Guidance for Industry 

Community-Acquired Bacterial 

Pneumonia: 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DRAFT GUIDANCE
 

This guidance document is being distributed for comment purposes only.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 electronic comments to http://www.regulations.gov. Submit written 

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 Sumathi Nambiar, MD, MPH or Joseph 

Toerner, MD, MPH at 301-796-1300. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
 

January 2014 

Clinical/Antimicrobial
 

Revision 2 

10223dft.doc 

01/08/14 
 

Guidance for Industry 

Community-Acquired Bacterial 

Pneumonia: 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)
 

January 2014 

Clinical/Antimicrobial
 

Revision 2 
TABLE OF CONTENTS
 

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

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

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

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

1. Nonclinical Development Considerations ....................................................................................... 3
 

2. Drug Development Population ........................................................................................................ 3
 

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

4. Safety Considerations ...................................................................................................................... 3
 

B. Specific Efficacy Trial Considerations ......................................................................................... 4
 

1. Trial Design ..................................................................................................................................... 4
 

2. Trial Population ............................................................................................................................... 4
 

3. Entry Criteria................................................................................................................................... 4
 

a. Clinical, radiographic, and microbiologic entry criteria ........................................................... 4
 

b. Exclusion criteria ...................................................................................................................... 5
 

4. Randomization and Blinding ............................................................................................................ 5
 

5. Specific Populations......................................................................................................................... 6
 

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

7. Choice of Comparators, Prior Antibacterial Drug Use, and Concomitant Therapy ....................... 6
 

8. Efficacy Endpoints ........................................................................................................................... 8
 

a. Primary endpoint ....................................................................................................................... 8
 

b. Secondary endpoints ................................................................................................................. 8
 

c. IV and oral formulations ........................................................................................................... 9
 

9. Trial Procedures and Timing of Assessments .................................................................................. 9
 

a. Entry visit .................................................................................................................................. 9
 

b. On-therapy visits ....................................................................................................................... 9
 

c. After therapy visit ..................................................................................................................... 9
 

10. Statistical Considerations.......................................................................................................... 10
 

a. Analysis populations ............................................................................................................... 10
 

b. Noninferiority margins ............................................................................................................ 11
 

c. Sample size considerations ..................................................................................................... 11
 

11. Risk-Benefit Considerations ...................................................................................................... 12
 

C. Other Considerations ................................................................................................................... 12
 

1. Pharmacokinetic/Pharmacodynamic Evaluation .......................................................................... 12
 

2. Labeling Considerations................................................................................................................ 13
 

REFERENCES............................................................................................................................ 14
 

APPENDIX: NONINFERIORITY MARGIN JUSTIFICATION FOR CABP .................... 16
 
 

 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

1 Guidance for Industry1 

2 Community-Acquired Bacterial Pneumonia: 

3 Developing Drugs for Treatment 

4 

5 

6 

7 

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

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

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

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

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

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

14 

15 

16 

17 

18 I. INTRODUCTION 

19 

20 The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 

21 treatment of community-acquired bacterial pneumonia (CABP). Specifically, this guidance 

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

23 development program and clinical trial designs for drugs to support an indication for the 

24 treatment of CABP.2

 This draft guidance is intended to serve as a focus for continued comments 

25 and discussions among the Division of Anti-Infective Products, pharmaceutical sponsors, the 

26 academic community, and the public.3 

27 

28 This guidance does not contain discussion of the general issues of statistical analysis or clinical 

29 trial design. Those topics are addressed in the ICH guidances for industry E9 Statistical 

30 Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 

31 Trials, respectively.4 

32 

1 

1

 This guidance has been prepared by the Division of Anti-Infective 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 guidances, sponsors are encouraged to contact the division to discuss specific issues that 

arise during drug development. 

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

Drugs guidance Web page at 

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

 

5

 There have been several public discussions with the FDA regarding CABP. For example: (1) a 2008 Clinical 

Infectious Diseases supplement that summarized a workshop co-sponsored by the FDA and professional societies, 

titled “Workshop on Issues in the Design and Conduct of Clinical Trials of Antibacterial Drugs in the Treatment of 

Community-Acquired Pneumonia” (Clinical Infectious Diseases, December 1, 2008; volume 47 (supplement 

number 3)); (2) a 2008 Anti-Infective Drugs Advisory Committee (AIDAC) meeting on endpoints and clinical trial 

design issues for CABP at http://www.fda.gov/ohrms/dockets/ac/cder08.html#AntiInfective; (3) the December 9, 

2009, AIDAC meeting on CABP issues at http://www.fda.gov/AdvisoryCommittees/Calendar/ucm187911.htm; and 

(4) the November 3, 2011, AIDAC meeting on CABP clinical trials at 

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiInfectiveDrugsAdvisoryCommittee/ucm242307.htm (the November 3, 2011, AIDAC meeting information is at the 

bottom of the Web page). Notably, this revised guidance provides new efficacy endpoint recommendations (section 

III.B.8., Efficacy Endpoints), allows enrollment of up to 25 percent of the patient population who have received 

prior antibacterial drug therapy (section III.B.7., Choice of Comparators, Prior Antibacterial Drug Use, and 

Concomitant Therapy), and recommends the intent-to-treat population as the primary analysis population (section 

III.B.10., Statistical Considerations). 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

33 This guidance revises the draft guidance for industry Community-Acquired Bacterial 

34 Pneumonia: Developing Drugs for Treatment that issued in March 2009. When final, this 

35 guidance will be considered the FDA’s current thinking regarding the development of drugs for 

36 the treatment of CABP. 

37 

38 FDA’s guidance documents, including this guidance, do not establish legally enforceable 

39 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

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

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

42 recommended, but not required. 

43 

44 

45 II. BACKGROUND 

46 

47 This guidance provides information to assist sponsors developing drugs for the treatment of 

48 CABP. CABP is defined as an acute bacterial infection of the pulmonary parenchyma associated 

49 with chest pain, cough, sputum production, difficulty breathing, chills, rigors, fever, or 

50 hypotension, and is accompanied by the presence of a new lobar or multilobar infiltrate on a 

51 chest radiograph. Common typical bacterial pathogens that cause CABP include Streptococcus 

52 pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. 

