Helicobacter pylori-Associated Duodenal Ulcer Disease in Adults: Developing Drugs for Treatment

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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
Disease in Adults: Developing Drugs for Treatment
2
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7
8 	This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current
thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
the appropriate number listed on the title page of this guidance.
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17
18 	I. 	INTRODUCTION
19
20 	The purpose of this guidance is to assist sponsors in clinical drug development for the treatment
of adults with duodenal ulcers caused by Helicobacter pylori (H. pylori) for the reduction of
duodenal ulcer recurrence. 2 Specifically, this guidance addresses the Food and Drug
Administration’s (FDA’s) current thinking regarding the overall development program and
clinical trial designs to support antimicrobial-containing H. pylori treatment regimens. This
guidance intends to serve as a focus for continued discussions among the Division of Special
Pathogen and Transplant Products, pharmaceutical sponsors, the academic community, and the
public. 3 As the science of this indication evolves, this guidance may be revised as new
information accumulates.
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29
30 	This guidance pertains to development of drugs for the treatment of adults with duodenal ulcers.
It does not address treatment of children, or those with other conditions also associated with H.
pylori, including gastric ulcers and non-ulcer dyspepsia. If sponsors are interested in pursuing an
indication for the treatment of patients with other conditions associated with H. pylori infection
or other endpoints not mentioned in this guidance, they are encouraged to discuss their proposals
with the division. Sponsors desiring to pursue an indication for ulcers caused by clarithromycin-
resistant organisms should discuss the types of data needed to support such a claim with the
division early in drug development.
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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.
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38
39 	This guidance, when finalized, will supersede advice given in the draft guidance for industry
Evaluating Clinical Studies of Antimicrobials in the Division of Anti-Infective Drug Products,
published in 1997, which contains section V, regarding indication 25 Helicobacter pylori. With
regard to the development of drugs to treat H. pylori-associated duodenal ulcer disease in adults,
this guidance also supersedes more general guidance issued many years ago (i.e., Clinical
Evaluation of Anti-Infective Drugs (Systemic) and Clinical Development and Labeling of Anti-
Infective Drug Products, 4 as well as the joint FDA/Infectious Disease Society of America’s
Guidelines for the Evaluation of Anti-Infective Drug Products). 5
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47
48 	This guidance does not contain discussion of the general issues of clinical trial design or
statistical analysis. Those topics are addressed in the ICH guidances for industry E8 General
Considerations for Clinical Trials, E9 Statistical Principles for Clinical Trials, and E10 Choice
of Control Group and Related Issues in Clinical Trials. This guidance focuses on specific drug
development and trial design issues that are unique to the study of duodenal ulcers caused by H.
pylori. For general information related to clinical trials of antimicrobial drugs, see the draft
guidance for industry Developing Antimicrobial Drugs — General Considerations for Clinical
Trials. 6
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54
55
56
57 	FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s 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.
58
59
60
61
62
63
64 	II. 	BACKGROUND
65
66 	H. pylori infection can be found in up to 95 percent of patients with peptic ulcer disease.
Following bacterial eradication, ulcer recurrence rates have been shown to be significantly and
reproducibly reduced compared to long-term acid suppressive therapy. In 1994, a National
Institutes of Health consensus panel recommended that “Since cure of H. pylori decreases ulcer
recurrence and facilitates healing, antibiotic therapy is definitely indicated for all H. pylori-
infected ulcer patients.” The panel further concluded that “ulcer patients with H. pylori infection
67
68
69
70
71
2
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 FDA’s 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.

Contains Nonbinding Recommendations
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72
73
require treatment with antimicrobial agents in addition to antisecretory drugs whether on first
presentation with the illness or on recurrence.” 7
74
75 	On October 26, 1995, a joint Anti-Infective and Gastrointestinal Drugs Advisory Committee met
to consider issues in clinical trial design for drugs being developed to treat duodenal ulcers
caused by H. pylori infection. 8 The committee recommended that H. pylori eradication at
greater than 28 days from the end of therapy should be used as the primary endpoint for
determining outcome in studies evaluating active duodenal ulcer treatment. This eradication
endpoint was considered a valid (and validated) surrogate endpoint for duodenal ulcer
recurrence, based on published studies demonstrating that H. pylori eradication in patients with
an active ulcer significantly reduced future ulcer recurrence. Therefore, clinical trials did not
need to include evaluation of ulcer recurrence to be approved for the ind ication below.
