Guidance for Industry 

Helicobacter pylori-Associated 

Duodenal Ulcer Disease in 

Adults:  Developing Drugs for 

Treatment 

 
 
 
 
 
DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852. All comments 
should be identified with the docket number listed in the notice of availability that publishes in 
the Federal Register. 
 
For questions regarding this draft document contact Joette Meyer at 301-796-1600.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
October 2009 

Clinical Antimicrobial 
 
 
I:\8345dft.doc 
 
09/14/09   
Guidance for Industry 

Helicobacter pylori-Associated 

Duodenal Ulcer Disease in 

Adults:  Developing Drugs for 

Treatment 

 
 
 
Additional copies are available from: 

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

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

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

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
October 2009 

Clinical Antimicrobial 
 
   
TABLE OF CONTENTS 

 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   DEVELOPMENT PROGRAM ....................................................................................... 3
  
A.   General Considerations .................................................................................................................3
  
B.   Specific Efficacy Trial Considerations .........................................................................................4
  
1.  Study Design.....................................................................................................................................4
  
a.   Substitution of a new drug for one component of an approved regimen ..................................5 
 
b.   Addition of a new drug to an approved regimen.......................................................................5
  
c.   Development of a new regimen not studied previously ............................................................5 
 
2.  Study Population ..............................................................................................................................5
  
3.  Entry Criteria ...................................................................................................................................6
  
a.   Inclusion criteria........................................................................................................................6
  
b.   Exclusion criteria ......................................................................................................................6
  
4.  Blinding ............................................................................................................................................7
  
5.  Efficacy Endpoints............................................................................................................................7
  
6.  Analysis Populations for Efficacy Analyses .....................................................................................7
  
7.  Study Procedures and Timing of Assessments..................................................................................8 
 
a.   Entry visit..................................................................................................................................8
  
b.   End-of-treatment visit ...............................................................................................................9
  
c.   Test-of-cure (post-treatment) visit.............................................................................................9
  
d.   Discontinuations .....................................................................................................................10
  
e.   Safety evaluations ...................................................................................................................10
  
8.  Statistical Considerations...............................................................................................................10
  
a.   Primary efficacy analysis ........................................................................................................10
  
b.   Missing data............................................................................................................................10
  
c.   Noninferiority trial design considerations...............................................................................11 
 
9.  Clinical Pharmacology Consideration...........................................................................................12
  
10.   Microbiology Considerations....................................................................................................12
  
C.   Labeling Considerations ..............................................................................................................13
  
APPENDIX: TABLES...............................................................................................................14
  
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
1 
Guidance for Industry  
1 
Helicobacter pylori-Associated Duodenal Ulcer  
2 
Disease in Adults:  Developing Drugs for Treatment 
3 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
9  thinking on this topic.  It does not create or confer any rights for or  on any  person and does not operate to 
10  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
11  the applicable statutes and regulations. If  you want to discuss an alternative approach, contact the FDA 
12  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
13  the appropriate number listed on the title page of this guidance.  
14   
15   
16   
17   
18  I.  INTRODUCTION  
19   
20  The purpose of this guidance is to assist sponsors in clinical drug development for the treatment 
21  of adults with duodenal ulcers caused by Helicobacter pylori (H. pylori) for the reduction of 
22  duodenal ulcer recurrence.2  Specifically, this guidance addresses the Food and Drug 
23  Administrations (FDAs) current thinking regarding the overall development program and 
24  clinical trial designs to support antimicrobial-containing H. pylori treatment regimens.  This 
25  guidance intends to serve as a focus for continued discussions among the Division of Special 
26  Pathogen and Transplant Products, pharmaceutical sponsors, the academic community, and the 
27  public.3  As the science of this indication evolves, this guidance may be revised as new  
28  information accumulates.  
29   
30  This guidance pertains to development of drugs for the treatment of adults with duodenal ulcers.  
31  It does not address treatment of children, or those with other conditions also associated with H. 
32  pylori, including gastric ulcers and non-ulcer dyspepsia.  If sponsors are interested in pursuing an 
33  indication for the treatment of patients with other conditions associated with H. pylori infection 
34  or other endpoints not mentioned in this guidance, they are encouraged to discuss their proposals 
35  with the division. Sponsors desiring to pursue an indication for ulcers caused by clarithromycin-
36  resistant organisms should discuss the types of data needed to support such a claim with the 
37  division early in drug development. 
                                                 
1 This  guidance has been  prepared by the Division of Special Pathogen and Transplant Products in the Center for 
Drug Evaluation and Research (CDER) at the Food and Drug  Administration.  
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  regulated by CDER  unless otherwise specified.   
 