53 Atypical bacterial pathogens such as Chlamydophila pneumoniae, Mycoplasma pneumoniae, and 

54 Legionella pneumophila also cause CABP. 

55 

56 Changes from the 2009 draft CABP guidance, based on public discussions and comments to the 

57 docket, have been incorporated into the appropriate sections below.5 These changes are intended 

58 to attain a greater degree of balance between the practicability of conducting CABP clinical trials 

59 and the trial procedures needed for a scientifically sound and interpretable trial. 

60 

61 

2 
 

 

Contains Nonbinding Recommendations 

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62 III. DEVELOPMENT PROGRAM 

63 

64 A. General Considerations 

65 

66 1. Nonclinical Development Considerations 

67 

68 New antibacterial drugs being studied for CABP should have nonclinical data documenting 

69 activity against the commonly implicated pathogens for CABP. 

70 

71 2. Drug Development Population 

72 

73 The trial population should include individuals most likely to have CABP, as defined above, and 

74 who can therefore benefit from antibacterial therapy. 

75 

76 3. Efficacy Considerations 

77 

78 Noninferiority trials are interpretable and acceptable to support approval of a drug for an 

79 indication for the treatment of CABP. A showing of superiority to an effective control is also 

80 readily interpretable and would be acceptable. 

81 

82 Historical data show that antibacterial drugs demonstrate a considerable treatment effect 

83 compared to nonantibacterial therapies on clinical responses evaluated during the first 5 days of 

84 therapy. 

85 

86 Although it remains important for a trial to demonstrate sustained clinical responses, currently 

87 there is insufficient historical evidence to define the treatment effect on endpoints at or after 

88 therapy completion. There is adequate information to define a reliable treatment effect on all89 cause mortality. 

90 

91 A single adequate and well-controlled trial in CABP supported by evidence of antibacterial 

92 activity accrued during a clinical development program (e.g., efficacy in another indication such 

93 as acute bacterial skin and skin structure infection; data from a phase 2 clinical trial in CABP) 

94 may provide evidence of effectiveness in CABP. Sponsors should discuss their proposed CABP 

95 development program with the FDA as well as the other independent evidence that would be 

96 used to support the findings from a single trial.6 

97 

98 4. Safety Considerations 

99 

100 If the same or greater dose and duration of the drug is used in clinical development for other 

101 infectious disease indications, safety data from the other infectious disease indications can be 

102 used in an overall safety database to support an indication for CABP. In general, a minimum of 

103 700 patients should be included in the safety database. For new drugs that have an important 

104 clinical benefit over existing therapies, depending on the benefit demonstrated, a smaller 

6

 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 

Products. 

3 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

105 premarketing safety database may be appropriate. Sponsors should discuss the appropriate size 

106 of the premarketing safety database with the FDA during clinical development. 

107 

108 B. Specific Efficacy Trial Considerations 

109 

110 1. Trial Design 

111 

112 CABP trials should be randomized, double-blind, and active-controlled using a noninferiority or 

113 superiority design. Placebo-controlled trials are not appropriate for this indication except when 

114 they are add-on superiority trials in which patients receive either placebo or investigational drug 

115 added to standard-of-care antibacterial drug treatment. 

116 

117 2. Trial Population 

118 

119 The trial population for efficacy trials should include patients with CABP based on the entry 

120 criteria described in section III.B.3., Entry Criteria. We recommend that at least 75 percent of 

121 patients in trials have Pneumonia Patient Outcomes Research Team (PORT) scores of III or 

122 higher (Fine, Auble, et al. 1997). For trials in which most patients would be treated as 

123 outpatients, sponsors should discuss the trial population and its level of baseline severity with the 

124 FDA in advance of a phase 3 trial (e.g., whether the trial may enroll patients with PORT scores 

125 of II or higher). 

126 

127 3. Entry Criteria 

128 

129 a. Clinical, radiographic, and microbiologic entry criteria 

130 

131 Sponsors should use entry criteria that select patients who have evidence of a diagnosis of CABP 

132 as outlined in Table 1. 

133 

134 Table 1. Summary of Entry Criteria for a CABP Trial 

At Least Two At Least Two At Least One Chest Microbiologic 

Symptoms Vital Sign 

Abnormalities 

Finding of Other 

Clinical Signs and 

Laboratory 

Abnormalities 

Radiograph 

Findings 

Criteria 

- Difficulty - Fever - Hypoxemia New Appropriate 

breathing - Hypotension - Clinical evidence of infiltrates in a sputum specimen: 

- Cough - Tachycardia pulmonary lobar or fewer than 10 

- Production of - Tachypnea consolidation multilobar squamous 

purulent sputum - An elevated total distribution epithelial cells and 

- Chest pain white blood cell count 

or leukopenia 

more than 25 

polymorphonuclear 

cells per low power 

field 

135 

136 An adequate specimen of respiratory secretions should be obtained in all patients and should be 

137 processed by the laboratory according to recognized methods for Gram stain, culture, and in vitro 

4 
 

 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

138 antibacterial susceptibility testing performed on appropriate organisms isolated from the 

139 specimen.7 

140 

141 Bacterial detection methods other than culture may be used to define the microbiological intent142 to-treat (micro-ITT) population (see section III.B.10.a., Analysis populations). Such methods 

143 may include the following: (1) use of rapid diagnostic tests (e.g., urinary antigen test for S. 

144 pneumoniae); and (2) nonculture methods of testing (e.g., serology, polymerase chain reaction). 

145 Use of rapid diagnostic tests may help to select a patient population with an identified bacterial 

146 etiology for CABP. 

147 

148 The clinical trial of an antibacterial drug also may provide an opportunity to contribute to the 

149 development and evaluation of a new diagnostic test. Sponsors interested in also using a clinical 

150 trial in patients with CABP as a means for the evaluation of a diagnostic test are encouraged to 

151 discuss this with the FDA. 

