Community-Acquired 
Bacterial Pneumonia:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2020 
Clinical/Antimicrobial 
 
 
   
Community-Acquired 
Bacterial Pneumonia:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD 20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2020 
Clinical/Antimicrobial 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  General Considerations ................................................................................................................. 2 
1. Nonclinical Development Considerations ....................................................................................... 2 
2. Drug Development Population ........................................................................................................ 2 
3. Efficacy Considerations ................................................................................................................... 2 
4. Safety Considerations ...................................................................................................................... 3 
B.  Specific Efficacy Trial Considerations ......................................................................................... 3 
1. Trial Design ..................................................................................................................................... 3 
2. Trial Population ............................................................................................................................... 3 
3. Entry Criteria ................................................................................................................................... 3 
a.  Clinical, radiographic, and microbiologic entry criteria ........................................................... 3 
b.  Exclusion criteria ...................................................................................................................... 4 
4. Randomization and Blinding ............................................................................................................ 4 
5. Specific Populations......................................................................................................................... 5 
6. Dose Selection .................................................................................................................................. 5 
7. Choice of Comparators, Prior Antibacterial Drug Use, and Concomitant Therapy ....................... 5 
8. Efficacy Endpoints ........................................................................................................................... 6 
a.  Primary endpoint ....................................................................................................................... 6 
b.  Secondary endpoints ................................................................................................................. 7 
c.  Intravenous and oral formulations ............................................................................................ 7 
9. Trial Procedures and Timing of Assessments .................................................................................. 8 
a.  Entry visit .................................................................................................................................. 8 
b.  On-therapy and end-of-therapy visits ....................................................................................... 8 
c.  After therapy visit ..................................................................................................................... 8 
10.  Statistical Considerations ............................................................................................................ 8 
a.  Analysis populations ................................................................................................................. 8 
b.  Noninferiority margins .............................................................................................................. 9 
c.  Sample size considerations ....................................................................................................... 9 
C.  Other Considerations ..................................................................................................................... 9 
1. Pharmacokinetic/Pharmacodynamic Evaluation ............................................................................ 9 
2. Labeling Considerations ................................................................................................................ 10 
REFERENCES ............................................................................................................................ 11 
APPENDIX:................................................................................................................................. 13 
  Contains Nonbinding Recommendations 
Community-Acquired Bacterial Pneumonia: 
Developing Drugs for Treatment 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page. 
 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
treatment of community-acquired bacterial pneumonia (CABP).  Specifically, this guidance 
addresses the FDAs current thinking about the overall development program and clinical trial 
designs for drugs to support an indication for the treatment of CABP.2 
 
This guidance does not discuss the general issues of statistical analysis or clinical trial design.  
Those topics are addressed in the ICH guidances for industry E9 Statistical Principles for 
Clinical Trials (September 1998) and E10 Choice of Control Group and Related Issues in 
Clinical Trials (May 2001), respectively.3 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
                                                 
1 This guidance has been prepared by the Division of Anti-Infectives 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 We update guidances periodically.  To make sure you have the most recent version of guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
1  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
CABP is defined as an acute bacterial infection of the pulmonary parenchyma associated with 
chest pain, cough, sputum production, difficulty breathing, chills, rigors, fever, or hypotension 
and is accompanied by the presence of a new lobar or multilobar infiltrate on a chest radiograph.  
Common typical bacterial pathogens that cause CABP include Streptococcus pneumoniae, 
Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. Atypical bacterial 
pathogens such as Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella 
pneumophila also cause CABP. 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Nonclinical Development Considerations 
 
In addition to the expected nonclinical toxicology/pharmacology studies (see Section III. C. 1, 
Pharmacokinetic/Pharmacodynamic Considerations), sponsors should provide nonclinical data 
from in vitro studies and in vivo animal studies demonstrating activity against one or more of the 
commonly implicated pathogens for CABP. 
 
2.  Drug Development Population 
 
The trial population should include individuals who have CABP, as defined in section II, 
Background. 
 
3.  Efficacy Considerations 
 
Noninferiority trials are acceptable to support an indication for the treatment of CABP.  A 
showing of superiority to an effective control would also be acceptable.  Historical data show 
that antibacterial drugs demonstrate a considerable treatment effect compared with 
nonantibacterial therapies on clinical response evaluated on day 4 of therapy. 
 