3 In addition to consulting  guidance documents, sponsors are encouraged  to contact the division to  discuss specific 
issues that arise during the development of  drugs intended to treat H. pylori. 
1 
 Contains Nonbinding Recommendations 
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38 
  
39  This guidance, when finalized, will supersede advice given in the draft guidance for industry 

40  Evaluating Clinical Studies of Antimicrobials in the Division of Anti-Infective Drug Products, 

41  published in 1997, which contains section V, regarding indication 25 Helicobacter pylori. With 

42  regard to the development of drugs to treat H. pylori-associated duodenal ulcer disease in adults, 

43  this guidance also supersedes more general guidance issued many years ago (i.e., Clinical 

44  Evaluation of Anti-Infective Drugs (Systemic) and Clinical Development and Labeling of Anti-
45  Infective Drug Products,4 as well as the joint FDA/Infectious Disease Society of Americas 

46  Guidelines for the Evaluation of Anti-Infective Drug Products).5
  
47 
  
48  This guidance does not contain discussion of the general issues of clinical trial design or 

49  statistical analysis. Those topics are addressed in the ICH guidances for industry E8  General 

50  Considerations for Clinical Trials, E9  Statistical Principles for Clinical Trials, and E10 Choice 

51  of Control Group and Related Issues in Clinical Trials. This guidance focuses on specific drug 

52  development and trial design issues that are unique to the study of duodenal ulcers caused by H. 

53  pylori. For general information related to clinical trials of antimicrobial drugs, see the draft 

54  guidance for industry Developing Antimicrobial Drugs  General Considerations for Clinical 

55  Trials.6
  
56 
  
57  FDAs guidance documents, including this guidance, do not establish legally enforceable 

58  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 

59  be viewed only as recommendations, unless specific regulatory or statutory requirements are 

60  cited. The use of the word should in Agency guidances means that something is suggested or 

61  recommended, but not required. 

62 
  
63 
  
64  II.  BACKGROUND  

65 
  
66  H. pylori infection can be found in up to 95 percent of patients with peptic ulcer disease.  

67  Following bacterial eradication, ulcer recurrence rates have been shown to be significantly and 

68  reproducibly reduced compared to long-term acid suppressive therapy.  In 1994, a National 

69  Institutes of Health consensus panel recommended that Since cure of H. pylori decreases ulcer 

70  recurrence and facilitates healing, antibiotic therapy is definitely indicated for all H. pylori-
71  infected ulcer patients. The panel further concluded that ulcer patients with H. pylori infection 

                                                 
4 See the following  PDFs, respectively: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM133315.pdf; 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070975.pdf. 
 
5  Beam, TR, DN  Gilbert, and CM Kunin, 1992, General Guidelines for the Clinical Evaluation  of Anti-Infective 
Drug Products, Infectious Disease Society of America and the Food and Drug Administration, Clinical Infectious  
Diseases, Nov.15, Supplement 1:S5-32. 
 
6  When final, this guidance will represent the FDAs current  thinking on this topic.   
For the most recent version of a guidance, check the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
2 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
72  require treatment with antimicrobial agents in addition to antisecretory drugs whether on first 
73  presentation with the illness or on recurrence. 7  
74   
75  On October 26, 1995, a joint Anti-Infective and Gastrointestinal Drugs Advisory Committee met 
76  to consider issues in clinical trial design for drugs being developed to treat duodenal ulcers 
77  caused by H. pylori infection.8  The committee recommended that H. pylori eradication at 
78  greater than 28 days from the end of therapy should be used as the primary endpoint for 
79  determining outcome in studies evaluating active duodenal ulcer treatment.  This eradication 
80  endpoint was considered a valid (and validated) surrogate endpoint for duodenal ulcer 
81  recurrence, based on published studies demonstrating that H. pylori eradication in patients with 
82  an active ulcer significantly reduced future ulcer recurrence.  Therefore, clinical trials did not 
83  need to include evaluation of ulcer recurrence to be approved for the ind ication below. 
84   
85  On December 13, 1995, the same joint advisory committee reconvened and recommended the 
86  following two-sentence statement for the Indications and Usage section of the package insert for 
87  drugs developed to treat H. pylori infection:9  
88   
89  Drug [X] is indicated for the treatment of patients with an active duodenal ulcer 
90  associated with H. pylori infection. The eradication of H. pylori has been demonstrated 
91  to reduce the risk of duodenal ulcer recurrence. 
92   
93  Subsequently, with the accumulation of additional clinical data, the division has broadened the 
94  indication to include H. pylori-infected patients with a recent history (within 5 years) of ulcer 
95  disease in addition to patients with an active duodenal ulcer: 
96   
97  Drug [X] is indicated for the treatment of patients with H. pylori infection and duodenal 
98  ulcer disease (active or history of within the past 5 years) to eradicate H. pylori . 
99  Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer 
100  recurrence. 
101   
102   
103  III.  DEVELOPMENT PROGRAM 
104   
105  A.  General Considerations 
106   
107  Sponsors should conduct at least two adequate and well-controlled trials for the purposes of 
108  establishing the safety and efficacy of antimicrobial-containing regimens to treat H. pylori-
109  associated duodenal ulcer disease.  The primary efficacy parameter should be a microbiological 
110  outcome at the test-of-cure visit (i.e., the proportion of H. pylori-infected ulcer patients who are 
111  cured of their infection). 
                                                 
7 NIH Consensus Development Panel on  Helicobacter pylori in Peptic Ulcer Disease, 1994, Helicobacter pylori in  
Peptic Ulcer Disease, JAMA, 272:65-9. 
 
