Guidance for Industry 

Acute Bacterial Exacerbations of 

Chronic Bronchitis in Patients with 

Chronic Obstructive Pulmonary 

Disease: Developing Antimicrobial 

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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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 Steven Gitterman at 301-796-1600. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

August 2008 

Clinical Antimicrobial 

Revision 1

I:\4511dft.doc 

07/21/08
Guidance for Industry 

Acute Bacterial Exacerbations of 

Chronic Bronchitis in Patients with 

Chronic Obstructive Pulmonary 

Disease: Developing Antimicrobial 

Drugs for Treatment 

Additional copies are available from: 

Office of Training and 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 

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

August 2008 

Clinical Antimicrobial 

Revision 1
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. DEVELOPMENT PROGRAM ....................................................................................... 3

A. General Considerations .................................................................................................................3

1. Early Phase Clinical Development Considerations .........................................................................3

2. Definition of ABECB-COPD ............................................................................................................3

3. Efficacy Considerations ...................................................................................................................3

4. Safety Considerations.......................................................................................................................4

B. Specific Efficacy Trial Considerations .........................................................................................5

1. Study Design.....................................................................................................................................5

2. Study Population ..............................................................................................................................6

3. Study Inclusion Criteria ...................................................................................................................6

a. Patient history and characteristics .............................................................................................7

b. Signs and symptoms..................................................................................................................7

4. Study Exclusion Criteria ..................................................................................................................8

5. Randomization, Stratification, and Blinding....................................................................................9

6. Dose Selection ..................................................................................................................................9

7. Choice of Comparators ....................................................................................................................9

8. Concomitant Medications.................................................................................................................9

9. Efficacy Endpoints..........................................................................................................................10

a. Evaluation of clinical response ...............................................................................................10

b. Clinical relapse or recurrence .................................................................................................11

c. Adverse events or receipt of additional antibacterial therapy .................................................12

d. Microbiological response........................................................................................................12

10. Study Visits and Timing of Assessments ....................................................................................12

a. Entry visit ................................................................................................................................12

b. On-therapy visits.....................................................................................................................14

c. Early follow-up visit................................................................................................................15

d. Late follow-up assessment ......................................................................................................16

e. Safety evaluations ...................................................................................................................16

11. Statistical Considerations..........................................................................................................16

a. Analysis populations ...............................................................................................................17

b. Noninferiority margins............................................................................................................18

c. Sample size..............................................................................................................................18

d. Missing data ............................................................................................................................18

e. Interim analyses and data and safety monitoring boards.........................................................18

f. Other analyses of interest and secondary endpoints ................................................................19

g. Statistical analysis plan ...........................................................................................................19

12. Ethical Considerations ..............................................................................................................19

C. Other Considerations...................................................................................................................20

1. Animal Models................................................................................................................................20

2. Labeling..........................................................................................................................................20

3. Antimicrobial Resistance Claims ...................................................................................................20
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

Guidance for Industry1 1 

2 

3 

4 

5 

6 

7 

Acute Bacterial Exacerbations of Chronic Bronchitis in Patients 

with Chronic Obstructive Pulmonary Disease: Developing 

Antimicrobial Drugs for Treatment 

8 

9 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

10 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

11 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

12 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

13 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

14 the appropriate number listed on the title page of this guidance. 

15 

16 

17 

18 

19 

20 

21 

22 

23 

24 

25 

26 

27 

28 

29 

30 

31 

32 

33 

34 

35 

36 

 

I. INTRODUCTION 

The purpose of this guidance is to assist sponsors in the clinical development of antimicrobial 

drugs for the treatment of acute bacterial exacerbations of chronic bronchitis in patients with 

chronic obstructive pulmonary disease (ABECB-COPD). Specifically, this guidance addresses 

the Food and Drug Administration’s (FDA’s) current thinking regarding the overall development 

program and designs of clinical trials for antimicrobial drug products to support an indication for 

treatment of ABECB-COPD.2 This guidance does not address issues related to the development 

of drugs for other purposes such as prevention of respiratory tract infections in patients with 

COPD or in other populations, such as otherwise healthy persons. We expect that this guidance 

will serve as a focus for continued discussions among the Division of Anti-Infective and 

Ophthalmology Products, the Division of Special Pathogen and Transplant Products, and 

pharmaceutical sponsors, the academic community, and the public.3 Since the science of this 

indication continues to evolve, this guidance may be revised as new information becomes 

available. 

This guidance revises the draft guidance for industry Acute Bacterial Exacerbation of Chronic 

Bronchitis — Developing Antimicrobial Drugs for Treatment published in 1998. It also 

1

 This guidance has been prepared by the Division of Anti-Infective and Ophthalmology Products and 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 unless otherwise specified. 

3

 In addition to consulting guidance documents, sponsors are encouraged to contact the divisions to discuss specific 

issues that arise during the development of antimicrobial drug products. 

1 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

supersedes, with regard to the development of drugs to treat ABECB-COPD, 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,

37 

38 

39 

40 

41 

42 

43 

44 

45 

46 

47 

48 

49 

50 

51 

52 

53 

54 

55 

56 

57 

58 

59 

60 

61 

62 

63 

64 

65 

66 

67 

 

4

 as well as the joint 

FDA/Infectious Disease Society of America’s Guidelines for the Evaluation of Anti-Infective 

Drug Products).5

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.

6

 This guidance focuses on specific drug 

development and trial design issues that are unique to the study of ABECB-COPD; it does not 

address issues regarding the development of drugs for COPD or COPD exacerbations caused by 

factors other than bacterial infection. Information regarding developing drugs for the treatment 

of COPD is available in the draft guidance for industry Chronic Obstructive Pulmonary Disease: 

Developing Drugs for Treatment.7

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. 

II. BACKGROUND 

Since the FDA published draft guidance on the development of antimicrobial drugs for the 

treatment of ABECB in 1998, there have been public discussions regarding the design of clinical 

trials to study indications for infections involving the respiratory tract, including the indication of 

ABECB-COPD.8 These discussions have focused on the appropriateness of noninferiority trial 

designs for ABECB-COPD and other important study design issues such as the following: 

4

 See the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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

 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

7

 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a 

guidance, check the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

8

 The design of ABECB clinical trials was discussed at a meeting of the Anti-Infective Drugs Advisory Committee 

on February 19, 2002, and an IDSA/PhRMA/FDA workshop on November 19-20, 2002. Transcripts of these 

meetings are available at http://www.fda.gov/cder/audiences/acspage/antiinfectivemeetings1.htm and 

http://www.fda.gov/cder/present/idsaphrma/default.htm, respectively. 

