5 
 
9.  Secondary Endpoints ........................................................................................................................6
  
10.   Trial Procedures and Timing of Assessments..............................................................................6 
 
11.   Statistical Considerations ............................................................................................................6
  
a.   Analysis populations ..................................................................................................................6
  
b.   Noninferiority margins ..............................................................................................................7
  
c.   Sample size ................................................................................................................................7
  
C.   Other Considerations .....................................................................................................................7
  
1.  Pharmacokinetic/Pharmacodynamic Considerations ......................................................................7
  
2.  Investigational Drugs With Activity Against N. gonorrhoeae and C. trachomatis  ..........................8 
 
3.  Labeling Considerations ..................................................................................................................8
  
REFERENCES.............................................................................................................................. 9
  
APPENDIX: JUSTIFICATION FOR NONINFERIORITY MARGIN ............................... 10 
 
 
 
  Contains Nonbinding Recommendations 
Uncomplicated Gonorrhea:  Developing Drugs for Treatment 

1
 
Guidance for Industry  
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not create any rights for any person and is not binding on FDA or the public.  You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To 
discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title 
page. 
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
treatment of uncomplicated gonorrhea.2  Specifically, this guidance addresses the Food and Drug 
Administrations (FDAs) current thinking regarding the overall development program and 
clinical trial designs for antibacterial drugs for the treatment of uncomplicated gonorrhea.   
 
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, respectively.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 
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  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 
II.  BACKGROUND 
 
Sexually transmitted infectious diseases are common in the United States.  The Centers for 
Disease Control and Prevention (CDC) estimated that approximately 820,000 incident cases of 
gonorrhea occurred in 2008 in the United States (Satterwhite, Torrone, et al. 2013).  
Antibacterial drug susceptibility profiles for Neisseria gonorrhoeae have continued to change to 
more resistant isolates since the 1940s (Kirkcaldy, Bolan, et al. 2013; Del Rio, Hall, et al. 2012).  
The potential for gonorrhea to become resistant to all currently available antibacterial drugs 
(Bolan, Sparling, et al. 2012) highlights the need for the development of new antibacterial drugs 
for the treatment of gonorrhea. 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Early Phase Development Considerations  
 
Sponsors involved in clinical development of an investigational antibacterial drug with in vitro 
activity against N. gonorrhoeae are encouraged to consider drug development for the treatment 
of uncomplicated gonorrhea.  
 
2.  Drug Development Population  
 
The clinical development population should include patients with uncomplicated urethral, 
cervical, rectal, or pharyngeal infections caused by N. gonorrhoeae. 
 
3.  Efficacy Considerations  
 
A single adequate and well-controlled noninferiority trial can provide evidence of effectiveness.4   
Sponsors should discuss with FDA the independent confirmatory evidence that would provide 
support for the evidence of effectiveness (e.g., the results of a trial in another infectious disease 
indication). If treatment of uncomplicated gonorrhea is the only indication being sought for an 
investigational drug, in general we recommend two adequate and well-controlled trials; however, 
in certain circumstances, a compelling outcome  in a single trial might provide evidence of 
effectiveness (e.g., showing superiority to a control drug in a planned noninferiority trial).   
 
                                                 
4 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human  Drug and Biological 
Products. 
2 
 Contains Nonbinding Recommendations 
4.  Safety Considerations   
 
In general, we recommend a preapproval safety database of approximately 500 patients at the 
proposed single dose, and a targeted duration of safety evaluation is approximately 3 to 7 days 
following the single dose administration.5  If the same or greater dose and duration of therapy for 
treatment of uncomplicated gonorrhea were used in clinical trials for other infectious disease 
indications, the safety information from clinical trials in other infectious disease indications can 
contribute to the overall preapproval safety database.6  Sponsors should discuss with FDA the 
appropriate size of the preapproval safety database during clinical development.  Sponsors 
should consider the option of unequal randomization in the efficacy trial (e.g., 2:1, 3:2) as a 
means of augmenting the overall safety database. 
 
B.  Specific Efficacy Trial Considerations 
 
1.  Trial Design, Populations, and Entry Criteria 
 
Trials should be prospective, randomized, and double-blinded.  The trial population should 
include patients with evidence of uncomplicated gonorrhea (i.e., infection of the urethra, cervix, 
pharynx, or rectum caused by N. gonorrhoeae). The entry criteria can be broad (e.g., including 
any patient who has uncomplicated gonorrhea) or focused (e.g., patients who have urethritis or 
cervicitis).  
 