8 A transcript  of the October 26, 1995, meeting can be found at: http://www.fda.gov/ohrms/dockets/ac/95mt.htm. 
 
9 A transcript of the December 13, 1995, meeting can be  found at http://www.fda.gov/ohrms/dockets/ac/95mt.htm.  
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112   
113  At least one of the trials should be conducted in the United States and/or Canada, because of 
114  known differences in H. pylori response rates and susceptibility patterns in various parts of the 
115  world.10  These trials should be conducted by multiple investigators from geographically diverse 
116  areas to ensure a broad range of patients and H. pylori strains are studied. 
117   
118  B.  Specific Efficacy Trial Considerations 
119   
120  1.  Study Design 
121   
122  All currently approved regimens are multidrug regimens consisting of antimicrobials plus anti-
123  ulcer medications because use of either drug type alone is unable to eradicate H. pylori. Previous 
124  studies have shown eradication rates of 0 percent for placebo,11 less than 5 percent for 
125  monotherapy with a proton pump inhibitor (3 to 4 percent with omeprazole,12 2 percent with 
126  lansoprazole13), and 0 percent for amoxicillin alone.14     
127   
128  Sponsors may wish to consider one of the following three possible study designs for new drugs 
129  or regimens to treat H. pylori: 1) substitution of a new drug for one component of an approved 
130  regimen; 2) addition of a new drug to an approved regimen; and 3) development of a new 
131  regimen not studied previously.  The appropriate study design depends upon the drug or regimen 
132  under development.   
133   
134  Depending on the design chosen, proof of efficacy may be determined based on a determination 
135  of superiority of the new drug containing regimen over the active-controlled drug containing 
136  regimen, or placebo containing regimen.  Alternatively, proof of efficacy can be based on the 
137  determination of noninferiority of the new drug containing regimen to the active-controlled drug 
138  containing regimen.  Note that the use of noninferiority studies relies on adequate historical 
139  information regarding the effect of the active control in the current regimen.  If adequate 
140  historical information is not available, noninferiority studies should not be considered.   
141   
142  In any of these situations, sponsors may wish to develop fixed-dose combination or co-packaged 
143  drug products. Fixed-dose combination drug products are subject to 21 CFR 300.50, and the 
                                                 
10 Fischbach, L, K  Goodman, M Feldman, et al., 2002, Sources of  Variation  of  Helicobacter pylori Treatment 
Success in Adults Worldwide:  A Meta-Analysis, Int J Epidemiol, 31:128-39. 
 
11 Peterson, WL, AA Ciociola, DL Sykes, et al., 1996, Ranitidine Bismuth  Citrate Plus Clarithromycin Is Effective 
for Healing Duodenal Ulcers, Eradicating H. pylori and Reducing Ulcer Recurrences, RBC H. pylori Study Group, 
Aliment Pharmacol Ther, 10:251-61. 
 
12 Laine, L, E Johnson, L Suchower, et al., 1998, US Double-blind, Controlled Trials of Omeprazole and  
Amoxicillin for Treatment of  Helicobacter pylori, Aliment Pharmacol Ther, 12:377-82.  
 
13 Schwartz, H, R Krause, B Sahba, et al., 1998, Triple  Versus Dual Therapy for Eradicating Helicobacter pylori and 
Preventing  Ulcer Recurrence:  A Randomized, Double-blind, Multicenter Study  of Lansoprazole, Clarithromycin, 
and/or Amoxicillin in Different Dosing Regimens, Am J Gastroenterol, 93:584-90. 
 