2 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

68 

69 

70 

71 

72 

73 

74 

75 

76 

77 

78 

79 

80 

81 

82 

83 

84 

85 

86 

87 

88 

89 

90 

91 

92 

93 

94 

95 

96 

97 

98 

99 

100 

101 

102 

103 

104 

105 

106 

107 

108 

109 

110 

111 

112 

113 

• Inclusion criteria 

• Application of appropriate diagnostic criteria 

• Use of appropriate definitions of clinical outcomes 

• Timing of outcome assessments 

• Use of concomitant medications 

• Role of microbiological outcomes 

Important changes from the 1998 draft guidance that are based on these discussions have been 

incorporated into the appropriate sections below. 

III. DEVELOPMENT PROGRAM 

A. General Considerations 

1. Early Phase Clinical Development Considerations 

New drugs being studied for ABECB-COPD should have preclinical data documenting activity 

against the pathogens most commonly associated with ABECB-COPD (i.e., S. pneumoniae, H. 

influenzae, and M. catarrhalis). 

2. Definition of ABECB-COPD 

The term ABECB-COPD is used in this guidance to more accurately identify the disease that has 

previously been referred to as acute bacterial exacerbations of chronic bronchitis. ABECBCOPD refers to a clinical diagnosis of presumptive bacterial infection superimposed on a chronic 

pulmonary condition. This situation is best described pathologically as bronchial inflammation 

associated with the isolation of pathogenic bacteria from sputum or bronchial lavage specimens. 

However, it is important to note that there is some uncertainty as to the role of bacteria in 

causing ABECB-COPD because chronic bacterial colonization may be present in the airways of 

patients with COPD. 

The acute component of ABECB-COPD is usually manifest as worsening of the same symptoms 

patients experience when they are not experiencing an acute infection. Accordingly, to enroll 

patients in studies of ABECB-COPD, clinical trials should be designed to: 

• Define and document the underlying pulmonary condition in enrolled patients 

• Accurately measure the symptoms of the acute episode at study entry 

• Define the criteria for occurrence of an episode of ABECB-COPD (i.e., the change in 

symptoms that define an acute episode against the background of chronic pulmonary 

disease) 

3. Efficacy Considerations 

FDA review of previous ABECB-COPD studies has not been able to establish a reliable estimate 

of the magnitude of benefit for treatment of ABECB-COPD by antimicrobials (a precondition for 

3 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

a noninferiority trial).9 Accordingly, only superiority trials are currently recommended for 

ABECB-COPD studies. 

114 

115 

116 

117 

118 

119 

120 

121 

122 

123 

124 

125 

126 

127 

128 

129 

130 

131 

132 

133 

134 

135 

136 

137 

138 

139 

140 

141 

142 

143 

144 

145 

146 

147 

148 

149 

150 

151 

152 

153 

154 

155 

156 

157 

 

The goal of ABECB-COPD clinical trials should be to demonstrate an effect of antibacterial 

therapy on the clinical course of ABECB-COPD presumptively associated with H. influenzae, S. 

pneumoniae, or M. catarrhalis. If sponsors wish to add additional organisms to this indication, 

they should provide data sufficient to substantiate the clinical relevance of the particular 

organism as a pathogen in ABECB-COPD. Bacteria that may be colonizers following recent 

antimicrobial therapy are unlikely to be pathogens in this setting. 

The number of studies that should be conducted in support of an ABECB-COPD indication 

depends on the overall development plan for the drug under consideration. If the development 

plan for a drug has ABECB-COPD as the sole marketed indication, then at least two adequate 

and well-controlled trials establishing safety and efficacy should be conducted. 

A single randomized, double-blind study supporting the indication may be appropriate if the 

sponsor has access to confirmatory evidence including data from other clinical studies 

demonstrating effectiveness in other lower respiratory tract diseases and there is additional 

supportive information such as pharmacokinetic (PK) and pharmacodynamic (PD) studies 

demonstrating concentration of the antibacterial drug in the bronchi at a level expected to be 

active against the common pathogens causing ABECB-COPD. For example, robust findings of 

efficacy from well-designed community-acquired pneumonia trials with similar dosing regimens 

may be supportive of a single superiority trial of ABECB-COPD. 

Currently, there are no surrogate markers accepted by the FDA as substituting for clinical 

outcomes in ABECB-COPD studies. Sponsors who wish to propose use of a surrogate marker 

should discuss this with the FDA early in the drug development process. 

4. Safety Considerations 

A sufficient number of patients should be studied at the exposure (dose and duration) proposed 

for use to draw appropriate conclusions regarding drug safety. This includes the ability to 

evaluate the potential for relatively uncommon serious adverse events as well as commonly 

expected adverse events. The information should be derived primarily from adequate and wellcontrolled studies of ABECB-COPD, but also can be derived from studies of the new drug for 

infections other than ABECB-COPD if exposure is similar to or greater than the exposure for 

ABECB-COPD. The total number of patients needed for a drug development program that 

includes an ABECB-COPD indication should be discussed with the FDA early in the drug 

development process. 

Antimicrobials with clinically significant toxicity may not be appropriate for study of ABECBCOPD unless the treatment goal is directed at a more seriously ill patient portion of the ABECBCOPD population. 

9

 See ICH E10 (http://www.fda.gov/cder/guidance/index.htm). 

4 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

158 B. Specific Efficacy Trial Considerations 

159 

160 

161 

162 

163 

164 

165 

166 

167 

168 

169 

170 

171 

172 

173 

174 

175 

176 

177 

178 

179 

180 

181 

182 

183 

184 

185 

186 

187 

188 

189 

190 

191 

192 

193 

194 

195 

196 

 

1. Study Design 

As previously mentioned, we recommend only superiority trials for ABECB-COPD studies.10 

Superiority trials in the treatment of ABECB-COPD can consist of the following forms: 

• Placebo-controlled study with a background of optimized nonantimicrobial therapy 

— Patients in one study arm receive an experimental drug added to a standardized 

nonantimicrobial regimen. To demonstrate efficacy, the arm receiving the test 

antimicrobial should demonstrate superiority to a control arm of the same standardized 

nonantimicrobial therapy plus matching placebo. 

A three-arm study with the experimental treatment group, an active control arm (e.g., an 

antibacterial drug approved for ABECB-COPD), and a placebo-controlled group permits 

the demonstration of superiority and also can provide risk-benefit information relative to 

an approved comparator. 

• Dose-response — Patients in each study arm receive different antimicrobial doses (or 

dosing regimens) together with standardized nonantimicrobial therapy. To demonstrate 

efficacy, the arm receiving a higher dose (or more intensive therapy) should be superior 

to the lower dose (or less intensive) regimen. 

• Delayed versus immediate therapy — Patients in both study arms receive an active 

therapy, but administration of the comparator treatment is delayed relative to the 

experimental drug (i.e., one group is started on placebo but then switched to active 

therapy after a protocol-defined interval). Both groups remain blinded to treatment 

assignment for the entire study; to demonstrate efficacy, immediate therapy should be 

superior to delayed therapy. 