152 

153 b. Exclusion criteria 

154 

155 Exclusion criteria should include the following: 

156 

157  Aspiration pneumonia 

158 

159  Hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia 

160 

161  Patients with known bronchial obstruction or a history of post-obstructive pneumonia 

162 (this criterion does not exclude patients who have chronic obstructive pulmonary disease) 

163 

164  Patients with primary or metastatic lung cancer 

165 

166  Patients with cystic fibrosis, known or suspected Pneumocystis jiroveci pneumonia, or 

167 known or suspected active tuberculosis 

168 

169 4. Randomization and Blinding 

170 

171 Patients should be randomized to treatment groups at enrollment. All trials should be double172 blind unless there is a compelling reason for not blinding treatment allocation. If trials are 

173 single-blind or open-label, sponsors should discuss potential biases with the FDA and how these 

174 biases will be addressed. 

175 

7

 Standard methods for in vitro susceptibility testing are developed by organizations such as the Clinical and 

Laboratory Standards Institute; see also the American Society for Microbiology, 2011, Manual of Clinical 

Microbiology, 10th edition. 

5 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

176 5. Specific Populations 

177 

178 The trials should include patients of both sexes and all races, as well as geriatric patients.8  

179 Patients with renal or hepatic impairment may be enrolled, provided pharmacokinetics of the 

180 drug have been evaluated in these patients and appropriate dosing regimens have been defined. 

181 

182 Sponsors should discuss drug development in the pediatric populations as early as is feasible. 

183 The Pediatric Research Equity Act (PREA), as amended by the Food and Drug Administration 

184 Safety and Innovation Act, states that initial plans for the conduct of pediatric studies (referred to 

185 as an initial pediatric study plan) shall be submitted to the FDA before the date on which 

186 required pediatric assessments are submitted under PREA and no later than (1) 60 days after the 

187 end-of-phase 2 meeting or (2) such other time as may be agreed upon by the FDA and the 

188 applicant.9  

189 

190 6. Dose Selection 

191 

192 To choose the dose or doses to be evaluated in phase 3 clinical trials, sponsors should integrate 

193 the findings from nonclinical toxicology studies, animal models of infection, pharmacokinetics, 

194 safety and tolerability information from phase 1 clinical trials, and safety and efficacy 

195 information from phase 2 dose-ranging clinical trials. Trials assessing drug penetration at the 

196 site of action (e.g., epithelial lining fluid) may be helpful in defining doses that achieve 

197 concentrations sufficient to exert an antibacterial effect. In addition, the pharmacokinetics of the 

198 drug in specific populations (e.g., geriatric patients, patients with renal or hepatic impairment) 

199 should be evaluated before initiation of phase 3 trials to determine whether dose adjustments are 

200 necessary. This evaluation may prevent the exclusion of such patients from phase 3 clinical 

201 trials. 

202 

203 7. Choice of Comparators, Prior Antibacterial Drug Use, and Concomitant Therapy 

204 

205 In general, the active comparator should be considered standard of care for this indication. 

206 When evaluating the current standard of care, we consider recommendations by authoritative 

207 scientific bodies (e.g., American Thoracic Society, Infectious Diseases Society of America) 

208 based on clinical evidence and other reliable information that reflects current clinical practice. 

209 

210 Ideally, patients enrolled in a CABP clinical trial should not have received prior antibacterial 

211 drug therapy because such therapy may have a number of potential consequences for a clinical 

212 trial. Prior antibacterial drug therapy could: 

213 

 

8

 See the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics and E7 Studies in 

Support of Special Populations: Geriatrics; Questions and Answers. 

9

 See PREA (Public Law 108-155; section 505B of the Federal Food, Drug, and Cosmetic Act; 21 U.S.C. 355c) as 

amended by the Food and Drug Administration Safety and Innovation Act of 2012 (Public Law 112-144) and the 

draft guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study 

Plans and Amended Pediatric Study Plans. When final, this guidance will represent the FDA’s current thinking on 

this topic. 

6 
 

 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

214  Obscure true treatment differences between an investigational drug and the control drug 

215 introducing bias toward a finding of no difference between treatment groups (i.e., a bias 

216 toward noninferiority)10 

217 

218  Particularly influence the efficacy findings based on an endpoint early in therapy (day 3 

219 to day 5) 

220 

221 However, exclusion of all patients who have received prior antibacterial therapy also may pose 

222 problems, including: 

223 

224  Excluding patients with greater disease severity (i.e., patients who received prompt 

225 administration of antibacterial drug therapy), which may result in a patient population 

226 with lesser severity of illness and greater potential for spontaneous recovery; this could 

227 bias trial results toward a finding of no difference between treatment groups (i.e., a bias 

228 toward noninferiority) 

229 

230  Certain trial sites may not participate in the clinical trial because of concerns that trial 

231 treatment would not represent standard of care. 

232 

233 A pragmatic approach to these concerns is to: (1) encourage prompt enrollment procedures so 

234 that patients can receive the clinical trial treatment initially, with no need for other antibacterial 

235 drug therapy; and (2) allow enrollment of some patients who have received a single dose of a 

236 short-acting antibacterial drug within 24 hours of enrollment (ideally there would be few such 

237 patients but up to 25 percent of the patient population could be allowed). This would permit 

238 patients in the trial to receive prompt antibacterial drug therapy as clinically necessary, consistent 

239 with the standard of care. The results in the subgroup of patients (i.e., the majority of patients) 

240 who did not receive prior effective antibacterial drug therapy would be important to evaluate. 

241 The primary analysis should be stratified by prior therapy to assess the consistency of the results 

242 across the two subgroups (i.e., patients who received prior therapy and those who did not receive 

243 prior therapy). 

244 

245 In general, concomitant antibacterial therapy with an antimicrobial spectrum that overlaps with 

246 the spectrum of the investigational drug should not be administered during the trial. We 

247 recognize the need in certain circumstances for the empirical coverage against atypical pathogens 

248 (e.g., Legionella species). The additional antibacterial coverage for atypical pathogens should be 

249 discussed with the FDA before trial initiation. The additional antibacterial coverage for atypical 

250 pathogens should be promptly discontinued after a determination has been made that CABP is 

251 not caused by an atypical pathogen of concern (e.g., a negative test result on a Legionella antigen 

252 assay). 