14 Harford,  W, F Lanza, A Arora, et al., 1996, Double-blind, Multicenter Evaluation of Lansoprazole and 
Amoxicillin Dual Therapy for the Cure of  Helicobacter pylori  Infection, Helicobacter, 1:243-50. 
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144  FDA has generally applied the principles outlined in 21 CFR 300.50 to co-packaged drug 
145  products. 
146   
147  a.  Substitution of a new drug for one component of an approved regimen  
148   
149  The component of the approved regimen that the new drug is replacing is considered the active 
150  control in this situation.  The remaining drugs are the background regimen and should be similar 
151  between the two arms.  Because each of the components of approved multidrug regimens for H. 
152  pylori appears to contribute to the observed treatment effect, it may be possible to perform  
153  noninferiority trials testing the new drug against an approved regimen.  When this approach is 
154  chosen, the noninferiority margin selected should be justified in the protocol, supported by 
155  evidence from past studies (21 CFR 314.126(b)(2)(iv)), and provided to the division for review.  
156  Sponsors also should provide data from the literature or earlier studies showing that each 
157  component of the new drug regimen is contributing to the efficacy of the regimen.   
158   
159  Sponsors should consult ICH E9 and ICH E10 for information on how to design a noninferiority 
160  trial and noninferiority margin. 
161   
162  b.  Addition of a new drug to an approved regimen 
163   
164  When an investigational drug is added to a previously approved regimen, the study design should 
165  be placebo-controlled; patients should be randomized to the approved regimen plus 
166  investigational drug versus the approved regimen plus placebo.  The goal should be to 
167  demonstrate superiority of the approved regimen plus investigational drug over the approved 
168  regimen plus placebo.  When considering an add-on study design, sponsors also should provide a 
169  discussion concerning the risks and benefits of a multidrug regimen. 
170   
171  c.  Development of a new regimen not studied previously 
172   
173  When developing a new multidrug regimen, sponsors should demonstrate the contribution of 
174  each component to the overall effect.  This can be done by conducting a trial with a factorial 
175  design. In factorial design trials, the primary analysis should evaluate the contribution of each 
176  component.  In addition, we recommend that an FDA-approved regimen be included as a 
177  positive control arm to interpret studies with unexpectedly low cure rates.  Given the high rates 
178  of efficacy with approved regimens, new regimens with lower than expected cure rates would be 
179  reflected in labeling in the description of clinical studies. 
180   
181  2.  Study Population 
182   
183  The population targeted for enrollment into clinical trials should consist of adult patients with H. 
184  pylori infection and an active duodenal ulcer or a documented history of duodenal ulcer disease 
185  within the past 5 years. 
186   
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187  3.  Entry Criteria  
188   
189  a.  Inclusion criteria 
190   
191  The following inclusion criteria should be used for patient enrollment in studies conducted for 
192  the treatment of H. pylori-associated duodenal ulcer disease. 
193   
194     Endoscopically or radiographically documented presence of an active duodenal ulcer 
195  with a diameter between 3 mm and 25 mm, or a history of duodenal ulcer (confirmed by 
196  endoscopy or radiography) within the previous 5 years before enrollment.15    
197   
198     Confirmed H. pylori infection based on biopsy specimens collected during upper 
199  endoscopy performed in all patients at baseline for inclusion into the study.  
200  Prerandomization evaluability, based on endoscopic diagnostic testing, is defined in 
201  Table 1 in the Appendix. 
202   
203     Confirmed H. pylori infection based on an FDA-approved urea breath test (UBT) 
204  performed in all patients before randomization for inclusion into the study, if this test is 
205  used to determine patient outcome at the test-of-cure visit.  The UBT can be performed as 
206  a screening test before or following endoscopy. 
207   
208  b.  Exclusion criteria 
209   
210  The following exclusion criteria should be used for patient enrollment in studies conducted for 
211  the treatment of H. pylori-associated duodenal ulcer disease. 
212   
213     Presence of ulcer smaller than 3 mm or larger than 25 mm.  
214     History of any previous esophageal or gastric surgery, except for simple closure of 
215  perforated ulcer. 
216     Gastric outlet obstruction. 
217     Hypersecretory states, such as Zollinger-Ellison Syndrome. 
218     History of gastric cancer or gastric biopsy positive for cancer on baseline endoscopy. 
219     Presence of both active gastric and duodenal ulcers, or presence of three or more active 
220  ulcers. Multiple ulcers are believed to potentially signify disease of other etiology (e.g., 
221  undiagnosed Zollinger-Ellison Syndrome). 
222     Treatment with proton pump inhibitors or full therapeutic doses of histamine H2-receptor 
223  antagonists within 14 days before diagnostic testing at screening. 
224     Treatment with systemic antibiotics known to have in vivo efficacy against H. pylori or  
225  bismuth-containing compounds within 28 days before diagnostic testing at screening. 
226   
                                                 