The Agency generally expects sponsors to conduct two adequate and well-controlled trials in 
CABP to establish substantial evidence of effectiveness.  Alternatively, a single adequate and 
well-controlled trial in CABP with confirmatory evidence (e.g., efficacy in another indication or 
data from a phase 2 clinical trial in CABP) can provide substantial evidence of effectiveness.  
Sponsors should discuss their proposed development program with the Agency, including the 
confirmatory evidence that would be used to support the efficacy findings from a single trial.4 
                                                 
4 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products (December 2019).  When final, this guidance will represent the FDAs current thinking on this 
topic.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
2  Contains Nonbinding Recommendations 
4.  Safety Considerations 
 
If the same or greater dose and treatment duration have been evaluated in other indications, 
safety data from these indications can be used to support safety for CABP.  Sponsors should 
discuss the appropriate size of the premarketing safety database with the Agency during 
development. 
 
B.  Specific Efficacy Trial Considerations 
 
1.  Trial Design 
 
CABP trials should be randomized, double-blind, and active-controlled using a noninferiority or 
superiority design.  See section III. B. 4, Randomization and Blinding, for additional discussion 
about double-blind trials.  Placebo-controlled trials are not appropriate for this indication except 
when they are add-on superiority trials in which patients receive either a placebo or an 
investigational drug added to standard-of-care antibacterial drug therapy. 
 
2.  Trial Population 
 
The trial population for efficacy trials should include patients with CABP based on the entry 
criteria described in section III. B. 3, Entry Criteria.  The FDA recommends that all patients in 
trials of an intravenously administered drug have a Pneumonia Patient Outcomes Research Team 
(PORT) classification of III or higher (Fine et al. 1997) and at least 25 percent should have a 
PORT classification of IV or V.  The reasons to exclude patients with a PORT II classification 
from trials for intravenously administered drugs include the milder severity of illness in general 
and the fact that patients with a PORT II classification are more likely to be treated appropriately 
with oral antibacterial drug therapy.  For trials in which most patients would be treated as 
outpatients, all patients should have PORT II or PORT III classifications, with at least 50 percent 
PORT III.  Sponsors should discuss the trial population with the Agency in advance of a phase 3 
trial. 
 
3.  Entry Criteria 
 
a.  Clinical, radiographic, and microbiologic entry criteria 
 
Sponsors should use radiographic evidence as well as the entry criteria outlined in Table 1 to 
select patients for enrollment in a CABP trial. 
 
Table 1.  Entry Criteria for a CABP Trial 
At Least Two  At Least Two Vital  At Least One Finding of Other Clinical 
Symptoms  Sign Abnormalities  Signs/Laboratory Abnormalities 
- Difficulty breathing  - Fever  - Hypoxemia  
- Cough  - Hypothermia  - Clinical evidence of pulmonary 
- Production of purulent  - Hypotension  consolidation 
sputum  - Tachycardia  - An elevated total white blood cell count or 
- Chest pain  - Tachypnea  leukopenia 
   
3  Contains Nonbinding Recommendations 
 
An adequate sputum specimen should be processed by a laboratory according to recognized 
methods for Gram stain, culture, and in vitro antibacterial susceptibility testing.5 
 
Use of rapid diagnostic or nonculture tests may help identify a patient for enrollment in a CABP 
trial (e.g., urinary antigen test for S. pneumoniae or L. pneumophila; polymerase chain reaction, 
serology).  If the tests being used are not FDA cleared, sponsors should provide sufficient 
information about the performance characteristics of the tests determined from analytical 
validation studies. 
 
The clinical trial of an antibacterial drug also may provide an opportunity to develop and 
evaluate a new diagnostic test.  Sponsors interested in using a clinical trial in patients with CABP 
as a means to also evaluate a diagnostic test are encouraged to discuss this with the Agency. 
 
b.  Exclusion criteria 
 
Exclusion criteria should include the following: 
 
  Aspiration pneumonia 
 
  Hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia 
 
  Patients with known bronchial obstruction or a history of postobstructive pneumonia (this 
criterion does not exclude patients who have chronic obstructive pulmonary disease) 
 
  Patients with primary or metastatic lung cancer 
 
  Patients with cystic fibrosis, known or suspected Pneumocystis jiroveci pneumonia, or 
known or suspected active tuberculosis 
 
4.  Randomization and Blinding 
 
Patients should be randomized to treatment groups at enrollment.  All trials should be double-
blind unless there is a compelling reason for not blinding treatment allocation.  If trials are 
single-blind or open-label, sponsors should discuss potential biases with the Agency and how 
these biases will be addressed before initiating the trial. 
 