• Superiority of the study antimicrobial to another antimicrobial — Patients in one 

arm receiving the test drug (with standardized background nonantimicrobial therapy) are 

compared to patients in a control arm receiving another antimicrobial drug approved for 

the treatment of ABECB-COPD (with standardized background nonantimicrobial 

therapy). To demonstrate efficacy, the arm receiving the test antimicrobial should 

demonstrate superiority to the arm receiving the control antimicrobial. 

A study design can be used where patients are enrolled at days 4 to 7 and a 3-day run-in period is 

used before randomization. Randomization of patients with symptoms that have not improved 

10 FDA review of previous ABECB-COPD studies has not been able to establish a reliable estimate of the magnitude 

of benefit for treatment of ABECB-COPD by antimicrobials (a precondition for a noninferiority trial). Sponsors 

who are considering a noninferiority trial for ABECB-COPD should justify to the FDA the proposed noninferiority 

margin by data that include reliable estimates of a well-defined efficacy outcome measure. Such justification should 

be discussed with the FDA as early as possible during protocol development and before study initiation. See also 

ICH E10 (http://www.fda.gov/cder/guidance/index.htm). 

5 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

over the 3-day run-in period may enrich the study population for patients with ABECB-COPD 

rather than a nonbacterial etiology for worsening of symptoms. 

197 

198 

199 

200 

201 

202 

203 

204 

205 

206 

207 

208 

209 

210 

211 

212 

213 

214 

215 

216 

217 

218 

219 

220 

221 

222 

223 

224 

225 

226 

227 

228 

229 

230 

231 

232 

233 

234 

235 

236 

237 

238 

239 

240 

 

ABECB-COPD trials should be parallel group designs because crossover designs may be subject 

to carryover and period effects. 

2. Study Population 

ABECB-COPD clinical trials should enroll males and females 35 years old and older because 

COPD occurs primarily in older individuals; a diagnosis in younger individuals may reflect 

misclassification. We anticipate that most patients in ABECB-COPD clinical trials will be older 

than 50 years of age. 

We recognize that it is not appropriate for patients with severe COPD (i.e., patients who are 

mechanically ventilated) to be enrolled in placebo-controlled studies of a new antibacterial for 

ABECB-COPD. We strongly encourage discussion with the appropriate review division if study 

of patients with severe COPD is being considered.11 It is essential that in any proposed trials, 

adequate provisions are in place so that human subjects are not exposed to an unreasonable and 

significant risk of illness or injury (21 CFR 312.42). 

3. Study Inclusion Criteria 

The diagnosis of ABECB-COPD can be challenging. Both a diagnosis of COPD and an acute 

change superimposed against the background of chronic symptoms are needed for study 

enrollment. 

Traditionally, COPD has been defined as containing aspects of chronic bronchitis and 

emphysema. A diagnosis of chronic bronchitis is made clinically based on the presence of 

symptoms of cough and sputum production on most days of 3 consecutive months in at least 2 

consecutive years. Although useful for clinical practice, this definition lacks specificity for 

clinical trials because there is no standardized definition of the number of days that constitutes 

most days of 3 months out of the year or quantification of degree of sputum and cough. 

Because of the overlap of symptoms in patients with chronic bronchitis and/or emphysema and 

the limitations of the definition of chronic bronchitis, it is more appropriate to use the term 

COPD to describe the underlying disease in this patient population. The definition and severity 

of underlying obstructive pulmonary disease is based on the results from spirometry testing 

compared to predicted normative values as follows: 

• Mild COPD = FEV1/FVC < 70% and FEV1 ≥ 80% predicted 

• Moderate COPD = FEV1/FVC < 70% and 50% ≤ FEV1 < 80% 

• Severe COPD = FEV1/FVC < 70% and 30% ≤ FEV1 < 50% 

• Very severe COPD = FEV1/FVC < 70%, and FEV1 < 30% predicted or FEV1 < 50% 

plus chronic respiratory failure 

11 See section III.B.12., Ethical Considerations. 

6 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

241 

242 

243 

244 

245 

246 

247 

248 

249 

250 

251 

252 

253 

254 

255 

256 

257 

258 

259 

260 

261 

262 

263 

264 

265 

266 

267 

268 

269 

270 

271 

272 

273 

274 

275 

276 

277 

278 

279 

280 

281 

282 

 

Spirometry may be difficult to perform at the time of an acute bacterial exacerbation of chronic 

bronchitis as these tests are effort dependent. Spirometry data used for enrollment should be 

obtained from recent medical records; patients without spirometry-documented COPD should 

not be enrolled in studies of ABECB-COPD. Spirometry data obtained at the time an episode of 

ABECB-COPD is diagnosed have not been demonstrated to be predictive of severity or outcome. 

The diagnosis of an acute exacerbation presents additional concerns. A diagnosis of ABECBCOPD reflects a change in patient symptoms from their usual baseline; for a trial to demonstrate 

efficacy of antimicrobial therapy to be effective, patients who have a true change in symptoms 

should be selected. 

The specificity of sputum cultures for selecting patients with bacterial disease is unknown in 

ABECB-COPD since sputum is not normally sterile between exacerbations in these patients, and 

the etiologic role of bacteria in ABECB-COPD is uncertain. However, if there is a pathogenic 

role for bacteria in this disease, a negative sputum culture may reduce the chance of 

demonstrating a significant benefit from an antibacterial drug. Sponsors may wish to restrict 

enrollment in trials to patients with a positive sputum culture at baseline for any one of the three 

most common bacteria implicated as a cause of ABECB-COPD (i.e., S. pneumoniae, H. 

influenzae, and M. catarrhalis).

12

The following inclusion criteria should be used for patient enrollment in studies conducted for 

the treatment of ABECB-COPD. 

a. Patient history and characteristics 

The following patient demographic characteristics should be used for a better chance of selecting 

patients more likely to have ABECB-COPD: 

• Male and female patients 35 years old and older 

• History of at least mild COPD previously defined by the spirometry criteria above 

• History of more than two previous episodes of acute bronchitis (acute exacerbations) in 

the previous year 

• History of tobacco use consistent with a diagnosis of COPD 

b. Signs and symptoms 

Signs and symptoms that can be present in patients with ABECB-COPD include the following: 

• Dyspnea or breathlessness 

• Cough 

• Chest tightness or discomfort 

12 This situation can be addressed by use of a run-in period, when patients with a negative culture at baseline are 

excluded before beginning study therapy or during analysis by analyzing patients with a positive culture at baseline 

separately. This is discussed further in sections III.B.10, Study Visits and Timing of Assessments, and III.B.11, 

Statistical Considerations. 