76
77
78
79
80
81
82
83
84
85 	On December 13, 1995, the same joint advisory committee reconvened and recommended the
following two-sentence statement for the Indications and Usage section of the package insert for
drugs developed to treat H. pylori infection: 9
86
87
88
89 	Drug [X] is “indicated for the treatment of patients with an active duodenal ulcer
associated with H. pylori infection. The eradication of H. pylori has been demonstrated
to reduce the risk of duodenal ulcer recurrence.”
90
91
92
93 	Subsequently, with the accumulation of additional clinical data, the division has broadened the
indication to include H. pylori-infected patients with a recent history (within 5 years) of ulcer
disease in addition to patients with an active duodenal ulcer:
94
95
96
97 	Drug [X] is “indicated for the treatment of patients with H. pylori infection and duodenal
ulcer disease (active or history of within the past 5 years) to eradicate H. pylori.
Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer
recurrence.”
98
99
100
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
establishing the safety and efficacy of antimicrobial-containing regimens to treat H. pylori-
associated duodenal ulcer disease. The primary efficacy parameter should be a microbiological
outcome at the test-of-cure visit (i.e., the proportion of H. pylori-infected ulcer patients who are
cured of their infection).
108
109
110
111
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
known differences in H. pylori response rates and susceptibility patterns in various parts of the
world. 10 These trials should be conducted by multiple investigators from geographically diverse
areas to ensure a broad range of patients and H. pylori strains are studied.
114
115
116
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-
ulcer medications because use of either drug type alone is unable to eradicate H. pylori. Previous
studies have shown eradication rates of 0 percent for placebo, 11 less than 5 percent for
monotherapy with a proton pump inhibitor (3 to 4 percent with omeprazole, 12 2 percent with
lansoprazole 13 ), and 0 percent for amoxicillin alone. 14
123
124
125
126
127
128 	Sponsors may wish to consider one of the following three possible study designs for new drugs
or regimens to treat H. pylori: 1) substitution of a new drug for one component of an approved
regimen; 2) addition of a new drug to an approved regimen; and 3) development of a new
regimen not studied previously. The appropriate study design depends upon the drug or regimen
under development.
129
130
131
132
133
134 	Depending on the design chosen, proof of efficacy may be determined based on a determination
of superiority of the new drug containing regimen over the active-controlled drug containing
regimen, or placebo containing regimen. Alternatively, proof of efficacy can be based on the
determination of noninferiority of the new drug containing regimen to the active-controlled drug
containing regimen. Note that the use of noninferiority studies relies on adequate historical
information regarding the effect of the active control in the current regimen. If adequate
historical information is not available, noninferiority studies should not be considered.
135
136
137
138
139
140
141
142 	In any of these situations, sponsors may wish to develop fixed-dose combination or co-packaged
drug products. Fixed-dose combination drug products are subject to 21 CFR 300.50, and the	143
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
products.	145
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
control in this situation. The remaining drugs are the background regimen and should be similar
between the two arms. Because each of the components of approved multidrug regimens for H.
pylori appears to contribute to the observed treatment effect, it may be possible to perform
noninferiority trials testing the new drug against an approved regimen. When this approach is
chosen, the noninferiority margin selected should be justified in the protocol, supported by
evidence from past studies (21 CFR 314.126(b)(2)(iv)), and provided to the division for review.
Sponsors also should provide data from the literature or earlier studies showing that each
component of the new drug regimen is contributing to the efficacy of the regimen.
150
151
152
153
154
155
156
157
158
159 	Sponsors should consult ICH E9 and ICH E10 for information on how to design a noninferiority
trial and noninferiority margin.	160
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
be placebo-controlled; patients should be randomized to the approved regimen plus
investigational drug versus the approved regimen plus placebo. The goal should be to
demonstrate superiority of the approved regimen plus investigational drug over the approved
regimen plus placebo. When considering an add-on study design, sponsors also should provide a
discussion concerning the risks and benefits of a multidrug regimen.
165
166
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168
169
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
each component to the overall effect. This can be done by conducting a trial with a factorial
design. In factorial design trials, the primary analysis should evaluate the contribution of each
component. In addition, we recommend that an FDA-approved regimen be included as a
positive control arm to interpret studies with unexpectedly low cure rates. Given the high rates
of efficacy with approved regimens, new regimens with lower than expected cure rates would be
reflected in labeling in the description of clinical studies.
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179
180
181 	2. 	Study Population
182
183 	The population targeted for enrollment into clinical trials should consist of adult patients with H.
pylori infection and an active duodenal ulcer or a documented history of duodenal ulcer disease
within the past 5 years.