                                                 
5 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. 
 
4  Contains Nonbinding Recommendations 
5.  Specific Populations 
 
The trials should include patients of both sexes, patients of all races, and geriatric patients.6  
Patients with renal or hepatic impairment may be enrolled, provided pharmacokinetics of the 
drug has been evaluated in these patients and appropriate dosing regimens have been defined. 
 
Sponsors should discuss drug development in the pediatric populations as early as feasible.  The 
Pediatric Research Equity Act (PREA), as amended by the Food and Drug Administration Safety 
and Innovation Act, states that initial plans for conducting pediatric studies (referred to as an 
initial pediatric study plan) shall be submitted to the FDA before the date on which required 
pediatric assessments are submitted under PREA and no later than (1) 60 days after the end-of-
phase 2 meeting or (2) such other time as may be agreed upon by the FDA and the applicant.7 
 
6.  Dose Selection 
 
To choose the dose or doses to be evaluated in phase 3 clinical trials, sponsors should integrate 
the findings from nonclinical toxicology studies; animal models of infection; pharmacokinetics, 
safety, and tolerability information from phase 1 clinical trials; and safety and efficacy 
information from phase 2 dose-ranging clinical trials.  Trials assessing drug penetration at the 
site of action (e.g., epithelial lining fluid) may be helpful in defining doses that achieve 
concentrations sufficient to exert an antibacterial effect. 
 
For products with both intravenous (IV) and oral formulations, sponsors should collect 
pharmacokinetic (PK) data in earlier phase studies to select the appropriate oral dose for the IV-
to-oral switch. 
 
7.  Choice of Comparators, Prior Antibacterial Drug Use, and Concomitant Therapy 
 
In general, the active comparator should be considered standard of care for this indication.  
When evaluating the current standard of care, the FDA considers recommendations by 
authoritative scientific bodies (e.g., American Thoracic Society, Infectious Diseases Society of 
America) that reflect current clinical practice based on clinical evidence and other reliable 
information. 
 
Ideally, patients enrolled in a CABP clinical trial should not have received antibacterial drug 
therapy for treatment of CABP before enrollment because such therapy could do the following: 
 
                                                 
6 See the ICH guidances for industry E7 Studies in Support of Special Populations:  Geriatrics (August 1994) and 
E7 Studies in Support of Special Populations:  Geriatrics; Questions and Answers (February 2012). 
 
7 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 (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 (March 2016).  When final, this guidance will represent the FDAs current 
thinking on this topic. 
5  Contains Nonbinding Recommendations 
  Obscure true treatment differences between an investigational drug and the control drug, 
introducing bias toward a finding of no difference between treatment groups (i.e., a bias 
toward noninferiority) (Pertel et al. 2008) 
 
  Particularly influence the efficacy findings based on an endpoint early in therapy (day 4) 
 
However, excluding all patients who have received prior antibacterial therapy also may pose 
problems, including the following: 
 
  Excluding patients with greater disease severity, which may result in a patient population 
with lesser severity of illness and greater potential for spontaneous recovery; this could 
bias trial results toward a finding of no difference between treatment groups (i.e., a bias 
toward noninferiority) 
 
  Certain trial sites may not participate because of concerns that trial treatment would not 
represent standard of care 
 
A pragmatic approach to these concerns is to (1) encourage prompt enrollment procedures so that 
patients can receive the clinical trial treatment as their initial therapy and (2) allow enrollment of 
some patients who have received a single dose of a short-acting antibacterial drug within 24 
hours of enrollment (ideally, there would be few such patients, but up to 25 percent of the patient 
population may be acceptable).  This approach would allow patients in the trial to receive prompt 
antibacterial drug therapy as clinically necessary, consistent with the standard of care.  A 
prespecified analysis of the efficacy results in the subgroup of patients (i.e., the majority of 
patients) who did not receive prior effective antibacterial drug therapy would be important to 
evaluate. 
 
In general, concomitant antibacterial therapy with an antimicrobial spectrum that overlaps with 
the spectrum of the investigational drug should not be administered during the trial.  Sponsors 
should discuss the additional antibacterial coverage for atypical pathogens with the FDA before 
initiating the trial. 
 