7 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

283 • Sleep disturbances (i.e., insomnia or sleepiness) 

284 

285 

286 

287 

288 

289 

290 

291 

292 

293 

294 

295 

296 

297 

298 

299 

300 

301 

302 

303 

304 

305 

306 

307 

308 

309 

310 

311 

312 

313 

314 

315 

316 

317 

318 

319 

320 

321 

322 

 

• Decrease in exercise tolerance or limitation of usual activities 

• Increase in sputum volume and/or sputum purulence 

• Wheezing 

• New or worsening crackles on auscultation of lung fields 

Generalized signs and symptoms that are consistent with a diagnosis of ABECB-COPD (but are 

otherwise nonspecific) include: 

• Fever (temperature greater than 38.5 degrees Centigrade) 

• Malaise or fatigue 

• Confusion or change in mental status 

All signs and symptoms that may be present in patients with ABECB-COPD should be captured 

on the case report form, as should current tobacco use.13 

4. Study Exclusion Criteria 

The following patients should be excluded from trials for the treatment of ABECB-COPD: 

• Patients with pneumonia documented by chest X ray at the time of initial screening. All 

patients should receive a screening chest X ray before or at enrollment. 

• Patients with asthma (i.e., reversible obstruction of airflow with administration of 

bronchodilators by pulmonary function testing or a history of asthma). 

• Patients with any concomitant illness that may confound the interpretation of the effect of 

study medications (e.g., pulmonary malignancy, congestive heart failure, bronchiectasis, 

pneumothorax). 

• Immunocompromised patients; however, patients receiving systemic corticosteroids at 

baseline for treatment of COPD can be enrolled. 

• Patients who are allergic to any of the study medications. 

Sponsors may wish to exclude patients with a negative sputum culture at baseline; however, if 

these patients are included, stratification for this baseline characteristic should be included and 

the statistical analysis plan should include testing for the potential effect of a positive baseline 

culture. Depending on the trial design, sponsors also may wish to exclude patients who have 

received antimicrobial therapy for the current episode of ABECB-COPD, or alternatively, permit 

enrollment of patients with prior antimicrobial use only if there is a positive sputum culture 

despite therapy. If patients who have received prior antimicrobial therapy are included, prior 

antibacterial drug therapy should be included as a stratification factor before enrollment. 

13 Use of a patient-reported outcome (PRO) instrument is recommended for capturing clinical response. PROs are 

discussed further in section III.B.9., Efficacy Endpoints. 

8 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

323 5. Randomization, Stratification, and Blinding 

324 

325 

326 

327 

328 

329 

330 

331 

332 

333 

334 

335 

336 

337 

338 

339 

340 

341 

342 

343 

344 

345 

346 

347 

348 

349 

350 

351 

352 

353 

354 

355 

356 

357 

358 

359 

360 

361 

362 

363 

364 

365 

366 

 

Patients should be randomized for receipt of study drugs at enrollment. All studies should be 

double-blinded for study therapy. 

6. Dose Selection 

Data from phase 1 and phase 2 studies and dose-ranging PK/PD studies (including information 

regarding bronchial/lung penetration of the drug) can be integral to selecting an appropriate dose 

for phase 3 clinical trials. 

7. Choice of Comparators 

As previously mentioned, only superiority trials for ABECB-COPD studies are recommended.14 

The control arm for these superiority studies can be placebo or another antibacterial drug. 

8. Concomitant Medications 

All patients should receive (or be receiving) bronchodilator and/or systemic corticosteroid 

therapy at the time of enrollment. Lack of standardization of concomitant medications can 

introduce an important source of confounding in clinical trials if there are imbalances in receipt 

of nonantimicrobial therapy between trial groups. Such confounding may occur even if the 

number of patients receiving concomitant medications is similar between study groups but the 

reasons for administering concomitant medications differ. Confounding also may occur when 

the patients in one group who receive concomitant medications differ in baseline characteristics 

from those patients who do not receive concomitant medications. Therefore, sponsors should 

make every attempt to control for potential confounders such as concomitant medications during 

the study. This can be accomplished through a protocol-specified nonantimicrobial background 

regimen with the dose and frequency of use similar for all patients in the trial (e.g., 

bronchodilator treatment or protocol-specified rules for the addition of nonantimicrobial therapy 

such as corticosteroids). At a minimum, the protocol should specify appropriate options for 

nonantimicrobial therapies during the study. 

We anticipate that changes in the use of the following medications will be monitored or specified 

in an ABECB-COPD study: 

• Changes in the frequency or dose of beta-agonist therapy, or the addition of new betaagonist therapy (long- or short-acting therapy) 

• Changes in the frequency or dose of anticholinergic therapy or the addition of an 

anticholinergic therapy 

• Addition of methylxanthine therapy 

• Changes or the addition of systemic corticosteroids; systemic corticosteroids should be 

administered in a standardized way to all patients with a pre-enrollment FEV1 of < 50% 

of predicted FEV1 

14 See note 9, supra. 

9 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

367 

368 

369 

370 

371 

372 

373 

374 

375 

376 

377 

378 

379 

380 

381 

382 

383 

384 

385 

386 

387 

388 

389 

390 

391 

392 

393 

394 

395 

396 

397 

398 

399 

400 

401 

402 

403 

404 

405 

 

Assessment of the need for concomitant medications as an endpoint may not be an accurate 

surrogate for persistent patient signs or symptoms; the presence of such signs or symptoms 

should be confirmed by a patient-reported outcome (PRO) instrument that shows continued signs 

or symptoms at the time of administration of the concomitant medication. Efforts should be 

made to capture all concomitant medication use on a PRO instrument and to relate this 

information to patient signs or symptoms. 

9. Efficacy Endpoints 

a. Evaluation of clinical response 

The primary emphasis of the study should be the effect of the antimicrobial drug on outcomes 

that are clinically important to patients. A well-defined and reliable method of assessing patient 

symptoms should be used for ABECB-COPD studies; accordingly, only use of a reliable PRO 

instrument is recommended as the primary outcome measure.15 The PRO also should be used at 

baseline to define enrollment criteria; there should be a sufficient score on the PRO instrument 

such that a clinically meaningful response (i.e., change on the PRO instrument) can be observed. 

The amount of improvement determined to be clinically meaningful (and therefore appropriate 

for regulatory decisions) should be determined during instrument development and should be 

discussed with the FDA before study initiation. Statistically significant differences between 

comparator regimens may not be sufficient for demonstrating benefit if response to treatment has 

not been confirmed to be clinically meaningful. For example, signs or symptoms used to 

diagnose ABECB-COPD that may be important to a clinician, such as the color of sputum, may 

not be an important outcome to patients and therefore would not be appropriate as part of the 

response instrument scale score. 