253 

10 For example, see Pertel, Bernardo, et al. 2008. 

7 
 

 

 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

254 8. Efficacy Endpoints 

255 

256 a. Primary endpoint 

257 

258 The primary efficacy endpoint of clinical success is defined as improvement at day 3 to day 5 in 

259 at least two of the following symptoms: chest pain, frequency or severity of cough, amount of 

260 productive sputum, and difficulty breathing.11 Symptoms should be evaluated on a four-point 

261 scale (absent, mild, moderate, severe) with improvement defined as at least a one-point 

262 improvement from baseline to the assessment at day 3 to day 5 (e.g., from severe to moderate, 

263 from moderate to absent, or from mild to absent).12 

264 

265 An endpoint of all-cause mortality at 28 days after enrollment may be used as a primary efficacy 

266 endpoint in CABP clinical trials in certain patient populations. However, sponsors considering 

267 the use of all-cause mortality as the primary efficacy endpoint should discuss the trial design 

268 with the FDA. 

269 

270 b. Secondary endpoints 

271 

272 Sponsors should evaluate the following as secondary endpoints: 

273 

274  Improvement at day 3 to day 5 in at least two of the following symptoms with no 

275 worsening in any of these symptoms of CABP compared to baseline: chest pain, 

276 frequency or severity of cough, amount of productive sputum, and difficulty breathing; 

277 and improvement in vital signs (i.e., body temperature, blood pressure, heart rate, 

278 respiratory rate).13 

279 

280  Clinical outcome at the end of therapy. 

281 

282  Clinical outcome at a fixed time point after therapy completion. Patients with resolution 

283 of symptoms and signs attributable to CABP at 5 to 10 days following completion of 

284 treatment and who did not receive nontrial antibacterial drugs for treatment of CABP 

285 should be considered successes on this secondary endpoint. 

286 

287 Other examples of secondary endpoints for consideration are as follows: 

288 

289  Changes in white blood cell counts from baseline to day 3 to day 5 

290  Changes in oxygenation from baseline to day 3 to day 5 

291 

11 See Talbot, Powers, et al. 2012. 

12 See Toerner, Burke, et al. 2012. For information regarding the development of patient-reported outcome 

measures, see the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 

Development to Support Labeling Claims. 

13 Improvement or stabilization of vital signs and other signs attributable to CABP should be defined in the protocol. 

For example, see table 10 in Mandel, Wunderink, et al. 2007. 

8 
 

 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

292 c. IV and oral formulations 

293 

294 For drugs that have only an intravenous (IV) formulation available, sponsors should conduct 

295 trials with the IV formulation alone until the day 3 to day 5 efficacy endpoint assessment is 

296 complete, if feasible, to allow for assessment of both the efficacy and safety of the 

297 investigational drug. Assessment of the primary endpoint at day 3 to day 5 before switching to 

298 an oral antibacterial drug should ensure that the evaluation of efficacy reflects the effects of the 

299 investigational IV drug. The overall duration of antibacterial drug therapy (i.e., days of IV 

300 therapy plus days of oral drug therapy) should not involve an unnecessarily long course of oral 

301 switch therapy, so that the contribution of the IV investigational drug to overall efficacy on 

302 secondary endpoints at 5 to 10 days after completion of treatment can be assessed. 

303 

304 For drugs that have both an IV and oral formulation, the protocol should specify the criteria that 

305 allow for IV-to-oral switch. The sponsor should collect pharmacokinetic (PK) data for IV and 

306 oral formulations in earlier phase studies to select the appropriate oral dose for the IV-to-oral 

307 switch. 

308 

309 9. Trial Procedures and Timing of Assessments 

310 

311 a. Entry visit 

312 

313 The following information should be captured at the entry visit (see section III.B.3., Entry 

314 Criteria, and section III.B.8., Efficacy Endpoints): 

315 

316  Appropriate demographic information 

317  History and physical examination findings 

318  Prior medication use 

319  Baseline assessments of symptoms 

320  Baseline assessments of clinical signs of CABP 

321  Baseline appropriate laboratory tests 

322  Chest radiographic findings 

323  Microbiological specimens 

324  Severity scores 

325 

326 b. On-therapy visits 

327 

328 Investigators should document findings from on-therapy clinical trial visits (e.g., history, 

329 physical examination, adverse effects, laboratory test results). Patients should be evaluated for 

330 the symptoms of chest pain, frequency or severity of cough, amount of productive sputum, and 

331 difficulty breathing at day 3 to day 5. Patients also should be evaluated at the end of therapy. 

332 

333 c. After therapy visit 

334 

335 At this visit at 5 to 10 days after completion of treatment, sponsors should capture physical 

336 examination findings, assessments of symptoms, assessments of signs, assessments and 

9 
 

Contains Nonbinding Recommendations 

Draft — Not for Implementation 

337 resolution of adverse effects, if any, and appropriate laboratory tests. Patients should be 

338 evaluated at day 28 for assessment of all-cause mortality. 

339 

340 10. Statistical Considerations 

341 

342 The trial hypotheses and the analysis methods should be prespecified in the protocol and in the 

343 statistical analysis plan, and should be finalized before trial initiation.14 

344 

345 a. Analysis populations 

346 

347 The following definitions apply to various analysis populations in CABP clinical trials: 

348 

349  Safety population — All patients who received at least one dose of drug during the trial. 

350 

351  Intent-to-treat (ITT) population — All patients who were randomized. 

352 

353  Micro-ITT population — All randomized patients who have a baseline bacterial pathogen 

354 known to cause CABP against which the investigational drug has antibacterial activity. 

355 This includes bacterial pathogens identified by standard culture methods of an 

356 appropriate sputum specimen or blood. Recently conducted trials suggest that 

357 approximately 25 percent of the ITT population will have bacterial pathogens identified 

358 by standard culture methods. In addition, nonculture methods of detection of bacterial 

359 pathogens (e.g., urinary antigen test) may be used to identify patients for inclusion in a 

360 micro-ITT analysis population. 

361 

362  Clinically evaluable or per-protocol populations — Patients who meet the definition for 

363 the ITT population and who follow important components of the trial as specified in the 

364 protocol. 

365 

366  Microbiologically evaluable populations — Patients who meet the definition for the 

367 micro-ITT population and who follow important components of the trial as specified in 

368 the protocol. 