Some patients who have gonococcal infections are asymptomatic, and infection may be 
established by tests during routine health care visits.  Such patients can be included in clinical 
trial populations. 
 
2.  General Exclusion Criteria 
 
The following patients should be excluded: 
 
 	  Patients who have gonococcal infections that require a different dose or duration of 
treatment (e.g., disseminated gonococcal infection, pelvic inflammatory disease, 
epididymitis, conjunctivitis)  
 
 	  Patients who have received any effective antibacterial therapy for the treatment of 
 
gonorrhea 

 
                                                 
5 See the draft guidance for industry Determining the Extent  of Safety Data  Collection Needed in  Late Stage 
Premarket and  Postapproval Clinical  Investigations. When final, this guidance will represent FDAs current 
thinking on this topic.  
 
6 See the guidance for industry Premarketing Risk Assessment. 
3 
 Contains Nonbinding Recommendations 
3.  Clinical Microbiology Considerations   
 
An adequate clinical specimen should be obtained for microbiologic evaluation, including Gram  
stain, culture, and in vitro antibacterial susceptibility testing.  Specimens should be collected, 
processed, and transported according to recognized methods (American Society for 
Microbiology 2011). Direct inoculation of the specimen on both selective and nonselective 
media maximizes the sensitivity, particularly for cervical specimens.  Methods to reliably 
exclude infection or colonization by Neisseria meningitidis are recommended for specimens 
from the rectum or pharynx.  This microbiological information is important for characterizing 
N. gonorrhoeae isolates and for developing susceptibility test interpretive criteria.  
 
For clinical trials evaluating an investigational drug, nucleic acid amplification tests (NAATs) 
should not replace culture for the diagnosis of gonococcal infection and establishment of a test of  
cure in which important microbiological information is obtained and evaluated by culture (e.g., 
in vitro susceptibility testing). However, NAATs  or other rapid diagnostic tests can be used to 
select patients for enrollment.  Subsequent confirmation of N. gonorrhoeae by culture can be 
used to define the primary analysis populations. 
 
The clinical trial of an antibacterial drug may also provide an opportunity to contribute to 
development and evaluation of a new diagnostic test.  Sponsors interested in using a clinical trial 
in patients with uncomplicated gonorrhea as a means for evaluation of a new diagnostic test are 
encouraged to discuss this with FDA. 
 
4.  Randomization, Stratification, and Blinding 
 
Eligible patients should be randomized to treatment groups at enrollment.  Sponsors should 
consider the option of stratification before randomization to ensure that treatment groups are 
balanced with regard to infection site and sex (e.g., women with cervicitis, men with urethritis).  
All trials should be multicenter and double-blinded to control for potential biases unless blinding 
is not feasible.  
 
5.  Specific Populations 
 
The trials should include patients of both sexes and all races.  Patients who have the human 
immunodeficiency virus infection can be included in clinical trials. 
 
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 FDA and the sponsor.7   
                                                 
7 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  of  
2012  (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 Pediatric Study Plans. When final,  this guidance will 
represent the  FDAs current thinking  on this topic. 
4 
 Contains Nonbinding Recommendations 
Adolescents should be included during preapproval drug development.  Adolescents can be 
enrolled in phase 3 clinical trials, if appropriate.   
 
In general, safe and effective treatments are available for pregnant patients with uncomplicated 
gonorrhea. 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 uncomplicated 
gonorrhea (e.g., pregnant patients infected with N. gonorrhoeae resistant to all available 
antibacterial drugs), it may be appropriate to characterize safety and pharmacokinetics in 
pregnant patients with uncomplicated gonorrhea 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 and 
developmental 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. 
 
6.  Dose Selection 
 
Drugs for the treatment of uncomplicated gonorrhea generally should be administered as a single 
dose. Sponsors should integrate findings from nonclinical studies, pharmacokinetics, and safety 
information from earlier stages of clinical development to select the dose or doses to be 
evaluated in phase 3 clinical trials. The pharmacokinetics of the drug in specific populations 
(e.g., adolescent patients, patients with renal or hepatic impairment) should be evaluated before 
initiation of phase 3 to determine whether dose adjustments are necessary.  This evaluation may 
prevent the exclusion of such patients from the phase 3 clinical trials.  
 
7.  Use of Active Comparators and Concomitant Therapy  
 
The active comparator in a phase 3 controlled trial should be an antibacterial drug that is 
recommended for treatment of uncomplicated gonorrhea by authoritative scientific bodies based 
on clinical evidence and that reflects current clinical practice.8  
 
In general, treatment for Chlamydia trachomatis should be offered to all patients with a 
diagnosis of uncomplicated gonorrhea (Del Rio, Hall, et al. 2012).  Sponsors should discuss with 
FDA the choice and timing of concomitant therapy if the investigational drug does not have 
activity against C. trachomatis. 
 