If an adequate instrument is not available for studying ABECB-COPD, we recommend that the 

new instrument development process begin well in advance of phase 3 clinical trials so that the 

instrument can be ready for incorporation into the phase 3 protocol. If the plan is to enroll 

patients with very severe COPD or acute exacerbations, use of a caregiver-reported outcome 

instrument may be necessary when patients cannot respond themselves. 

Assessment of clinical response at each time point should not be limited solely to symptoms 

identified at enrollment but should also capture symptoms that occur after study entry. A 

combined endpoint, including symptom assessment by a PRO instrument and other significant 

events (e.g., respiratory failure), is most appropriate in ABECB-COPD, with the expectation that 

the overall study result will be driven primarily by outcomes related to patient symptoms. 

15 The use of a well-defined and reliable PRO instrument, even for a categorical response, can yield greater 

assurance that symptoms are being measured in a consistent manner across patients. For more information 

regarding the development of PRO measures, see the draft guidance for industry Patient-Reported Outcome 

Measures: Use in Medical Product Development to Support Labeling Claims. When final, this guidance will 

represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

10 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

406 

407 

408 

409 

410 

411 

412 

413 

414 

415 

416 

417 

418 

419 

420 

421 

422 

423 

424 

425 

426 

427 

428 

429 

430 

431 

432 

433 

434 

435 

436 

437 

438 

439 

440 

441 

442 

443 

444 

445 

446 

447 

448 

449 

450 

Patients with ABECB-COPD are unlikely to be asymptomatic at the end of study treatment, and 

may not even return to their baseline status before the onset of the acute episode. Improvement 

of symptoms over time as measured by a well-defined and reliable PRO measure should be the 

primary efficacy endpoint rather than return to previous baseline. 

Since exacerbations are often associated with precipitous declines in airflow, the rapidity of 

recovery of a pulmonary function measures, such as FEV1, following an exacerbation to preexacerbation status also can be considered as an important possible primary efficacy endpoint. 

However, use of this endpoint involves the collection of recent pre-exacerbation FEV1 

measurements. 

A fixed time endpoint may not be as sensitive a measure of treatment effect as a time-toresolution analysis. For example, clinical outcome at greater than 3 weeks after onset of therapy 

may not show a difference between treatment arms since many patients may have resolution of 

the acute exacerbation by this time, regardless of the administration of antibacterial drug therapy. 

Sponsors who choose to use response at a fixed time point as the primary outcome (i.e., as the 

test-of-cure assessment) should provide evidence to support the selection of that specific time 

point. 

An outcome scale can be used for describing categorical responses (e.g., improvement or failure) 

at each time point if the criteria for the categories are well-defined and reliable. Overall response 

should also incorporate survival and the absence of complications of ABECB-COPD (e.g., the 

development of pneumonia should be considered a clinical failure) as part of the overall response 

assessment. Failure criteria should be defined a priori (e.g., protocol defined worsening of 

symptoms, failure to improve at certain time points after treatment onset). Failure should likely 

mandate a change in treatment, which would now include active therapy for the placebo arm. 

Objective measures such as peak expiratory flow or exercise testing (e.g., a six-minute walk) can 

be incorporated into a clinical protocol and should be considered secondary outcome measures. 

Patients designated as clinical failures at any time point should be designated as clinical failures 

for all subsequent follow-up visits. 

Early clinical assessment for treatment failure is needed in a placebo-controlled trial so that 

rescue therapy can be incorporated into the study design at the time a failure outcome is 

assigned; this process can serve to mitigate concerns regarding inclusion of a placebo arm in an 

ABECB-COPD trial. 

b. Clinical relapse or recurrence 

Since it is unlikely that patients will exhibit a complete resolution of symptoms, there should be 

no separate categories for success or relapse. However, patients who return to baseline at the end 

of study treatment can be assessed for the recurrence of symptoms that meet the study definition 

of ABECB-COPD. These patients should be evaluated (clinically and microbiologically) as 

would a new patient being entered into the study. This may be useful for studies that examine 

11 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

recurrence as a secondary endpoint (i.e., assessment of the prolonged effect from antibacterial 

treatment of a single episode). 

451 

452 

453 

454 

455 

456 

457 

458 

459 

460 

461 

462 

463 

464 

465 

466 

467 

468 

469 

470 

471 

472 

473 

474 

475 

476 

477 

478 

479 

480 

481 

482 

483 

484 

485 

486 

487 

488 

489 

490 

491 

 

c. Adverse events or receipt of additional antibacterial therapy 

Patients who discontinue therapy because of an adverse event should be evaluated at the time of 

discontinuation of the study medication. These patients should not necessarily be considered 

withdrawn from the study in terms of overall evaluation; investigators should continue to follow 

all such patients at scheduled study visits and continue to record information on both safety and 

efficacy outcomes. If at the time study medication is discontinued the patient is alive, without 

complications, and does not receive additional antimicrobial therapy, then the patient should be 

evaluated following the protocol criteria; discontinuation of therapy because of an adverse event 

should not automatically be considered a clinical failure. 

Patients who receive another antibacterial drug while on study drug should be identified since 

these patients generally should be considered failures in an efficacy analysis. 

d. Microbiological response 

Although microbiological outcome may provide useful information regarding the biological 

activity of antimicrobials, microbiological outcome is not a direct measure of benefit to patients 

and, therefore, should be viewed as being supportive information but not as a substitute for 

clinical outcome in a specific trial.16

If follow-up specimens for culture are obtained from patients, the most useful specimens are 

those obtained at least 72 hours after the completion of drug therapy since negative culture 

results obtained while on therapy may represent suppression rather than elimination of 

organisms. Any target pathogens isolated from follow-up specimens should be tested for 

susceptibility to the antimicrobial used to treat the disease. 

All target pathogens isolated from patients during clinical trials should be appropriately saved in 

the event that there is a need to do additional studies with the bacteria. 

10. Study Visits and Timing of Assessments 

a. Entry visit 

At entry, the investigator should evaluate the patient by performing an appropriate history and 

physical examination. Information recorded on the case report form during the entry 

examination should include the following. 

16 Microbiological outcomes may be valuable in phase 2 studies addressing dosing regimens (i.e., where time to no 

growth on culture is being used as an outcome to optimize dose and/or dosing frequency) that will be evaluated in 

phase 3 studies. 

12 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

492 • History and demographic characteristics 

493 

494 

495 

496 

497 

498 

499 

500 

501 

502 

503 

504 

505 

506 

507 

508 

509 

510 

511 

512 

513 

514 

515 

516 

517 

518 

519 

520 

521 

522 

523 

524 

525 

526 

527 

 

− Date of visit. 

− Age, sex, and weight. 

− Underlying medical condition(s). 

− Current medications. 

− Number of distinct and well-documented episodes of acute bronchitis in the past, 

including how this information is obtained (i.e., chart review or patient recall); dates, 

treatment regimens, and outcomes should be recorded. 