369 

370 Sponsors should discuss with the FDA the prespecified primary analysis population in advance 

371 of trial initiation. The ITT population may be considered as the primary analysis population 

372 when (1) the trial enrolls patients who are most likely to have a bacterial etiology for pneumonia 

373 and (2) the investigational antibacterial drug can be administered as monotherapy that has 

374 antibacterial activity against the typical bacterial pathogens that cause CABP.15 

375 

376 The ITT population is likely to have a substantial fraction of patients who do not have a bacterial 

377 pathogen identified on sputum culture. Nonetheless, the ITT population (i.e., patients who meet 

14 See ICH E9 and ICH E10, and the draft guidance for industry Non-Inferiority Clinical Trials (when final, this 

guidance will represent the FDA’s current thinking on this topic). 

15 The micro-ITT population is an important analysis population, in particular if the investigational antibacterial 

drug has a narrow spectrum of activity (e.g., a drug active against a single genus and species of bacteria). 

10
 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

378 the inclusion criteria described in section III.B.3, Entry Criteria) may be informative based on 

379 observations from previously conducted trials and evaluations. For instance, among patients 

380 who did not receive prior therapy in a trial in which there was an observed treatment difference 

381 between two antibacterial drugs (Pertel, Bernardo, et al. 2008), the subgroup of patients who did 

382 not have a positive sputum culture for a bacterial pathogen showed a treatment difference similar 

383 to the treatment difference among the subgroup of patients with a positive culture. This indicates 

384 a strong likelihood that the patients enrolled in this trial without a positive sputum culture 

385 actually had bacterial disease (Rubin, Toerner, et al. 2012). In addition, extensive nonculture 

386 methods performed in a research setting from sputum specimens identified a possible bacterial 

387 etiology for pneumonia in some patients who did not have a bacterial pathogen identified on a 

388 sputum or blood culture (Johansson, Kalin, et al. 2010). Another evaluation of patients with 

389 pneumonia who did not have a bacterial pathogen identified on a sputum or blood culture found 

390 that a more invasive search can identify a bacterial etiology in a large proportion of patients 

391 (Ruiz-González, Falguera, et al. 1999). 

392 

393 However, sponsors planning to develop a drug for the sole indication of the treatment of CABP 

394 should consider conducting two adequate and well-controlled trials of identical design. Each of 

395 these trials could potentially be powered based on the ITT population of that trial. Further, a 

396 noninferiority efficacy analysis in a micro-ITT population could potentially use data pooled from 

397 both trials. Sponsors planning to conduct a single CABP trial, with other supportive data, to 

398 support approval for CABP should discuss this plan with the FDA in advance and are 

399 encouraged to submit a special protocol assessment.16 

400 

401 The micro-ITT population should allow a sufficient description of baseline microbiological 

402 findings for adequate labeling information. 

403 

404 b. Noninferiority margins 

405 

406 Historical experience indicates that there is a relatively large treatment effect of antibacterial 

407 therapy on clinical recovery at day 3 to day 5 (see the Appendix). In general, the selection of a 

408 noninferiority margin (M2) of 12.5 percent is reasonable for CABP clinical trials using a clinical 

409 recovery endpoint at day 3 to day 5. In certain circumstances (e.g., a narrow spectrum drug for a 

410 limited population with unmet medical need), it may be reasonable to consider a noninferiority 

411 margin greater than 12.5 percent. Sponsors should discuss with the FDA a clinically appropriate 

412 noninferiority margin in advance of trial initiation. 

413 

414 c. Sample size considerations 

415 

416 A general framework is provided for sponsors to begin to discuss sample size considerations 

417 with the FDA during protocol development. In this illustrative sample size calculation, 

418 approximately 225 patients per group is estimated based on the following assumptions: (1) a rate 

419 of clinical success for the active-controlled therapy of 80 percent; (2) two-sided type I error (α) 

420 of 0.05; (3) type II error (β) of 0.10 (power 0.90); (4) a noninferiority margin of 12.5 percent (see 

421 the Appendix); and (5) an ITT analysis population. 

422 

 

16 See the guidance for industry Special Protocol Assessment. 

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423 11. Risk-Benefit Considerations 

424 

425 Risk-benefit considerations may depend on the population being studied. For example, for an 

426 IV-administered antibacterial drug targeted for treatment of hospitalized patients seriously ill 

427 with CABP, certain types of adverse effects that can be monitored in a hospital setting might 

428 result in a risk-benefit consideration that is appropriate, while such adverse effects might result 

429 in a risk-benefit consideration that is not appropriate for an orally administered antibacterial drug 

430 targeted for treatment of mildly ill outpatients. 

431 

432 C. Other Considerations 

433 

434 1. Pharmacokinetic/Pharmacodynamic Evaluation 

435 

436 The PK/pharmacodynamic (PD) characteristics of the drug should be evaluated using in vitro 

437 methods and animal models of infection. 

438 

439 The limitations of S. pneumoniae pneumonia and H. influenzae pneumonia animal models, when 

440 considering their implications for humans, include the differences among the animal models in 

441 the mode of infection and in the reproducibility of infection (Tessier, Kim, et al. 2002; Gavalda, 

442 Capdevila, et al. 1997; Legget 1999; Miyazaki, Nunoya, et al. 1997), and differences in the effect 

443 of animal lung secretions versus human lung secretions on the activity of the antibacterial drug 

444 (Silverman, Mortin, et al. 2005). Animal studies are not a substitute for clinical trials in patients 

445 with CABP.17 

446 

447 The PK/PD characteristics of the drug (including the relationships to the minimum inhibitory 

448 concentrations) should be integrated with the findings from phase 1 PK clinical trials to help 

449 identify appropriate dosing regimens for evaluation in phase 2 and phase 3 clinical trials. A 

450 dose-response trial may be considered as an option for clinical trials early in development to 

451 weigh risks and benefits when selecting doses and to ensure that suboptimal doses or excessive 

452 doses (beyond those that add to efficacy) are not used in the phase 3 trial, offering some 

453 protection against unexpected and unrecognized dose-related toxicity.18 

454 

455 Sponsors should consider obtaining blood samples from all patients in phase 2 and phase 3 

456 clinical trials (sparse sampling) to allow for the estimation of drug exposure in each patient. A 

457 retrospective exposure-response analysis based on the population PK model should be performed 

458 to assess the relationship between exposure and observed clinical and microbiologic outcomes. 