184
185
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
the treatment of H. pylori-associated duodenal ulcer disease.	192
193
194 	• 	Endoscopically or radiographically documented presence of an active duodenal ulcer
with a diameter between 3 mm and 25 mm, or a history of duodenal ulcer (confirmed by
endoscopy or radiography) within the previous 5 years before enrollment. 15
195
196
197
198 	• 	Confirmed H. pylori infection based on biopsy specimens collected during upper
endoscopy performed in all patients at baseline for inclusion into the study.
Prerandomization evaluability, based on endoscopic diagnostic testing, is defined in
Table 1 in the Appendix.
199
200
201
202
203 	• 	Confirmed H. pylori infection based on an FDA-approved urea breath test (UBT)
performed in all patients before randomization for inclusion into the study, if this test is
used to determine patient outcome at the test-of-cure visit. The UBT can be performed as
a screening test before or following endoscopy.
204
205
206
207
208 	b. 	Exclusion criteria
209
210 	The following exclusion criteria should be used for patient enrollment in studies conducted for
the treatment of H. pylori-associated duodenal ulcer disease.	211
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
perforated ulcer.	215
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
ulcers. Multiple ulcers are believed to potentially signify disease of other etiology (e.g.,
undiagnosed Zollinger-Ellison Syndrome).
220
221
222 	• 	Treatment with proton pump inhibitors or full therapeutic doses of histamine H2-receptor
antagonists within 14 days before diagnostic testing at screening.	223
224 	• 	Treatment with systemic antibiotics known to have in vivo efficacy against H. pylori or
bismuth-containing compounds within 28 days before diagnostic testing at screening.	225
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.
Appropriate blinding procedures should be discussed with the division before beginning the trial.
All participants involved in the trial including patients should be blinded to treatment. The
following additional recommendations apply to blinding:
230
231
232
233
234 	• 	The investigator and the endoscopist should be blinded to treatment
235 	• 	The microbiologist should be blinded to treatment, clinical information, endoscopic
information, and all H. pylori endoscopic tests other than culture	236
237 	• 	The pathologist should be blinded to treatment, clinical information, endoscopic
information, and results of all H. pylori diagnostic information other than histology	238
239 	• 	The investigator that performs other diagnostic tests (e.g., UBT) should be blinded to
treatment and all other H. pylori diagnostic information	240
241
242 	5. 	Efficacy Endpoints
243
244 	The primary efficacy endpoint should be eradication of H. pylori measured at least 28 days, but
no more than 56 days from the end of the treatment (see section III.B.7.c., Test-of-cure (post-
treatment) visit). A patient should be considered as a failure of therapy in the primary analysis if
there was no determination of whether his or her H. pylori infection was eradicated. See section
III.B.8.b., Missing data, for a discussion of missing data.
245
246
247
248
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,
occurring between 28 and 56 days from the end of treatment. Eradication should be
defined by a single negative UBT result at the test-of-cure visit. If an endoscopy is used
in place of a UBT at the test-of-cure visit, eradication should be defined as described in
Table 2 in the Appendix.
252
253
254
255
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
treatment (see Table 2 in the Appendix).	258
259 	− 	A test-of-cure visit less than 28 days or more than 56 days from the end of treatment
(for an analysis of the modified intent-to-treat (MITT) population, see below).	260
261 	− 	A test-of-cure visit at least 28 days from the end of treatment and an outcome
reported as not determined, not assessable, or missing (see Table 2 in the Appendix)
(for an analysis of the MITT population, see below).
262
263
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,
as described below. In addition, a third population, the intent-to-treat (ITT) population, which
can also be called the safety population, should be defined as all patients who took at least one
dose of trial medication, regardless of baseline infection status. Sponsors should analyze the ITT
population for safety outcomes.