15 An active ulcer is defined as endoscopic evidence of a break in the gastrointestinal mucosa that penetrates the 
muscularis mucosa and has a fibrinous surface. 
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227  4.  Blinding 
228   
229  A double-dummy trial design should be used to maintain blinding in comparative trials.  
230  Appropriate blinding procedures should be discussed with the division before beginning the trial.  
231  All participants involved in the trial including patients should be blinded to treatment.  The 
232  following additional recommendations apply to blinding: 
233   
234     The investigator and the endoscopist should be blinded to treatment 
235     The microbiologist should be blinded to treatment, clinical information, endoscopic 
236  information, and all H. pylori endoscopic tests other than culture 
237     The pathologist should be blinded to treatment, clinical information, endoscopic 
238  information, and results of all H. pylori diagnostic information other than histology 
239     The investigator that performs other diagnostic tests (e.g., UBT) should be blinded to 
240  treatment and all other H. pylori diagnostic information  
241   
242  5.  Efficacy Endpoints 
243   
244  The primary efficacy endpoint should be eradication of H. pylori measured at least 28 days, but 
245  no more than 56 days from the end of the treatment (see section III.B.7.c., Test-of-cure (post-
246  treatment) visit).  A patient should be considered as a failure of therapy in the primary analysis if 
247  there was no determination of whether his or her H. pylori infection was eradicated.  See section 
248  III.B.8.b., Missing data, for a discussion of missing data. 
249   
250  Outcomes for patients should be defined as follows: 
251     Success. Eradication of H. pylori infection is documented at the test-of-cure visit, 
252  occurring between 28 and 56 days from the end of treatment.  Eradication should be 
253  defined by a single negative UBT result at the test-of-cure visit.  If an endoscopy is used 
254  in place of a UBT at the test-of-cure visit, eradication should be defined as described in 
255  Table 2 in the Appendix. 
256     Failure. Does not meet the criteria for success and can include the following: 
257     Persistence of  H. pylori infection is documented by UBT or endoscopy anytime after 
258  treatment (see Table 2 in the Appendix). 
259     A test-of-cure visit less than 28 days or more than 56 days from the end of treatment 
260  (for an analysis of the modified intent-to-treat (MITT) population, see below). 
261     A test-of-cure visit at least 28 days from the end of treatment and an outcome  
262  reported as not determined, not assessable, or missing (see Table 2 in the Appendix) 
263  (for an analysis of the MITT population, see below). 
264     No test-of-cure visit (for an analysis of the MITT population, see below). 
265   
266  6.  Analysis Populations for Efficacy Analyses 
267   
268  Sponsors should perform efficacy analyses on two specific populations: MITT and per-protocol, 
269  as described below. In addition, a third population, the intent-to-treat (ITT) population, which 
270  can also be called the safety population, should be defined as all patients who took at least one 
271  dose of trial medication, regardless of baseline infection status. Sponsors should analyze the ITT 
272  population for safety outcomes. 
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273   
274  The specific definitions and outcomes of the MITT and per-protocol populations should be as 
275  follows: 
276   
277  MITT population 
278  A patient should be included in the MITT population if all of the following occur: 
279     H. pylori infection is documented by UBT or endoscopy before treatment (see Table 
280  1 in the Appendix) 
281     At least one dose of trial medication is taken 
282     An active duodenal ulcer with a diameter between 3 mm and 25 mm is documented at 
283  the baseline endoscopy or a history of duodenal ulcer within the previous 5 years is 
284  documented (by endoscopy or radiograph) before enrollment 
285   
286  Per-protocol population 
287  A patient should be included in the per-protocol population if all of the following occur: 
288     The patient is included in the MITT population 
289     The test-of-cure visit occurs between 28 and 56 days from the end of treatment with 
290  documented diagnostic testing by UBT or endoscopy (see Table 2 in the Appendix), 
291  unless the patient has documented persistence of H. pylori infection at any time after 
292  the end of treatment 
293     At least 75 percent of each medication was taken and/or less than 20 percent of 
294  consecutive doses of each medication were missed, unless caused by treatment failure 
295     An antimicrobial known to be effective against H. pylori before (within 7 days), 
296  during, or following treatment was not taken, unless given for treatment failure 
297     A proton pump inhibitor or high dose H2-receptor antagonist was not taken within 14  
298  days of the baseline and/or follow-up endoscopy (if applicable) or during treatment, 
299  unless given for treatment failure  
300   
301  Patients can use non-ulcer healing doses of H2-receptor antagonists following 
302  treatment, as indicated below, and still be included in the per-protocol population: 
303     ranitidine less than 300 mg/day 
304     cimetidine less than or equal to 400 mg/day 
305     famotidine less than 40 mg/day 
306     nizatidine less than 300 mg/day  
307   
308  7.  Study Procedures and Timing of Assessments 
309   
310  The timing of key study visits and associated procedures is discussed below. 
311   
312  a.  Entry visit 
313   
314  The pretreatment (entry) visit should occur within 1 week of beginning trial treatment and may 
315  require two separate visits. Investigators should perform an upper endoscopy and obtain biopsy 
316  specimens for H. pylori diagnostic testing (see Table 1 in the Appendix) in all patients upon 
317  entry. Investigators should document (e.g., photograph) any ulcers at the time of the procedure.  
318  Randomization to treatment can occur at a separate visit that occurs within 4 days of the 
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319  diagnosis of H. pylori, which is based upon the results of diagnostic testing (as shown in Table 
320  1). Effort should be made to ensure that results are available from all three endoscopic tests (i.e., 
321  culture, histology, and rapid urease test) because missing data from one or more tests can result 
322  in exclusion of patients from the efficacy populations. 
323   
324  Investigators can perform the UBT as a screening test before or following endoscopy, depending 
325  on the clinical presentation of the patients.  If the UBT also will be used as the primary endpoint, 
326  a positive UBT result should be documented before the patient is randomized to treatment, so the 
327  test can be used to determine patient outcome at the test-of-cure visit.  
328   
329  For patients with a history of ulcer disease, investigators should procure an official radiographic 
330  or endoscopic report documenting a prior ulcer.   
331   
332  Investigators should obtain the patients history, a physical examination, vital signs, a pregnancy 
333  test (when appropriate), serum chemistry, and hematology before randomization.  
334   
335  Investigators should evaluate whether patients meet the inclusion and exclusion criteria and 
336  obtain their informed consent. 
337   
338  b.  End-of-treatment visit 
339   
340  The end-of-treatment visit should include a physical examination, laboratory determinations, 
341  assessment of adverse events and concomitant medications, symptom assessment, and a 
342  medication compliance assessment. 
343   
344  The end-of-treatment visit should not replace the test-of-cure visit.   
345   
346  c.  Test-of-cure (post-treatment) visit 
347   
348  The post-treatment visit should occur at least 28 days but not more than 56 days after the last 
349  dose of the study treatment and is considered the test-of-cure visit. The test-of-cure visit should 
350  occur at the same time point for all treatment arms, regardless of the duration of treatment.  
351  Sponsors should determine the timing of the test-of-cure visit based upon the treatment arm with 
352  the longest duration of treatment. 
353   
354  At this visit, investigators should evaluate the primary endpoint.  If a UBT is used to determine 
355  patient outcome (i.e., H. pylori eradication or persistence), a repeat upper endoscopy should not 
356  be needed for all patients. However, investigators should repeat an upper endoscopy and obtain 
357  biopsies for culture and antimicrobial susceptibility testing in patients with a positive UBT result, 
358  indicating persistence of H. pylori infection. 
359   
360  Alternatively, sponsors can choose to use endoscopy at the post-treatment visit in place of a UBT 
361  to determine patient outcome.  If endoscopy is used, investigators should obtain biopsies in all 
362  patients for histology, rapid urease test, and culture with antimicrobial susceptibility testing. 
363   
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364  The choice of post-treatment diagnostic test (UBT or endoscopy) should be prespecified and 