− Detailed history of COPD including results of prior pulmonary function testing. This 

history is best obtained from objective sources (e.g., patient medical records). 

− History of tobacco use. 

− Recent or current use of antibacterial drugs, and the indication or reason for use. 

− Bacteria previously isolated from sputum during previous exacerbations, with 

antimicrobial susceptibility profile. 

• Symptoms 

A well-defined and reliable PRO instrument, as discussed in section III.B.9., Efficacy 

Endpoints, should be used to assess symptoms at baseline. 

• Signs 

− Vital signs, including body temperature measurement 

− Posteroanterior and lateral chest X rays17

− Electrocardiography (to rule out arrhythmia and for safety analysis) 

− Other laboratory tests for evaluation of safety parameters (e.g., complete blood count, 

serum chemistries) 

• Sputum sample collection 

The entry visit should include baseline sputum gram stain with submission of sputum for 

culture and susceptibility testing. Sponsors should describe in the protocol the methods 

of obtaining specimens, specimen processing, and culture techniques. For 

microbiological assessment, the investigator should collect the following information: 

17 Patients should have a baseline chest X ray to rule out pneumonia and other confounding illnesses such as 

congestive heart failure, malignancy, or bronchiectasis. Spiral computed tomography and D-dimer testing may be 

indicated in selected patients to exclude pulmonary embolism. 

13 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

− A description of how the sample was obtained (e.g., expectoration, induced sputum, 

aspiration), processed, and transported to the laboratory. 

528 

529 

530 

531 

532 

533 

534 

535 

536 

537 

538 

539 

540 

541 

542 

543 

544 

545 

546 

547 

548 

549 

550 

551 

552 

553 

554 

555 

556 

557 

558 

559 

560 

 

− The adequacy of the specimen in terms of numbers of polymorphonuclear cells and 

epithelial cells present.18

− Identification of bacterial isolates.19

− In vitro susceptibility (preferably minimum inhibitory concentration) testing of the 

isolates to both the study and control drugs. In vitro susceptibility testing should be 

performed by using standardized methods, such as the Clinical and Laboratory 

Standards Institute methods, unless otherwise justified. 

Microbiological information that is not part of the entry criteria (e.g., susceptibility 

results) should remain blinded to investigators. 

If a positive sputum culture is used as one of the entry criteria for a clinical trial,20 then 

no growth of pathogens on culture may allow exclusion of a significant number of 

patients whose exacerbation may be caused by factors other than bacterial infection (e.g., 

viruses, pollutants, allergens, cigarette smoke). Previous studies have shown that patients 

with the following characteristics may be more likely to have bacteria isolated by sputum 

culture at baseline: 

− Purulent sputum 

− Patients with more than two episodes of acute bronchitis per year 

− Patients with a positive baseline sputum gram stain 

Sputum culture data for S. pneumoniae, M. catarrhalis, and H. influenzae should be 

correlated with clinical outcome. 

b. On-therapy visits 

Each patient should have daily on-therapy assessments of signs and symptoms using a welldefined and reliable PRO instrument. Regardless of how the assessment is conducted (e.g., 

interview, interactive voice response via telephone, diary), the questioning of patients should be 

performed in a reproducible and structured way so that any potential biases in the method of 

18 Investigators should evaluate the adequacy of sputum samples by ensuring that the specimen is most likely from 

lower respiratory secretions by use of the following criteria: greater than 25 white blood cells per field at 100x 

magnification (low power, 10x objective) confirming the impression of sputum purulence and less than 10 

squamous epithelial cells at 100x magnification (low power 10x objective). 

19 This information should remain blinded while the patient is receiving study medication. 

20 If it is believed that treatment should not be given unless patients are bacteriologically confirmed, then enrollment 

and treatment should be delayed until positive culture results return. If that is not the case, then an alternative is to 

enroll all patients at the time of presentation with screening by sputum gram stain, then analyze patients in the 

modified intent-to-treat (MITT) population. This situation is discussed further in section III.B.11., Statistical 

Considerations. We strongly recommend that patients enrolled at the time of screening continue to be followed per 

protocol, regardless of whether sputum culture is subsequently positive or not. 

14 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

questioning do not affect study outcome.21 The ability to detect differences between study 

therapies for a time-to-resolution endpoint may be increased if assessments are done more often 

(e.g., twice daily). Therapy should be continued as described in the study protocol regardless of 

whether symptoms have improved. Investigators should attempt to allow a minimum of 72 

hours on therapy with the study medication before classifying a patient as a clinical failure; 

accordingly, investigators may wish to include a 48- to 72-hour visit to ensure there is not 

substantial clinical worsening at this time. 

561 

562 

563 

564 

565 

566 

567 

568 

569 

570 

571 

572 

573 

574 

575 

576 

577 

578 

579 

580 

581 

582 

583 

584 

585 

586 

587 

588 

589 

590 

591 

592 

593 

594 

595 

596 

597 

598 

599 

600 

601 

 

Assigning an outcome of clinical failure and permitting use of rescue antibacterial therapy 

should be reserved for patients who are worsening on their assigned treatment arm; specific 

criteria to identify these patients should be included in the protocol. It is important that 

investigators distinguish patients who are worsening (i.e., where rescue therapy is appropriate) 

from patients who are slow to improve but may still remain on assigned therapy. The protocol 

should also specify a failure endpoint if symptoms have not improved by a certain day on study, 

even if the symptoms are not clearly clinically worsening at that time; this may be most objective 

if defined as a score remaining above a certain threshold for a PRO instrument. In general, 

patients should not be unblinded if a criterion for rescue therapy is met. 

In the case of clinical failure, therapy should be changed to include initiation of antimicrobial 

therapy (or alternative antimicrobial therapy if appropriate) and/or other appropriate therapeutic 

modifications as necessary. If failure is assigned, the investigator should attempt to obtain a 

repeat sputum culture and the sample should be sent for culture and susceptibility testing. 

Patients who meet study criteria for clinical failure should continue to have the identical 

protocol-specified assessments as patients who continue to receive their originally assigned 

treatment. 

Investigators should document findings from on-therapy office visits (e.g., history, physical 

examination, and laboratory test results) on the case report form. If the investigator contacts the 

patient by telephone or by another interactive technology, documentation of the specific 

questions asked, how they were asked, and the responses given should be captured on the case 

report form. If a well-defined and reliable diary is used to capture patient symptoms during this 

study visit, this information also should be recorded on the case report form. 

c. Early follow-up visit 

The early follow-up visit should occur after completion of all study medication at a time when 

the drug is expected to be clear from the infection site (usually at least 5 half-lives). For 

example, if a study drug with a short half-life is administered for 10 days, this study visit can 

occur on days 0 to 4 after completion of therapy; this study visit should occur later for drugs with 

a longer half-life. At this visit, the investigator should perform a directed medical history and 

physical examination, as well as appropriate laboratory measurements. The investigator also 

21 When interviews are used they should be standardized; in addition, symptoms recorded from the patient should be 

recorded without interpretation by the interviewer. (See the draft guidance for industry Patient-Reported Outcome 

Measures: Use in Medical Product Development to Support Labeling Claims. When final, this guidance will 

represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm.) 