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270
271
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273
274 	The specific definitions and outcomes of the MITT and per-protocol populations should be as
follows:	275
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
1 in the Appendix)	280
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
the baseline endoscopy or a history of duodenal ulcer within the previous 5 years is
documented (by endoscopy or radiograph) before enrollment
283
284
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
documented diagnostic testing by UBT or endoscopy (see Table 2 in the Appendix),
unless the patient has documented persistence of H. pylori infection at any time afte
the end of treatment
290
291 	r
292
293 	• 	At least 75 percent of each medication was taken and/or less than 20 percent of
consecutive doses of each medication were missed, unless caused by treatment failure	294
295 	• 	An antimicrobial known to be effective against H. pylori before (within 7 days),
during, or following treatment was not taken, unless given for treatment failure	296
297 	• 	A proton pump inhibitor or high dose H2-receptor antagonist was not taken within 14
days of the baseline and/or follow-up endoscopy (if applicable) or during treatment,
unless given for treatment failure
298
299
300
301 	Patients can use non-ulcer healing doses of H2-receptor antagonists following
treatment, as indicated below, and still be included in the per-protocol population:	302
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
require two separate visits. Investigators should perform an upper endoscopy and obtain biopsy
specimens for H. pylori diagnostic testing (see Table 1 in the Appendix) in all patients upon
entry. Investigators should document (e.g., photograph) any ulcers at the time of the procedure.
Randomization to treatment can occur at a separate visit that occurs within 4 days of the
315
316
317
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319 	diagnosis of H. pylori, which is based upon the results of diagnostic testing (as shown in Table
1). Effort should be made to ensure that results are available from all three endoscopic tests (i.e.,
culture, histology, and rapid urease test) because missing data from one or more tests can result
in exclusion of patients from the efficacy populations.
320
321
322
323
324 	Investigators can perform the UBT as a screening test before or following endoscopy, depending
on the clinical presentation of the patients. If the UBT also will be used as the primary endpoint,
a positive UBT result should be documented before the patient is randomized to treatment, so the
test can be used to determine patient outcome at the test-of-cure visit.
325
326
327
328
329 	For patients with a history of ulcer disease, investigators should procure an official radiographic
or endoscopic report documenting a prior ulcer.	330
331
332 	Investigators should obtain the patient’s history, a physical examination, vital signs, a pregnancy
test (when appropriate), serum chemistry, and hematology before randomization.	333
334
335 	Investigators should evaluate whether patients meet the inclusion and exclusion criteria and
obtain their informed consent.	336
337
338 	b. 	End-of-treatment visit
339
340 	The end-of-treatment visit should include a physical examination, laboratory determinations,
assessment of adverse events and concomitant medications, symptom assessment, and a
medication compliance assessment.
341
342
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
dose of the study treatment and is considered the test-of-cure visit. The test-of-cure visit should
occur at the same time point for all treatment arms, regardless of the duration of treatment.
Sponsors should determine the timing of the test-of-cure visit based upon the treatment arm with
the longest duration of treatment.
349
350
351
352
353
354 	At this visit, investigators should evaluate the primary endpoint. If a UBT is used to determine
patient outcome (i.e., H. pylori eradication or persistence), a repeat upper endoscopy should not
be needed for all patients. However, investigators should repeat an upper endoscopy and obtain
biopsies for culture and antimicrobial susceptibility testing in patients with a positive UBT result,
indicating persistence of H. pylori infection.
355
356
357
358
359
360 	Alternatively, sponsors can choose to use endoscopy at the post-treatment visit in place of a UBT
to determine patient outcome. If endoscopy is used, investigators should obtain biopsies in all
patients for histology, rapid urease test, and culture with antimicrobial susceptibility testing.
361
362
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364 	The choice of post-treatment diagnostic test (UBT or endoscopy) should be prespecified and
consistent across all study arms in a given trial.	365
366
367 	Investigators should obtain serum chemistry and hematology profiles and assess patients for
adverse events.	368
369
370 	d. 	Discontinuations
371
372 	Patients discontinuing study therapy prematurely should have post-treatment procedures
performed at the time of termination. In addition, if appropriate, patients also should be
evaluated at the time of the test-of-cure visit (at least 28 days but not more than 56 days after the
last dose of the study treatment). The reason for early discontinuation from the study treatment
and/or the trial should be documented in the case report form.
373
374
375
376
377
378 	e. 	Safety evaluations
379
380 	The protocol should clearly specify the methods to be used to obtain safety data during the
course of the study. Both adverse event information and safety laboratory data should be
collected during the study. Age- and sex-appropriate normal laboratory values should be
included with clinical measurements when reporting laboratory data. Additional safety
evaluations also may be needed because of the preclinical and clinical profile of the specific drug
under study (e.g., additional electrocardiogram measurements). Longer-term assessment of
adverse events after discontinuation or completion of the antimicrobial also can be considered
depending on the specific drug being studied.
381
382
383
384
385
386
387
388
389 	All patients should be evaluated for safety at the time of each study visit or assessment,
regardless of whether the test drug has been discontinued. All adverse events should be followed
until resolution, even if time on study would otherwise have been completed. For specific safety
reporting recommendations during clinical trials, see the ICH guidance for industry E2A Clinical
Safety Data Management: Definitions and Standards for Expedited Reporting.