365  consistent across all study arms in a given trial. 
366   
367  Investigators should obtain serum chemistry and hematology profiles and assess patients for 
368  adverse events. 
369   
370  d.  Discontinuations  
371   
372  Patients discontinuing study therapy prematurely should have post-treatment procedures 
373  performed at the time of termination.  In addition, if appropriate, patients also should be 
374  evaluated at the time of the test-of-cure visit (at least 28 days but not more than 56 days after the 
375  last dose of the study treatment).  The reason for early discontinuation from the study treatment 
376  and/or the trial should be documented in the case report form.   
377   
378  e.  Safety evaluations 
379   
380  The protocol should clearly specify the methods to be used to obtain safety data during the 
381  course of the study. Both adverse event information and safety laboratory data should be 
382  collected during the study. Age- and sex-appropriate normal laboratory values should be 
383  included with clinical measurements when reporting laboratory data.  Additional safety 
384  evaluations also may be needed because of the preclinical and clinical profile of the specific drug 
385  under study (e.g., additional electrocardiogram measurements).  Longer-term assessment of 
386  adverse events after discontinuation or completion of the antimicrobial also can be considered 
387  depending on the specific drug being studied. 
388   
389  All patients should be evaluated for safety at the time of each study visit or assessment, 
390  regardless of whether the test drug has been discontinued.  All adverse events should be followed 
391  until resolution, even if time on study would otherwise have been completed.  For specific safety 
392  reporting recommendations during clinical trials, see the ICH guidance for industry E2A Clinical 
393  Safety Data Management: Definitions and Standards for Expedited Reporting. 
394   
395  8.  Statistical Considerations 
396   
397  a.  Primary efficacy analysis 
398   
399  The primary efficacy analysis should be a comparison of the percent of successes in the MITT 
400  population, as described above. Note that patients with missing data will be automatically 
401  counted as failures in this analysis. The method for analysis should be clearly stated in the 
402  protocol.  Specific details can be provided in a separate document (i.e., data analysis plan).   
403   
404  b.  Missing data 
405   
406  All efforts should be made to obtain data from the test-of-cure visit for each patient enrolled in 
407  clinical trials. Given that some missing data will occur, however, we recommend that the 
408  sponsor define prospectively the method for handling missing data and perform secondary 
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409  analyses in which data are analyzed in several different ways to assess the effect on 
410  interpretation and conclusions in the MITT analysis.   
411   
412  The following three methods are examples of ways to handle missing data in H. pylori clinical 
413  trials; however, other methods can be used. 
414   
415  1.   Calculating eradication rates by treatment in patients with observed data, and assuming 
416  eradication rates are the same in patients with unobserved (missing) data.  
417   
418  2.   Assuming all active-controlled patients with missing data are eradicated while all patients 
419  treated with the investigational regimen are not eradicated.  This method is used only to 
420  give an upper bound on the upper limit of the confidence interval for the difference in 
421  eradication rates because such a scenario would be unlikely to actually occur. 
422   
423  3.   Assuming all patients with missing data are successes. 
424   
425  c.  Noninferiority trial design considerations 
426   
427  As mentioned earlier, for some  H. pylori-associated duodenal ulcer trials, it may be possible to 
428  use a noninferiority trial design if adequate historical information exists that allows for the 
429  determination of a valid noninferiority margin.  In those cases, the active-controlled arm of the 
430  trial should be treated with an approved regimen consisting of an active control of interest plus a 
431  specified background regimen.  The test arm of the trial should be treated with the new regimen 
432  consisting of the new test drug, replacing the active control of the approved regimen, but keeping 
433  the same background regimen of the approved regimen of the control arm.  The noninferiority 
434  trial will compare the test regimen arm with the active-controlled regimen arm. The purpose of 
435  such a comparison would be to show that the treatment difference C  T (i.e., the difference 
436  between the response rate of the active-controlled regimen minus that for the test regimen) is 
437  smaller than some prespecified noninferiority margin.  
438   
439  The following should be noted when designing noninferiority trials: 
440   
441     Assay sensitivity of the current noninferiority trial. This is a critical property of a 
442  noninferiority trial. A noninferiority trial that lacks assay sensitivity may conclude that 
443  an ineffective treatment is noninferior to a control and can lead to an erroneous 
444  conclusion of efficacy. Before initiating a noninferiority trial, sponsors should evaluate 
445  and determine the treatment effect of the active control with background regimen over 
446  placebo with background regimen from adequate historical trials.  This treatment effect is 
447  referred to as M1. A discounted M1 should be chosen as a conservative estimate of the 
448  treatment effect caused by uncertainties in the estimate of the treatment effect. 
449   
450     The constancy assumption.  The current noninferiority trial should be sufficiently 
451  similar to past historical trials with respect to all design and conduct features that can 
452  influence the estimation of M1.  These design features include the characteristics of the 
453  patient population, important concomitant treatments (besides the fixed background 
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454  regimen), definition and ascertainments of study endpoints, dose of active control and 
455  background regimen, entry criteria, and analytic methods. 
456   
457     The quality of the current noninferiority trial. Undesirable conduct features of the 
458  trial would tend to minimize the difference, C  T, causing bias toward the null.  These 
459  undesirable features include imprecise or poorly implemented entry criteria, poor 
460  compliance, the use of concomitant treatments whose effects may overlap with the test 
461  drug under study, inadequate measurement techniques, or errors in treatment 
462  assignments. 
463   
464  9.  Clinical Pharmacology Consideration 
465   
466  CYP450 enzymes and efflux/uptake transporters are involved in the absorption and hepatic 
467  clearance of certain antimicrobials and proton pump inhibitors, which are components of many 
468  approved regimens.  These enzymes and transporters may alter the overall systemic exposure 
469  (oral bioavailability) of these drugs.  Therefore, sponsors should consider determining the 
470  association between drug exposure and enzymes or transporters to assess clinical efficacy and 
471  safety of the regimen in various subpopulations.  For additional information on submission of 
472  genomic data, see the draft guidance for industry Pharmacogenomic Data Submissions  
473  Companion Guidance. 16  
474   
475  10.  Microbiology Considerations 
476   
477  Special attention should be given to reliable methods for obtaining, culturing, and determining 
478  the in vitro susceptibility of  H. pylori because most clinical laboratories do not routinely perform  
479  these procedures.  Sponsors should provide details as part of each protocol for the following 
480  microbiological procedures used in the trial: collection and transport of biopsy specimens, 
481  isolation of H. pylori from biopsy specimens, identification of H. pylori, antimicrobial 
482  susceptibility testing, and quality control.  
483   
484  Investigators should collect at least one antral and one corpus biopsy specimen during endoscopy 
485  from all randomized patients for culture and subsequent antimicrobial susceptibility testing 
486  pretreatment and at the test-of-cure visit.  In trials where sponsors use the UBT to determine 
487  patient outcome at the test-of-cure visit, a repeat endoscopy with biopsies collected for culture 
488  and subsequent antimicrobial susceptibility testing should be performed in patients with a 
489  positive UBT result.  In trials where sponsors use endoscopy to determine patient outcome at the 
490  test-of-cure visit, all patients should have a repeat endoscopy with biopsies collected for culture 
491  and subsequent antimicrobial susceptibility testing. 
492   
493  Investigators should also collect at least two antral and two corpus biopsy specimens during 
494  endoscopy from all randomized patients for histopathologic examination pretreatment and at the 
495  test-of-cure visit, in all patients in trials where endoscopy is used to determine outcome at the 
496  test-of-cure visit.   
                                                 