8.  Efficacy Endpoint 
 
The primary efficacy endpoint should be the establishment of a negative culture at the infection 
site or sites approximately 3 to 7 days after receipt of antibacterial drug therapy (microbiological 
cure).  
 
                                                 
8 The CDC  publishes guidelines for the treatment of sexually transmitted diseases and periodically updates those 
guidelines (see, for example, Del Rio, Hall, et al. 2012). 
5 
 Contains Nonbinding Recommendations 
9.  Secondary Endpoints 
 
Suggested secondary endpoints for the trial include the following: 
 
   The results of a NAAT following treatment 
 
   Symptom resolution in the subgroup of patients who have baseline symptoms attributable 
to uncomplicated gonorrhea9  
 
10.  Trial Procedures and Timing of Assessments 
 
The following bullet points outline the recommended trial procedures and the timing of 
assessments:  
 
	   Entry visit: Appropriate demographic information, history and physical examination 
findings, a microbiological specimen, and safety laboratory tests should be collected at 
this visit; patients should receive investigational antibacterial drug treatment at this visit. 
 
 	  Visit at approximately 3 to 7 days after receipt of treatment:  This visit should assess 
microbiological cure using a microbiological specimen from the baseline infected site or 
sites. Adverse effect information and, if appropriate, safety laboratory tests should also 
be collected.   
 
11.  Statistical Considerations 
 
In general, a detailed statistical analysis plan stating the trial hypotheses and the analysis 
methods should be submitted before trial initiation.  The primary efficacy analysis should be 
based on a comparison of the proportions of patients achieving a microbiological cure. 
 
a.  Analysis populations 
 
Sponsors should consider the following definitions of analysis populations for uncomplicated 
gonorrhea trials: 
 
   Safety population  All patients who received the investigational drug during the trial 
 
   Intent-to-treat population  All patients who were randomized 
 
   Microbiological intent-to-treat (micro-ITT) population  All patients randomized who 
have N. gonorrhoeae isolated on baseline culture 
 
   Per-protocol population  Patients who follow important components of the trial 
                                                 
9 Symptoms and their resolutions, although important to evaluate as a secondary endpoint, are not  well defined and  
reliable in  uncomplicated gonorrhea for the following reasons:  (1) some  patients who have uncomplicated 
gonorrhea are asymptomatic; and (2) patients who failed antibacterial drug treatment in the setting of drug resistance 
had symptom resolution  (see, for example, Allen, Mitterni, et al. 2013). 
6 
 Contains Nonbinding Recommendations 
 
 	  Per-protocol microbiologically evaluable population  Patients who follow important 
components of the trial and have N. gonorrhoeae isolated on baseline culture (e.g., 
micro-ITT patients who follow important components of the trial)  
 
The micro-ITT population should be considered the primary analysis population.  In general, 
sponsors should not consider analyses of the per-protocol populations as primary because after-
randomization events or characteristics potentially could bias results in this population.  
However, consistency of the results should be evaluated in all patient populations.  Every attempt 
should be made to limit the loss of patients from the trial such that the micro-ITT population and 
per-protocol microbiologically evaluable population are similar.  The method for handling 
missing data should be specified in the protocol. 
 
b.  Noninferiority margins 
 
Noninferiority trials are informative only if there is reliable and reproducible evidence of 
treatment effect for the active-controlled drug.10  A noninferiority margin for the primary 
efficacy endpoint of microbiological cure based on the demonstration of a negative culture result 
is supported by historical data (see the Appendix).  Sponsors should discuss the selection of the 
noninferiority margin with FDA in advance of trial initiation. 
 
c.  Sample size 
 
An estimate of the sample size for a noninferiority trial with 1:1 randomization is approximately 
190 patients per group based on a noninferiority margin selection of 10 percent and a 
microbiological cure rate in the micro-ITT population of 90 percent in the control group (see the 
results from the clinical trials in Table 1 of the Appendix).  The trial should rule out a greater 
than 10 percent inferiority of the investigational drug to the control drug (upper bound of the 
two-sided 95 percent confidence interval (CI) for the microbiological cure rate of the control 
drug minus the investigational drug). 
 