459 The relationship between drug exposure and clinically relevant adverse events also should be 

460 explored to identify potential risks with different dosing regimens (if applicable) and specific 

461 patient populations. 

462 

17 See 21 CFR 314.600 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=314.600) 

18 See the guidance for industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory 

Applications and the ICH guidance for industry E4 Dose-Response Information to Support Drug Registration. 

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463 2. Labeling Considerations 

464 

465 Generally, the labeled indication should be the treatment of CABP caused by the specific 

466 bacteria identified in a sufficient number of patients in the clinical trials and should reflect the 

467 patient population enrolled in the clinical trials. 

468 

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469 REFERENCES 

470 

471 Austrian, R and J Gold, 1964, Pneumococcal Bacteremia With Especial Reference to Bacteremic 

472 Pneumococcal Pneumonia, Ann Intern Med, 60:759-776. 

473 

474 Bullowa, JGW, 1937, The Course, Symptoms and Physical Findings, In: Bullowa JGW, editor, 

475 The Management of Pneumonias, Oxford University Press; New York. 

476 

477 Dowling, HG and MH Lepper, 1951, The Effect of Antibiotics (Penicillin, Aureomycin and 

478 Terramycin) on the Fatality Rate and Incidence of Complications in Pneumococcic Pneumonia: 

479 A Comparison With Other Methods of Therapy, AM J Med Sci, 222:396-402. 

480 

481 Fine, MJ, TE Auble, DM Yealy, BH Hanusa, LA Weissfeld, DE Singer, CM Coley, TJ Marrie, 

482 and WN Kapoor, 1997, A Prediction Rule to Identify Low-Risk Patients With Community483 Acquired Pneumonia, N Engl J Med, 336:243-50. 

484 

485 Finland, M, 1943, Chemotherapy in the Bacteremia, Conn State Med J, 7:92-100. 

486 

487 Finland, M, WC Spring, and FC Lowell, 1940, Specific Treatment of the Pneumococcic 

488 Pneumonias; An Analysis of the Results of Serum Therapy and Chemotherapy at the Boston City 

489 Hospital From July 1938 Through June 1939, Annals of Internal Medicine, 13:1567-1593. 

490 

491 Flippin, HF, JS Lockwood, DS Pepper, and L Schwartz, 1939, The Treatment of Pneumococcic 

492 Pneumonia With Sulfapyridine, JAMA, 112:529-534. 

493 

494 Gavaldà, J, JA Capdevila, B Almirante et al., 1997, Treatment of Experimental Pneumonia due 

495 to Penicillin-Resistant Streptococcus Pneumoniae in Immunocompetent Rats, Antimicrob Agents 

496 Chemother, 41:795-801. 

497 

498 Higgins, K, M Singer, T Valappil, S Nambiar, D Lin, and E Cox, 2008, Overview of Recent 

499 Studies of Community-Acquired Pneumonia, Clin Infect Dis, 47 (Suppl 3) S150-S156. 

500 

501 Johansson, N, M Kalin, A Tivelijung-Lindell, CG Giske, and J Hedlund, 2010, Etiology of 

502 Community-Acquired Pneumonia: Increased Microbial Yield With New Diagnostic Methods, 

503 Clin Infect Dis, 50:202-209. 

504 

505 Kingston, JR, RM Chanock, MA Mufson et al., 1961, Eaton Agent Pneumonia, JAMA, 176:118­

506 123. 

507 

508 Legget, J, 1999, Murine Models of Pneumonia Using Aerosol Infection, In: Zak O, Sande MA, 

509 eds., Handbook of Animal Infections: San Diego, Academic Press, 533-538. 

510 

511 Mandell, LA, RG Wunderink, A Anzueto et al., 2007, Infectious Diseases Society of 

512 America/American Thoracic Society Consensus Guidelines on the Management of Community513 Acquired Pneumonia in Adults, Clin Infect Dis, 44:S27-72. 

514 

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515 Meakins, JC and FR Hanson, 1939, The Treatment of Pneumoccic Pneumonia With 

516 Sulfapyridine, The Canadian Medical Association Journal, April, 333-336. 

517 

518 Miyazaki, S, T Nunoya, T Matsumoto, K Tateda, and K Yamaguchi, 1997, New Murine Model 

519 of Bronchopneumonia due to Cell-Bound Haemophilus Influenzae, J Infect Dis, 175:205-209. 

520 

521 Pertel, PE, P Bernardo, C Fogarty et al., 2008, Effects of Prior Effective Therapy on the Efficacy 

522 of Daptomycin and Ceftriaxone for the Treatment of Community-Acquired Pneumonia, Clin 

523 Infect Dis, 46:1142-1151. 

524 

525 Rubin, D, J Toerner, T Valappil et al., 2012, Impact of Prior Antibacterial Therapy in 

526 Community-Acquired Bacterial Pneumonia (CABP) Trials, Infectious Diseases Society of 

527 America, October 17-21, Abstract number 36677. 

528 

529 Ruiz-González, A, M Falguera, A Nogués, and M Rubio-Caballero, 1999, Is Streptococcus 

530 Pneumoniae the Leading Cause of Pneumonia of Unknown Etiology? A Microbiologic Study of 

531 Lung Aspirates in Consecutive Patients With Community-Acquired Pneumonia, Am J Med., 

532 Apr, 106(4):385-90. 

533 

534 Silverman, JA, LI Mortin, AD Vanpraagh, T Li, and J Alder, 2005, Inhibition of Daptomycin by 

535 Pulmonary Surfactant: In Vitro Modeling and Clinical Impact, J Infect Dis, 191(12):2149-2152. 

536 

537 Singer, M, S Nambiar, T Valappil, K Higgins, and S Gitterman, 2008, Historical and Regulatory 

538 Perspectives on the Treatment Effect of Antibacterial Drugs for Community-Acquired 

539 Pneumonia, Clin Infect Dis, 47 (Suppl 3): S216-S224. 

540 

541 Talbot, GH, JH Powers, TR Fleming et al., 2012, Progress on Developing Endpoints for 

542 Registrational Clinical Trials of Community-Acquired Pneumonia and Acute Bacterial Skin and 

543 Skin Structure Infections: Update From the Biomarkers Consortium of the Foundation for the 

544 National Institutes of Health, Clin Infect Dis, 55:1114-1121. 

545 

546 Tessier, PR, MK Kim, W Zhou et al., 2002, Pharmacodynamic Assessment of Clarithromycin in 

547 a Murine Model of Pneumococcal Pneumonia, Antimicrob Agents Chemother, 46:1425-1434. 