16  When final, this guidance will represent the FDAs current  thinking on this topic.   
For the most recent version of a guidance, check the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
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497   
498  Agar dilution minimum inhibitory concentration (MIC) methodology is the reference method for 
499  antimicrobial susceptibility testing and has been standardized for testing certain antimicrobials 
500  against H. pylori by the Clinical Laboratory Standards Institute (CLSI).  If sponsors use a 
501  method other than that recommended by the CLSI, we strongly recommend that they contact the 
502  division before study initiation. If an experimental assay is used for any microbiologic 
503  measurement, then the performance characteristics of the assay should be provided for review. 
504   
505  Sponsors should present complete microbiology data, including individual MIC values for all 
506  tested antimicrobials. Sponsors should also calculate MIC  and MIC  values for the  
50 90
507  pretreatment isolates.  Where applicable, sponsors should analyze the data to determine the 
508  percentage of patients with pretreatment antimicrobial resistance, the bacteriologic efficacy 
509  among patients with antimicrobial resistant strains pretreatment, and the emergence of 
510  antimicrobial resistance on therapy.   
511   
512  Sponsors should include information on the mechanism of action of the therapeutic agents 
513  against H. pylori, if known. 
514   
515  Sponsors should also include information on the mechanism  of antimicrobial resistance for H. 
516  pylori, if known. If the antimicrobial resistance mechanism of resistance is not known, sponsors 
517  should make an effort to assess the mechanism  to better understand the spread of resistance and 
518  clinical failure. 
519   
520  In general, a four-fold or greater increase in MIC suggests a change in antimicrobial 
521  susceptibility. Sponsors should record such changes, even if the shift in endpoint does not 
522  represent a change in the proposed interpretive category.  Newer microbiological methods may 
523  allow detection of drug resistance by genotyping to identify mutants, and may also differentiate 
524  between new infection and relapse.  If any of these methods are used in a clinical trial, the details 
525  of these methods and performance characteristics of the assay should be included for review.   
526   
527  C.  Labeling Considerations 
528   
529  In addition to the statistical outcome regarding efficacy of study drug therapy in the clinical trials 
530  (as described in section III.B.8., Statistical Considerations), approvability and product labeling 
531  depends on the assessment of multiple factors, including safety, tolerability, and emerging 
532  antimicrobial resistance as a result of drug therapy.  In general, product labeling will reflect the 
533  manner in which the drugs were used in clinical  trials.  For example, use in combination with 
534  specific other drugs, as well as the dose and duration studied. 
535   
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536  APPENDIX:  TABLES 
537 
  