C.  Other Considerations 
 
1.  Pharmacokinetic/Pharmacodynamic Considerations 
 
The pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of the drug should be 
evaluated in nonclinical models (e.g., in vitro PK/PD models, animal models of infection).  
Nonclinical PK/PD assessments should be integrated with findings from phase 1 PK assessments 
to help identify appropriate dose and dosing regimens for evaluation in phase 2 and phase 3 
clinical trials. Collection of PK data in phase 2 trials can be used to explore dose-response 
relationships to support dose selection for further evaluation in phase 3 trials. 
 
                                                 
10 See the draft guidance for industry Non-Inferiority Clinical Trials. When  final, this guidance will represent 
FDAs current  thinking on this topic.  
7 
 Contains Nonbinding Recommendations 
2.  Investigational Drugs With Activity Against N. gonorrhoeae and C. trachomatis 
 
Investigational drugs that have potential to treat both gonorrhea and chlamydia can have 
concurrent clinical development programs.  For example, a phase 3 trial can enroll patients with 
clinical evidence of infection caused by N. gonorrhoeae and/or C. trachomatis. NAATs or other 
rapid diagnostic testing could direct patients into groups intended to evaluate treatment of 
gonorrhea, chlamydia, or both.  Sponsors should discuss a concurrent phase 3 development 
program with FDA. 
 
3.  Labeling Considerations 
 
The labeled indication for the treatment of uncomplicated gonorrhea generally should reflect the 
population for which there is substantial evidence of safety and effectiveness, which is usually 
based on the types of patients evaluated in the clinical development program.  
 
For example, if the clinical development program evaluated patients who had cervicitis or 
urethritis (and patients with oropharyngeal or rectal gonorrhea were specifically excluded from  
drug development), the indication should reflect that patient population: 
 
Drug X is indicated for the treatment of uncomplicated gonorrhea (cervicitis/urethritis)  
caused by susceptible strains of Neisseria gonorrhoeae.  
 
 
8 
 Contains Nonbinding Recommendations 
REFERENCES  
 
Allen VG, L Mitterni, C Seah, et al., 2013, Neisseria gonorrhoeae Treatment Failure and 
Susceptibility to Cefixime in Toronto, Canada, JAMA, 309(2):163-170. 
 
American Society for Microbiology, 2011, Manual of Clinical Microbiology, ASM Press, 
Washington DC, 10th edition. 
 
Apewokin SN, WM Geisler, and LH Bachmann, 2010, Spontaneous Resolution of Extragenital 
Chlamydial and Gonococcal Infections Prior to Therapy, Sex Transm Dis, 37:343-344.  
 
Aplasca de los Reyes MR, V Pato-Mesola, JD Klausner, et al., 2001, A Randomized Trial of 
Ciprofloxacin versus Cefixime for Treatment of Gonorrhea after Rapid Emergence of 
Gonococcal Ciprofloxacin Resistance in The Philippines, Clin Infect Dis, 32:1313-1318. 
 
Bolan GA, PF Sparling, and JN Wasserheit, 2012, The Emerging Threat of Untreatable 
Gonococcal Infection, N Engl J Med, 366(6):485-487. 
 
Del Rio C, G Hall, K Holmes, et al., 2012, Update to CDCs Sexually Transmitted Diseases 
Treatment Guidelines, 2010:  Oral Cephalosporins No Longer a Recommended Treatment for 
Gonococcal Infections, Morbidity and Mortality Weekly Report, 61:590-594. 
 
DerSimonian R and N Laird, 1986, Meta-Analysis in Clinical Trials, Control Clin Trials, 7:177-
188. 
 
Handsfield HH, TO Lipman, JP Harnisch, E Tronca, and KK Holmes, 1974, Asymptomatic 
Gonorrhea in Men. Diagnosis, Natural Course, Prevalence and Significance, N Engl J Med, 
290(3):117-123. 
 
Hook EW 3rd, FN Judson, MS Verdon, JM Ehret, and HH Handsfield, 1986, Comparative Study 
of Cefoperazone and Spectinomycin for Treatment of Uncomplicated Gonorrhea in Men, 
Antimicrob Agents Chemother, 30(4):619-621. 
 
Hutt DM and FN Judson, 1986, Epidemiology and Treatment of Oropharyngeal Gonorrhea, Ann 
Intern Med, 104:655-658. 
 
Kirkcaldy RD, GA Bolan, and JN Wasserheit, 2013, Cephalosporin-Resistant Gonorrhea in 
North America, JAMA, 309(2):185-187. 
 