390
391
392
393
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
population, as described above. Note that patients with missing data will be automatically
counted as failures in this analysis. The method for analysis should be clearly stated in the
protocol. Specific details can be provided in a separate document (i.e., data analysis plan).
400
401
402
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
clinical trials. Given that some missing data will occur, however, we recommend that the
sponsor define prospectively the method for handling missing data and perform secondary
407
408
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409 	analyses in which data are analyzed in several different ways to assess the effect on
interpretation and conclusions in the MITT analysis.	410
411
412 	The following three methods are examples of ways to handle missing data in H. pylori clinical
trials; however, other methods can be used.	413
414
415 	1. 	Calculating eradication rates by treatment in patients with observed data, and assuming
eradication rates are the same in patients with unobserved (missing) data.	416
417
418 	2. 	Assuming all active-controlled patients with missing data are eradicated while all patients
treated with the investigational regimen are not eradicated. This method is used only to
give an upper bound on the upper limit of the confidence interval for the difference in
eradication rates because such a scenario would be unlikely to actually occur.
419
420
421
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
use a noninferiority trial design if adequate historical information exists that allows for the
determination of a valid noninferiority margin. In those cases, the active-controlled arm of the
trial should be treated with an approved regimen consisting of an active control of interest plus a
specified background regimen. The test arm of the trial should be treated with the new regimen
consisting of the new test drug, replacing the active control of the approved regimen, but keeping
the same background regimen of the approved regimen of the control arm. The noninferiority
trial will compare the test regimen arm with the active-controlled regimen arm. The purpose of
such a comparison would be to show that the treatment difference C – T (i.e., the difference
between the response rate of the active-controlled regimen minus that for the test regimen) is
smaller than some prespecified noninferiority margin.
428
429
430
431
432
433
434
435
436
437
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
noninferiority trial. A noninferiority trial that lacks assay sensitivity may conclude that
an ineffective treatment is noninferior to a control and can lead to an erroneous
conclusion of efficacy. Before initiating a noninferiority trial, sponsors should evaluate
and determine the treatment effect of the active control with background regimen over
placebo with background regimen from adequate historical trials. This treatment effect is
referred to as M1. A discounted M1 should be chosen as a conservative estimate of the
treatment effect caused by uncertainties in the estimate of the treatment effect.
442
443
444
445
446
447
448
449
450 	• 	The constancy assumption. The current noninferiority trial should be sufficiently
similar to past historical trials with respect to all design and conduct features that can
influence the estimation of M1. These design features include the characteristics of the
patient population, important concomitant treatments (besides the fixed background
451
452
453
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454 	regimen), definition and ascertainments of study endpoints, dose of active control and
background regimen, entry criteria, and analytic methods.	455
456
457 	• 	The quality of the current noninferiority trial. Undesirable conduct features of the
trial would tend to minimize the difference, C – T, causing bias toward the null. These
undesirable features include imprecise or poorly implemented entry criteria, poor
compliance, the use of concomitant treatments whose effects may overlap with the test
drug under study, inadequate measurement techniques, or errors in treatment
assignments.
458
459
460
461
462
463
464 	9. 	Clinical Pharmacology Consideration
465
466 	CYP450 enzymes and efflux/uptake transporters are involved in the absorption and hepatic
clearance of certain antimicrobials and proton pump inhibitors, which are components of many
approved regimens. These enzymes and transporters may alter the overall systemic exposure
(oral bioavailability) of these drugs. Therefore, sponsors should consider determining the
association between drug exposure and enzymes or transporters to assess clinical efficacy and
safety of the regimen in various subpopulations. For additional information on submission of
genomic data, see the draft guidance for industry Pharmacogenomic Data Submissions —
Companion Guidance. 16
467
468
469
470
471
472
473
474
475 	10. 	Microbiology Considerations
476
477 	Special attention should be given to reliable methods for obtaining, culturing, and determining
the in vitro susceptibility of H. pylori because most clinical laboratories do not routinely perform
these procedures. Sponsors should provide details as part of each protocol for the following
microbiological procedures used in the trial: collection and transport of biopsy specimens,
isolation of H. pylori from biopsy specimens, identification of H. pylori, antimicrobial
susceptibility testing, and quality control.