538  Table 1. Prerandomization Evaluability Based on Three Endoscopic H. pylori Tests1
  
H. pylori Tests Obtained Prerandomization2   Patient  Evaluability3  
Culture  Histology  Rapid Urease Test   
Three Tests Available 
+  +  +  Included 
+  +  - Included 
+  - +  Included 
+  - - Included 
- +  +  Included 
- - +  Excluded 
- +  - Excluded 
- - - Excluded 
Two Tests Available 
+  +  N/A  Included 
+  - N/A  Included 
- +  N/A  Excluded 
- - N/A  Excluded 
+  N/A  +  Included 
+  N/A  - Included 
- N/A  +  Excluded 
- N/A  - Excluded 
N/A  +  +  Included 
N/A  +  - Excluded 
N/A  - +  Excluded 
N/A  - - Excluded 
One Test Available 
+  N/A  N/A  Included 
- N/A  N/A  Excluded 
N/A  N/A  +  Excluded 
N/A  N/A  - Excluded 
N/A  +  N/A  Excluded 
N/A  - N/A  Excluded 
539  1 All patients should have a positive UBT result, in addition to endoscopic diagnostic testing, if the UBT 

540  is used to determine patient  outcome at the test-of-cure visit. 

541  2 N/A indicates not available or missing result.  

542  3 This column  relates to  whether or not  patients are considered Included or Excluded in the efficacy 

543  populations and is not necessarily used as criteria for inclusion into  or exclusion  from the trial.  When 
 
544  incongruent test results  preclude an accurate H. pylori diagnosis, patients should be considered  Excluded 
 
545  and should not  be included in  either the MITT analysis  or per-protocol  populations. 
  
546 
  
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547  Table 2. Test-of-Cure Evaluability Based on Three Endoscopic H. pylori Tests1  
H. pylori Tests Obtained at Test-of-Cure Visit2   Patient  Outcome3  
Culture  Histology  Rapid Urease Test   
Three Tests Available 
+  +  +  Persistence 
+  +  - Persistence 
+  - +  Persistence 
+  - - Persistence 
- +  +  Persistence 
- - +  Persistence 
- +  - Persistence 
- - - Eradicated 
Two Tests Available 
+  +  N/A  Persistence 
+  - N/A  Persistence 
- +  N/A  Persistence 
- - N/A  Eradicated 
+  N/A  +  Persistence 
+  N/A  - Persistence 
- N/A  +  Persistence 
- N/A  - Eradicated 
N/A  +  +  Persistence 
N/A  +  - Persistence 
N/A  - +  Persistence 
N/A  - - Eradicated 
One Test Available 
+  N/A  N/A  Persistence 
- N/A  N/A  Indeterminate 
N/A  N/A  +  Persistence 
N/A  N/A  - Indeterminate 
N/A  +  N/A  Persistence 
N/A  - N/A  Indeterminate 
548  1 A UBT that is FDA-approved for monitoring the effectiveness of treatment can be used at the test-of-
549  cure visit (at least 28 days following the end of treatment) in place of endoscopy.  If this test is negative, 

550  no further testing is needed.   

551  2 N/A indicates not available or missing result.  

552  3 An  Indeterminate assessment at test-of-cure visit indicates that the patient should be considered to 
 
553  have  Persistence for the MITT analysis and be Excluded  for the per-protocol analysis.  Persistence 

554  should  be considered synonymous with infected. 

555 
  
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