548 

549 Toerner, JG, L Burke, S Komo, E Papadopoulos, 2012, A Collaborative Model for Endpoint 

550 Development for Acute Bacterial Skin and Skin Structure Infections and Community-Acquired 

551 Bacterial Pneumonia, Clin Infect Dis, 55:1122-1123. 

552 

553 Wilson, AT, AH Spreen, ML Cooper et al., 1939, Sulfapyridine in the Treatment of Pneumonia 

554 in Infancy and Childhood, JAMA, 112:1435-1439. 

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555 APPENDIX: 

556 NONINFERIORITY MARGIN JUSTIFICATION FOR CABP 

557 

558 Background 

559 

560 The selection of a noninferiority margin depends on a reliable estimate of the treatment effect of 

561 the active comparator (i.e., effect of the active comparator over placebo, referred to as M1), 

562 usually based upon placebo-controlled trials, that can be assumed to hold for the noninferiority 

563 trial. After M1 is established, clinical judgment determines how much of the estimated treatment 

564 effect (M1) should be preserved in determining a clinically acceptable noninferiority margin, 

565 referred to as M2. 

566 

567 Historical studies and clinical trials of antibacterial treatment of bacterial pneumonia provide 

568 evidence that antibacterial drugs have the following effects: 

569 

570  Achievement of a greater proportion of patients with favorable clinical responses at time 

571 points earlier in the course of antibacterial drug therapy (i.e., at day 3 to day 5) 

572 

573  Reduction of mortality in patients with pneumococcal or lobar pneumonia 

574 

575 An area of uncertainty in evaluating historical data is the spectrum of bacterial pathogens that 

576 cause CABP today. In most of the historical studies and historical-controlled clinical trials, 

577 CABP was considered synonymous with pneumococcal pneumonia because S. pneumoniae was 

578 regularly identified. A review of recently conducted trials showed that less than 20 percent of 

579 the total patient populations had documented S. pneumoniae (Higgins, Singer, et al. 2008). 

580 CABP is also caused by other pathogens such as H. influenzae, H. parainfluenzae, S. aureus, and 

581 M. catarrhalis, as well as atypical bacteria such as M. pneumoniae, C. pneumoniae, and 

582 Legionella species. Limited information is available on antibacterial treatment effect in CABP 

583 caused by M. pneumoniae (Kingston, Chanock, et al. 1961). A fundamental assumption is that 

584 historical response rates in infections such as S. pneumoniae CABP are relevant to response rates 

585 in modern infections with sensitive organisms. 

586 

587 We describe the steps taken to determine a noninferiority margin for two primary outcome 

588 measures: (1) an endpoint based on the outcome assessments of chest pain, frequency or severity 

589 of cough, amount of productive sputum, and difficulty breathing; and (2) all-cause mortality 

590 endpoint. 

591 

592 1. Endpoint Based on Clinical Outcome Assessments at Day 3 to Day 5 After Enrollment 

593 

594 Studies conducted around the time of the introduction of antibacterial drug therapy described 

595 clinical responses among untreated patients and patients treated with antibacterial drugs. These 

596 observational studies provide an estimate of the effect of antibacterial drugs on clinical response 

597 endpoints other than mortality. 

598 

599 Several papers described the clinical course of patients with pneumococcal pneumonia in a 

600 similar way; patients were recorded as having a successful clinical result by the demonstration of 

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601 fever resolution and accompanying improvement and resolution of other signs and symptoms of 

602 pneumonia. For example, a description in one of the papers stated, “This fall in temperature was 

603 in all cases accompanied by a conspicuous reduction in the pulse and respiratory rates, and the 

604 patients were improved subjectively” (Meakins and Hanson 1939). One study described the 

605 clinical course of 663 patients who did not receive antibacterial drug therapy (Bullowa 1937), 

606 while two other studies included patients who received antibacterial drug therapy. One study 

607 described the clinical course in 100 patients with pneumococcal pneumonia (Flippin, Lockwood, 

608 et al. 1939) and another study described the clinical course in 30 patients with pneumococcal 

609 pneumonia (Meakins and Hanson 1939). Figure A compares the three studies in the rates of 

610 clinical recovery, defined generally as the improvement in both clinical signs and symptoms. 

611 

612 Figure A. Rates of Clinical Recovery Recorded at Each Day 

Sample sizes: Bullowa: N = 663; Flippin: N = 100; Meakins: N = 30 

100% 

Recovery (%) 

90% 

80% 

70% 

60% 

50% 

40% 

30% 

20% 

10% 

0% 

Untreated (Bullowa) 

Sulfapyridine (Flippin) 

Sulfapyridine (Meakins) 

1 2 3 4 5 6 7 

Days 

613 

614 

615 The difference in clinical recovery rates between patients in the two treatment studies and 

616 patients in the study without treatment were 72 percent and 77 percent. 

617 

618 Figure B shows the rates of clinical recovery in an observational study of patients with 

619 pneumococcal pneumonia who received antibacterial drug therapy (sulfapyridine) and a group of 

620 patients who received no specific therapy. Clinical recovery was defined as “permanent drop in 

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621 oral temperature below 100°F, with subsidence of other symptoms of acute infection” (Finland, 

622 Spring, et al. 1940). Time points at 36 to 48 hours and 48 to 72 hours after therapy initiation 

623 demonstrate the greatest treatment effect of clinical recovery. The treatment difference is 

624 approximately 30 percent (95 percent confidence interval: 22 percent, 37 percent) at the 48- to 

625 72-hour time point. Clinical observations that were reported at any time after the 48- to 72-hour 

626 assessment are displayed as 72+ in Figure B. The time points after 72 hours (i.e., 72+) included 

627 recovery time points out to several weeks following therapy completion. 