15 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

should inquire about adverse events. Depending on the study design, follow-up sputum culture 

may be appropriate at this visit. 

602 

603 

604 

605 

606 

607 

608 

609 

610 

611 

612 

613 

614 

615 

616 

617 

618 

619 

620 

621 

622 

623 

624 

625 

626 

627 

628 

629 

630 

631 

632 

633 

634 

635 

636 

637 

638 

639 

640 

641 

642 

 

d. Late follow-up assessment 

The late follow-up assessment should occur 10 to 14 days after the completion of all study 

medication (e.g., if study drug is administered for 10 days, this assessment can occur on days 20 

to 25 after initiation of therapy (unless a drug with a long t1/2 has been studied)). For patients 

with adverse events occurring at or after the early follow-up assessment, investigators should 

perform an assessment that includes a medical history, a physical examination, appropriate 

laboratory evaluations, identification of any new adverse events, and follow-up on unresolved 

adverse events. All adverse events should be followed to resolution. 

e. Safety evaluations 

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 antibacterial drug therapy also can be 

considered depending on the specific drug being studied. 

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.22 All adverse events should be 

followed until resolution, even if time on study would otherwise have been completed. 

11. Statistical Considerations 

Sponsors should designate the hypotheses to be tested before initiation of the trial. These 

hypotheses should be clearly stated in the protocol or statistical analysis plan, and the trial should 

be powered to detect differences between study arms if group differences exist. If sponsors 

choose to test multiple hypotheses, they should address issues related to the potential increase in 

obtaining false positive results (type I error) because of multiple comparisons, either by adjusting 

the type I error or using a stepwise, closed testing strategy for hypothesis testing. If sponsors use 

a closed testing hypothesis strategy, they should specify the order of hypothesis testing before 

initiation of the trial and the method for controlling the overall type I error rate. These issues 

should be discussed with the FDA in advance of enrollment in the trial, and should be 

incorporated into the statistical analysis plan as appropriate. 

22 For specific safety reporting recommendations during clinical trials, see the ICH guideline for industry 

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

(http://www.fda.gov/cder/guidance/index.htm). 

16 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

643 a. Analysis populations 

644 

645 

646 

647 

648 

649 

650 

651 

652 

653 

654 

655 

656 

657 

658 

659 

660 

661 

662 

663 

664 

665 

666 

667 

668 

669 

670 

671 

672 

673 

674 

675 

676 

677 

678 

679 

680 

681 

682 

683 

684 

685 

686 

 

The following definitions apply to various populations for analyses in ABECB-COPD clinical 

trials: 

• Safety population — All patients who receive at least one dose of assigned therapy 

during the study. 

• Intent-to-treat (ITT) population — All patients who are randomized. 

• Modified intent-to-treat (MITT) population (also sometimes referred to as 

microbiological intent-to-treat population) — All patients who are randomized and 

who have a pathogen associated with ABECB-COPD isolated at baseline. Patients 

should not be excluded from this population based upon events that are measured postrandomization (e.g., loss to follow-up). If a positive culture is required for study entry, 

this population is identical to the ITT population.23 

• Per-protocol populations (also referred to as the clinically evaluable or 

microbiologically evaluable populations) — The population of patients who meet the 

definition for the primary analysis population (ITT or MITT population) and who follow 

important components of the protocol as specified (e.g., administration of a specified 

minimum amount of study medication). Traditionally, adequacy of therapy for a perprotocol analysis population has been defined as patients who have received greater than 

80 percent (or within 80 to 120 percent) of the prescribed dose amount and/or dosing 

regimen. Sponsors should document compliance with dosing (e.g., daily assessment, 

patient diary, urine testing, or MEMS caps). 

To ensure consistency of results, the ITT and/or MITT populations in the study should be 

evaluated as well as the population of patients who follow important aspects of the protocol (i.e., 

the per-protocol populations). However, it is also important to note that the per-protocol 

population analyses are subgroup analyses since they exclude patients based upon events that 

occur after randomization. Patients in such subgroup analyses may differ by important factors 

(both measured and unmeasured) other than the drug received; because of this, analyses based on 

the ITT (or MITT) population should be considered the primary study analyses, with analyses 

based on a per-protocol population reviewed for consistency of results. Results in both 

populations should provide evidence of effectiveness. 

The primary and secondary analyses should be defined in the protocol before starting the study. 

Depending on the exact hypothesis being tested, sponsors may prefer to specify either the ITT or 

MITT population as the primary population for analysis; for example, if patients are enrolled 

before results of the sputum culture return but the primary hypothesis is that an effect is most 

likely to be seen in patients with S. pneumoniae or other likely pathogens isolated, then the study 

should be powered for the MITT population and this should be the primary analysis. If it is 

expected that the treatment arm will be superior to the placebo arm for all patients enrolled, even 

23 The culture results (i.e., the specific bacterial organisms) that define whether a patient should be included in the 

MITT population should be stated in the protocol. 

17 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

including patients who did not have a pathogen isolated, then an ITT population would be the 

most appropriate primary analysis population. The choice of population (i.e., MITT or ITT) for 

the primary analysis may guide the details of product labeling if the drug is approved. 

687 

688 

689 

690 

691 

692 

693 

694 

695 

696 

697 

698 

699 

700 

701 

702 

703 

704 

705 

706 

707 

708 

709 

710 

711 

712 

713 

714 

715 

716 

717 

718 

719 

720 

721 

722 

723 

724 

725 

726 

727 

728 

729 

730 

 

b. Noninferiority margins 

As mentioned, FDA review of previous ABECB-COPD studies has not been able to establish a 

reliable estimate of the magnitude of benefit for treatment of ABECB-COPD with antibacterial 

drug therapy; because of this, noninferiority trials currently are not considered adequate to 

establish evidence of effectiveness for regulatory approval of a new indication for ABECBCOPD. For additional information regarding noninferiority studies in general and in 

antibacterial trials, see ICH E10 and the draft guidance for industry Antibacterial Drug Products: 

Use of Noninferiority Studies to Support Approval.