478
479
480
481
482
483
484 	Investigators should collect at least one antral and one corpus biopsy specimen during endoscopy
from all randomized patients for culture and subsequent antimicrobial susceptibility testing
pretreatment and at the test-of-cure visit. In trials where sponsors use the UBT to determine
patient outcome at the test-of-cure visit, a repeat endoscopy with biopsies collected for culture
and subsequent antimicrobial susceptibility testing should be performed in patients with a
positive UBT result. In trials where sponsors use endoscopy to determine patient outcome at the
test-of-cure visit, all patients should have a repeat endoscopy with biopsies collected for culture
and subsequent antimicrobial susceptibility testing.
485
486
487
488
489
490
491
492
493 	Investigators should also collect at least two antral and two corpus biopsy specimens during
endoscopy from all randomized patients for histopathologic examination pretreatment and at the
test-of-cure visit, in all patients in trials where endoscopy is used to determine outcome at the
test-of-cure visit.
494
495
496
16 When final, this guidance will represent the FDA’s 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
antimicrobial susceptibility testing and has been standardized for testing certain antimicrobials
against H. pylori by the Clinical Laboratory Standards Institute (CLSI). If sponsors use a
method other than that recommended by the CLSI, we strongly recommend that they contact the
division before study initiation. If an experimental assay is used for any microbiologic
measurement, then the performance characteristics of the assay should be provided for review.
499
500
501
502
503
504
505 	Sponsors should present complete microbiology data, including individual MIC values for all
tested antimicrobials. Sponsors should also calculate MIC 50 and MIC90 values for the
pretreatment isolates. Where applicable, sponsors should analyze the data to determine the
percentage of patients with pretreatment antimicrobial resistance, the bacteriologic efficacy
among patients with antimicrobial resistant strains pretreatment, and the emergence of
antimicrobial resistance on therapy.
506
507
508
509
510
511
512 	Sponsors should include information on the mechanism of action of the therapeutic agents
against H. pylori, if known.	513
514
515 	Sponsors should also include information on the mechanism of antimicrobial resistance for H.
pylori, if known. If the antimicrobial resistance mechanism of resistance is not known, sponsors
should make an effort to assess the mechanism to better understand the spread of resistance and
clinical failure.
516
517
518
519
520 	In general, a four-fold or greater increase in MIC suggests a change in antimicrobial
susceptibility. Sponsors should record such changes, even if the shift in endpoint does not
represent a change in the proposed interpretive category. Newer microbiological methods may
allow detection of drug resistance by genotyping to identify mutants, and may also differentiate
between new infection and relapse. If any of these methods are used in a clinical trial, the details
of these methods and performance characteristics of the assay should be included for review.
521
522
523
524
525
526
527 	C. 	Labeling Considerations
528
529 	In addition to the statistical outcome regarding efficacy of study drug therapy in the clinical trials
(as described in section III.B.8., Statistical Considerations), approvability and product labeling
depends on the assessment of multiple factors, including safety, tolerability, and emerging
antimicrobial resistance as a result of drug therapy. In general, product labeling will reflect the
manner in which the drugs were used in clinical trials. For example, use in combination with
specific other drugs, as well as the dose and duration studied.
530
531
532
533
534
535
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539
540
541
542
543
544
545
546
536
Contains Nonbinding Recommendations
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APPENDIX: TABLES
537
538 	Table 1. Prerandomization Evaluability Based on Three Endoscopic H. pylori Tests 1
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
1 All patients should have a positive UBT result, in addition to endoscopic diagnostic testing, if the UBT
is used to determine patient outcome at the test-of-cure visit.
2 N/A indicates not available or missing result.
3 This column relates to whether or not patients are considered Included or Excluded in the efficacy
populations and is not necessarily used as criteria for inclusion into or exclusion from the trial. When
incongruent test results preclude an accurate H. pylori diagnosis, patients should be considered Excluded
and should not be included in either the MITT analysis or per-protocol populations.
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548
549
550
551
552
553
554
555
547
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Table 2. Test-of-Cure Evaluability Based on Three Endoscopic H. pylori Tests 1
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
1 A UBT that is FDA-approved for monitoring the effectiveness of treatment can be used at the test-of-
cure visit (at least 28 days following the end of treatment) in place of endoscopy. If this test is negative,
no further testing is needed.
2 N/A indicates not available or missing result.
3 An Indeterminate assessment at test-of-cure visit indicates that the patient should be considered to
have Persistence for the MITT analysis and be Excluded for the per-protocol analysis. Persistence
should be considered synonymous with infected.
15