Sandberg ET, PS Pegram, RE Roddy, et al., 1986, Dose Ranging Study of Cefpimizole (U-
63196E) for Treatment of Uncomplicated Gonorrhea in Men, Antimicrob Agents Chemother, 
29(5):849-851. 
 
Satterwhite CL, E Torrone, E Mietes, et al., 2013, Sexually Transmitted Infections Among US 
Women and Men:  Prevalence and Incidence Estimates, 2008, Sex Transm Dis, 40(3):187-193. 
9 
 Contains Nonbinding Recommendations 
APPENDIX:  JUSTIFICATION FOR NONINFERIORITY MARGIN 

 
A search of the historical literature identified three prospective, randomized, and blinded trials in 
which effective therapy was compared to ineffective or less effective therapy.  Because the 
ineffective or less effective therapy used for comparison probably had some overall effect, these 
trials gave a conservative estimate of the effect of a fully effective therapy.  Table 1 outlines each 
trial and the results of a random effects meta-analysis. 
 
Table 1. Prospective, Randomized, Blinded Trials in Uncomplicated Gonorrhea  
Trial  Population   Design  Endpoint  Results in  Results in  Difference 
Publication  (Micro-ITT;   (Success =  Effective  Ineffective/Less  (95% CI)  
Missing =  Negative  Therapy  Effective  
Failure)  Culture)   Group  Therapy Group 
Aplasca de   Females,  Prospective,  Repeat  Cefixime   Ciprofloxacin  27%  
los Reyes,  cervicitis  double-blind  culture at  (susceptible)  (resistance   (11.2%,  
Pato- 4-7 days     identified)  42.7%)  
Mesola, et    25/28 (89.0%)    
al. 2001  48/77  
  (62.3%)  
Hook 3rd,  Males,  Randomized,  Repeat  Cefoperazone  Cefoperazone  14.7%  
Judson, et  anogenital  dose-response  cultures 3- higher dose  lower dose   (1%,  
al. 1986  infection   single-blind,  8 days       28.9%)  
  (most  phase 2  trial  post-Rx   61/68 (89.7%)   36/48  
urethritis)  (75%)  
Sandberg,  Males,  Randomized,  Return 3-7   Cefpimizole  Cefpimizole  25.3%  
Pegram, et  anogenital or   dose-response,   days for  highest dose   lowest dose   (5%,  
al. 1986  pharyngeal   single-blind,   repeat      46.1%)  
infection,   phase 2  trial  culture  23/25   18/27  
(most  (92%)   (66.7%)  
urethritis) 
Random effects meta-analysis (DerSimonian and Laird 1986):  
Risk difference 21.3%, lower  bound of the two-sided  95% CI = 11.9% 
 
As noted above, these trials gave a conservative estimate of the treatment effect based on a 
negative culture for N. gonorrhoeae at approximately 3 to 8 days following administration of a 
single dose of an antibacterial drug.  The lower bound of the two-sided 95 percent CI for the risk 
difference was 11.9 percent. 
 
Three other studies provided evidence that a treatment difference of 11.9 percent is a 
conservative estimate of the effect of an antibacterial drug in the treatment of uncomplicated 
gonorrhea. Patients who were not treated for oropharyngeal gonococcal infection at a baseline 
visit (and were later identified by a positive culture at baseline) had spontaneous resolution rates 
of approximately 10 percent, 20 percent, and 50 percent when repeat culture of the pharynx was 
obtained at day 3, day 5, and day 7, respectively (Hutt and Judson 1986).  Untreated patients 
with oropharyngeal gonorrhea showed spontaneous resolution in 3 out of 11 (27 percent) patients 
on repeat cultures obtained at an average of 11 days, whereas none of the 6 patients with 
untreated rectal gonorrhea showed spontaneous resolution (Apewokin, Geisler, et al. 2010).  An 
assessment of the natural course of asymptomatic urethral gonorrhea demonstrated that 5 out of 
28 (18 percent) untreated patients had spontaneous resolution (Handsfield, Lipman, et al. 1974). 
 
10 
  Contains Nonbinding Recommendations 
If spontaneous resolution rates for uncomplicated gonorrhea were used as a comparison to 
effective treatment, the estimated treatment difference would be much larger than 11.9 percent.  
Therefore, an effectiveness margin of the active-controlled drug relative to placebo (M ) defined 
1
at approximately 11.9 percent is a conservative estimate.  In general, a noninferiority margin 
(M ) selected at 10 percent is supported by the historical literature using an endpoint of the 
2
establishment of a negative culture for N. gonorrhoeae at approximately 3 to 7 days following 
treatment. 
11