24

c. Sample size 

The appropriate sample size for a clinical trial should be based upon the number of patients 

needed to answer the research question posed by the study. The sample size is influenced by 

several factors including the prespecified type I and type II error rates, the expected success rate, 

and the noninferiority margin (for a noninferiority trial), or the amount by which the study drug 

is expected to be superior to the control in a superiority trial. Sample size should be based upon 

the number of patients needed to draw conclusions in the ITT or MITT analysis population. 

d. Missing data 

There is no single optimal way to deal with missing data from clinical trials. Sponsors should 

make every attempt to limit loss of patients from the trial. Analyses that exclude patients are 

subgroup analyses, and patients who do not complete the trial may differ substantially from 

patients who remain in the trial in both measured and unmeasured ways. Therefore, sponsors 

should prespecify in the protocol the method of how missing data will be addressed in the 

analysis of trial results. Sponsors also should present sensitivity analyses in the final study report 

such as including all missing patients as failures, including all missing patients as successes, and 

including all missing data as successes or failures in each study group respectively. 

Different rates of missing data or differences in the reasons for missing data across treatment 

arms can be a cause for concern in the interpretation of a clinical trial. If this occurs, it should be 

addressed in the study report. 

e. Interim analyses and data and safety monitoring boards 

If interim (or futility) analyses will be performed, they should be specified in the analysis plan. 

The purpose of the interim analysis should be clearly stated in the analysis; it is important that 

the interim analysis does not affect study conduct and thereby compromise study results. Study 

data also should be examined at the time of interim analysis for any emerging safety signals. We 

24 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a 

guidance, check the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

18 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

encourage sponsors to discuss their plans with the review division before initiation of the trial to 

ensure that the overall study significance tests properly address the effect of interim testing. 

731 

732 

733 

734 

735 

736 

737 

738 

739 

740 

741 

742 

743 

744 

745 

746 

747 

748 

749 

750 

751 

752 

753 

754 

755 

756 

757 

758 

759 

760 

761 

762 

763 

764 

765 

766 

767 

768 

769 

770 

 

Use of a data and safety monitoring board (DSMB) may be appropriate depending on the design 

of the proposed phase 3 trial and the patient population that the trial will enroll. If a DSMB is 

used, a detailed charter with the composition of the committee members and the operational 

details should be provided for review.25

f. Other analyses of interest and secondary endpoints 

Analyses of secondary and additional endpoints should be considered exploratory since a trial 

usually is not designed to address the questions raised by these analyses, either because of 

multiple comparisons and/or concerns with subgroup analyses. However, the conclusions of 

such analyses can be strengthened if hypotheses related to these endpoints are prespecified in the 

protocol, if adjustments for multiple comparisons (maintenance of type I error) are outlined in 

the protocol, and if the trial is appropriately powered to determine differences between groups 

related to these variables. Analyses of secondary and additional endpoints can be most helpful 

for identifying areas for study in future trials. 

g. Statistical analysis plan 

If a statistical analysis plan is developed to expand on the details of the analysis from that in the 

protocol, the sponsor should submit the analysis plan for any phase 3 ABECB-COPD study to 

the FDA before initiation of the trial.26 

Clinical and microbiological outcomes from blinded studies also can be used for assessing the 

accuracy of an established or tentative microbiological breakpoint for the treatment under study. 

12. Ethical Considerations 

Review of previous placebo-controlled studies of the treatment of ABECB-COPD has shown 

variable results, with several placebo-controlled studies showing no effect for antimicrobial 

treatment of exacerbations. Accordingly, for patients with mild to moderate disease, studies 

have not shown a risk to placebo-treated patients that make future placebo-controlled trials 

unethical; the risk from placebo treatment may be similar to that associated with antibacterial 

therapy since low-frequency severe events (e.g., pseudomembranous colitis or serious allergic 

reactions) have been observed with almost all antibacterial drugs. The occurrence of common 

but less-severe adverse events (e.g., diarrhea) from antibacterial drugs also can be relevant in 

assessing the risk-benefit to patients in a placebo-controlled trial where the expected treatment 

effect may be small. Rescue therapy can be incorporated into the study design so that individual 

25 For more detailed information, see the guidance for clinical trial sponsors Establishment and Operation of 

Clinical Trial Data Monitoring Committees (http://www.fda.gov/cder/guidance/index.htm). 

26 For more detailed information, see the draft guidance for industry Developing Antimicrobial Drugs — 

General Considerations for Clinical Trials. When final, this guidance will represent the FDA’s current 

thinking on this topic. For the most recent version of a guidance, check the CDER guidance Web page at 

http://www.fda.gov/cder/guidance/index.htm. 

19 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

771 

772 

773 

774 

775 

776 

777 

778 

779 

780 

781 

782 

783 

784 

785 

786 

787 

788 

789 

790 

791 

792 

793 

794 

795 

796 

797 

798 

799 

800 

801 

802 

803 

804 

805 

806 

807 

808 

809 

810 

811 

812 

patients are treated at the time a failure outcome is assigned; this addition may serve to mitigate 

concerns regarding inclusion of a placebo arm in an ABECB-COPD trial. All study designs 

should provide appropriate provisions for patient safety. 

Although study results have been varied, some prior studies of ABECB-COPD have shown 

clinically significant benefit in severely ill patients. We strongly encourage discussion with the 

appropriate review division regarding design of placebo-controlled studies if enrollment will 

include patients with clinically severe disease (e.g., patients requiring hospitalization or at 

immediate risk of respiratory failure). 

C. Other Considerations 

1. Animal Models 

Currently, there are no animal models for ABECB-COPD. However, animal models for other 

upper and lower bacterial infections by the same microorganisms implicated as a cause of 

ABECB-COPD may be useful in determining antimicrobial candidates for further study in the 

treatment of ABECB-COPD. 

2. Labeling 

The following is an example of a labeled indication for the treatment of ABECB-COPD: 

“[Drug] is indicated in the treatment of acute exacerbations of chronic bronchitis in patients 

with underlying chronic obstructive pulmonary disease (ABECB-COPD) due to susceptible 

isolates of [relevant pathogens based on trial results].” 

3. Antimicrobial Resistance Claims 

To date, the FDA has not granted resistance claims for ABECB-COPD caused by antimicrobial 

resistant bacteria. To propose a claim for antimicrobial resistant pathogens in ABECB-COPD, 

data from within the clinical trials should be presented that clearly demonstrate the adverse 

clinical effect(s) of in vitro resistance and the ability of the study antimicrobial to significantly 

reduce or eliminate the adverse clinical effect(s). If resistance is mediated by different 

mechanisms within the same class of resistance (e.g., extended-spectrum beta-lactamases), the 

effect of the study drug to eliminate bacteria with the various different mechanisms of resistance 

should be demonstrated clinically. Resistance claims should be relevant to ABECB-COPD (e.g., 

amoxicillin resistance is more clinically relevant than penicillin resistance since the latter is 

rarely prescribed for ABECB-COPD). Sponsors seeking resistance claims should contact the 

review division before initiating clinical trials to discuss appropriate study designs that may be 

suitable to achieve the desired resistance claims. 

20