628 

629 Figure B. Rates of Clinical Recovery of Acute Bacterial Pneumonia (Finland, Spring, et al. 

630 1940) 

90% 

Recovery (%) 

80% 

70% 

60% 

50% 

40% 

30% 

20% 

10% 

0% 

69% 

16% 

33% 

55% 

63% 

71% 

79% 

41% 

31% 

28% 

21% 

12% 

≤12 12--24 24--36 36--48 48--72 72+ 

Hours 

Sulfapyridine (N=225) 

No Therapy (N=472) 

631 

632 Another paper described the outcomes among pediatric patients with pneumococcal pneumonia 

633 and provides additional support for a treatment effect of antibacterial drugs relatively early in 

634 therapy. The mean time to clinical recovery was 4.7 days among patients who received 

635 antibacterial drug therapy while patients who did not receive antibacterial drug therapy had a 

636 mean time to clinical recovery of 8.9 days (Wilson, Spreen, et al. 1939). 

637 

638 The clinical response endpoints that were evaluated in each of these studies were not well 

639 defined. The studies evaluated both signs and symptoms together. A large treatment effect was 

640 observed at the early time point in the course of therapy (i.e., day 3 to day 5 after therapy 

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641 initiation) for an endpoint that included improvement in both signs and symptoms. The studies 

642 show that the treatment differences become smaller at times beyond day 3 to day 5 of therapy. 

643 Aspects that support the use of these studies as an estimate of M1 include the following: 

644 

645  The studies documented bacterial pneumonia, all as S. pneumoniae. 

646 

647  The estimate of the treatment difference appears to be large and is consistent across 

648 studies. 

649 

650  Some patients included in the no therapy group in Figure B were patients who had signs 

651 and symptoms of milder pneumonia. Even after the availability of antibacterial drugs, 

652 the clinician chose not to treat such patients with antibacterial drug therapy because of the 

653 likelihood of spontaneous recovery. The inclusion of patients more likely to experience 

654 spontaneous recovery of pneumonia in the no therapy group leads to an underestimate of 

655 the true treatment difference among patients with more serious disease. 

656 

657  The clinical response measurements are plausible consequences of treating an infection. 

658 

659 The limitations of these studies include the following: 

660 

661  The studies were not randomized 

662 

663  Historically controlled studies create a greater level of uncertainty in the estimate of 

664 treatment differences 

665 

666  The clinical response evaluations were not defined 

667 

668  The clinical response evaluations included improvement in both signs and symptoms 

669 together and did not separately evaluate improvement in chest pain, frequency or severity 

670 of cough, amount of productive sputum, and difficulty breathing 

671 

672 The treatment difference appears to be large for an endpoint based on clinical outcome 

673 assessments earlier in the course of therapy for CABP. However, the results are variable, 

674 ranging from the point estimate of 30 percent treatment difference at a 48- to 72-hour time point 

675 noted in Figure B to a point estimate of 77 percent treatment difference at day 3 noted in Figure 

676 A. 

677 

678 It is difficult to provide a precise numerical value for the treatment effect of a proposed primary 

679 endpoint of symptom improvement at day 3 to day 5. However, an M1 of at least 20 percent 

680 appears to be a reasonably appropriate and conservative estimate, accounting for the 

681 uncertainties with clinical recovery in the historical literature. A conservative estimate of M1 at 

682 20 percent is still large enough to support the selection of a noninferiority margin (M2) of 12.5 

683 percent for the endpoint of symptom improvement at day 3 to day 5. The selection of the 

684 noninferiority margin (M2) is a matter of clinical judgment and should be justified by the 

685 sponsor. 

686 

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687 2. All-Cause Mortality Endpoint 

688 

689 Table A provides an overview of the types of historical data used to support the identification of 

690 a treatment effect based on all-cause mortality. 

691 

692 Table A. Mortality in Observational Studies of Pneumococcal Pneumonia1 

Publication Population Mortality (%) 

Untreated 

(Study Years) 

Mortality (%) 

AntibacterialTreated 

(Study Years) 

Treatment Difference 

Untreated-Treated 

(95% Confidence 

Interval) 

Finland (1943)2 ≥ 12 years old 

bacteremic and 

nonbacteremic 

N=2,832 

(1929-1940)* 

41% 

N=1,220 

(1939-1941) 

17% (sulfonamides) 

24% (21%, 27%) 

Dowling and 

Lepper (1951)3 

≥ 10 years old 

bacteremic and 

nonbacteremic 

N=1,087 

(1939, 1940)* 

30.5% 

N=1,274 

(1938-1950) 

12.3% (sulfonamides) 

N=920 

(1938-1950) 

5.1% 

(penicillins and 

tetracyclines) 

18.2% (15%, 21%) 

25.4% (22%, 28%) 

Austrian and 

Gold (1964)4 

≥ 12 years old 

bacteremic 

N=17 

(1952-1962) 

82% 

N=437 

(1952-1962) 

17% 

65% (41%, 79%) 

693 1 Singer, Nambiar, et al. 2008 

694 2 Finland 1943 

695 3 Dowling and Lepper 1951 

696 4 Austrian and Gold 1964 

697 * Historical controls 

698 

699 The lower bounds of the 95 percent confidence interval for the treatment effect varied from 15 to 

700 41 percent in the observational studies in patients with pneumococcal pneumonia. Thus, a 

701 conservative estimate of M1 for the endpoint of all-cause mortality in a CABP trial is at least 15 

702 percent. 

703 

704 Summary 

705 

706 Based on data from historical studies and clinical trials, appropriate approaches to selecting 

707 noninferiority margins for CABP trials have been described. The available data support a 

708 noninferiority margin justification for two efficacy outcome assessments: 

709 

710 1. An endpoint based on symptom improvement at day 3 to day 5 compared to baseline 

711 

712 2. All-cause mortality endpoint 

20