8.  Efficacy Endpoints 
 
a.  Primary endpoint 
 
The primary efficacy endpoint of clinical success should be defined as improvement at day 4 in 
at least two (with no worsening) of the following symptoms of CABP compared with baseline: 
chest pain, cough, amount of productive sputum, and difficulty breathing (Talbot et al. 2016).  
The protocol should specify symptom evaluations on a four-point scale (absent, mild, moderate, 
severe), defining improvement as at least a one-point improvement from baseline to the 
assessment at day 4 (e.g., from severe to moderate, from moderate to mild, or from mild to 
6  Contains Nonbinding Recommendations 
absent).8  The protocol should clearly describe the ascertainment of patients symptoms as 
improvement, no change, or worsening based on the four-point scale. 
 
Another efficacy endpoint can be all-cause mortality at 28 days after enrollment, but feasibility would be 
an issue in clinical trials in certain patient populations with a greater severity of CABP.  Sponsors 
considering using all-cause mortality as the primary efficacy endpoint should discuss the trial design with 
the Agency. 
 
b.  Secondary endpoints 
 
Following are some examples of secondary endpoints that could be evaluated: 
 
  Improvement at day 4 in at least two (with no worsening) of the following symptoms of 
CABP compared with baseline: chest pain, cough, amount of productive sputum, and 
difficulty breathing; and improvement in vital signs (i.e., body temperature, blood 
pressure, heart rate, and respiratory rate)9 
 
  Clinical outcome (i.e., improvement/resolution of symptoms of CABP) at the end of 
therapy) 
 
  Clinical outcome (i.e., resolution of symptoms of CABP) at a fixed time point after 
randomization and completion of therapy) 
 
c.  Intravenous and oral formulations 
 
For drugs available only as an IV formulation, sponsors should conduct trials with the IV 
formulation alone for the entire duration of therapy, if feasible, or at least until the day 4 
assessment is complete.  This will allow for the assessment of both the efficacy and the safety of 
the investigational drug before switching to an oral antibacterial drug.  Ideally, the duration of 
oral antibacterial drug therapy (i.e., days of IV therapy plus days of oral drug therapy) should be 
as short as possible so sponsors can assess the contribution of the IV investigational drug to 
overall efficacy after completion of treatment.  The criteria for switching to oral antibacterial 
drug therapy should be included in the protocol. 
 
For drugs that have both an IV and an oral formulation, the protocol should specify the criteria that 
allow for IV-to-oral switch. 
 
                                                 
8 The Appendix describes the historical treatment benefit of antibacterial therapy at 3 to 5 days following initiation 
of antibacterial drug therapy.  Day 4 was selected as the recommended timing of the primary efficacy endpoint to 
allow for clinical protocols to provide a window period for assessing the primary efficacy endpoint (i.e., a 24-hour 
window before and after day 4).  Sponsors should discuss with the Agency if a day 3 or a day 5 time point is being 
considered for the timing of the primary efficacy endpoint in the protocol.  See also Toerner et al. 2012.  For 
information about 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 (December 2009). 
 
9 Improvement or stabilization of vital signs and other signs attributable to CABP should be defined in the protocol.  
For example, see table 10 in Mandell et al. 2007. 
7  Contains Nonbinding Recommendations 
9.  Trial Procedures and Timing of Assessments 
 
a.  Entry visit 
 
Sponsors should collect baseline demographic and clinical information at the entry visit, in 
addition to microbiologic specimens and laboratory tests, as appropriate. 
 
b.  On-therapy and end-of-therapy visits 
 
The protocol should specify the evaluation of patients on therapy and at the end of therapy.  
These visits should capture patient symptoms, physical examination findings, assessments and 
resolution of adverse effects, if any, and appropriate laboratory tests. 
 
c.  After therapy visit 
 
The protocol should specify the evaluation of patients 5 to 10 days after completion of treatment.  
These visits, used to evaluated secondary endpoints, should capture patient symptoms, physical 
examination findings, assessments and resolution of adverse effects, if any, and appropriate 
laboratory tests.  The trial should assess all-cause mortality at day 28. 
 
10.  Statistical Considerations 
 
In general, sponsors should submit a detailed statistical analysis plan stating the trial hypotheses 
and the analysis methods before trial initiation. 
 
a.  Analysis populations 
 
The following definitions apply to various analysis populations in CABP clinical trials: 
 
  Safety population  All patients who received at least one dose of drug during the trial. 
 
  Intent-to-treat (ITT) population  All patients who were randomized. 
 
  Microbiological-ITT (micro-ITT) population  All randomized patients who have a 
baseline bacterial pathogen that is known to cause CABP and that is susceptible to the 
investigational drug and the active control, from an appropriate sputum specimen or 
blood. 
 
  Clinically evaluable or per-protocol populations  Patients who meet the definition for 
the ITT population and who complete the trial as specified in the protocol. 
 
  Microbiologically evaluable populations  Patients who meet the definition for the 
micro-ITT population and who complete the trial as specified in the protocol. 
 
Sponsors should discuss with the Agency the prespecified primary analysis population before 
initiating the trial.  In general, it is acceptable to consider the ITT population as the primary 
8  Contains Nonbinding Recommendations 
analysis population.  For antibacterial drugs with a narrow spectrum of activity (e.g., a drug 
active against a single genus and species of bacteria), the micro-ITT population will be 
considered the primary analysis population. 
 
b.  Noninferiority margins 
 
Historical experience indicates that there is a relatively large treatment effect of antibacterial 
drug therapy on clinical response at day 4 (see the Appendix).  In general, the selection of a 
noninferiority margin of 12.5 percent is reasonable for CABP clinical trials using a clinical 
response endpoint at day 4.  In certain circumstances, sponsors may consider a noninferiority 
margin greater than 12.5 percent.  Sponsors should discuss with the Agency a clinically 
appropriate noninferiority margin before initiating the trial. 
 
c.  Sample size considerations 
 
A general framework is provided for sponsors to begin to discuss sample size considerations 
with the Agency during protocol development.  In this illustrative sample size calculation, 
approximately 225 patients per group is estimated based on the following assumptions: (1) a rate 
of clinical success for the active control and test therapy of 80 percent, (2) two-sided type I error 
() of 0.05, (3) type II error () of 0.10 (power 0.90), (4) a noninferiority margin of 12.5 percent 
(see the Appendix), and (5) an ITT analysis population. 
 
C.  Other Considerations 
 
1.  Pharmacokinetic/Pharmacodynamic Evaluation 
 
Sponsors should evaluate the PK/pharmacodynamic (PD) characteristics of the drug using in 
vitro methods and animal models of infection.  Sponsors should also consider the limitations of 
such models before evaluating the antibacterial drug (Tessier et al. 2002; Gavalda et al. 1997; 
Legget 1999; Miyazaki et al. 1997; Silverman et al. 2005). 
 
Integration of these PK/PD characteristics of the drug with the findings from phase 1 clinical 
trials can assist identification of appropriate dosing regimens for evaluation in phase 2 and phase 
3 clinical trials.10 
 
Sponsors should obtain blood samples from patients in phase 2 and phase 3 clinical trials (sparse 
sampling) to estimate drug exposure in each patient.  Sponsors should perform an exposure-
response analysis for clinical outcomes, microbiologic outcomes, and clinically relevant adverse 
events.  If phase 3 trials include a previously unstudied specific population, such as patients with 
renal or hepatic impairment, collecting plasma drug concentrations from those specific 
populations can aid in determining necessary dose adjustments. 
 
                                                 
10 See the guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory 
Applications (April 2003) and the ICH guidance for industry E4 Dose-Response Information to Support Drug 
Registration (November 1994). 
9  Contains Nonbinding Recommendations 
2.  Labeling Considerations 
 
Generally, the labeled indication should be the treatment of CABP caused by the specific 
bacteria identified in the clinical trials. 
10  Contains Nonbinding Recommendations 
1  REFERENCES 
2   
3  Austrian, R and J Gold, 1964, Pneumococcal Bacteremia With Especial Reference to Bacteremic 
4  Pneumococcal Pneumonia, Ann Intern Med, 60:759776. 
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6  Bullowa, JGW, 1937, The Course, Symptoms and Physical Findings, In:  Bullowa JGW, editor, 
7  The Management of Pneumonias, Oxford University Press; New York. 
8   
9  Dowling, HG and MH Lepper, 1951, The Effect of Antibiotics (Penicillin, Aureomycin, and 
10  Terramycin) on the Fatality Rate and Incidence of Complications in Pneumococcic Pneumonia:  
11  A Comparison With Other Methods of Therapy, AM J Med Sci, 222(4):396403. 
12   
13  Fine, MJ, TE Auble, DM Yealy, BH Hanusa, LA Weissfeld, DE Singer, CM Coley, TJ Marrie, 
14  and WN Kapoor, 1997, A Prediction Rule to Identify Low-Risk Patients With Community-
15  Acquired Pneumonia, N Engl J Med, 336:243250. 
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17  Finland, M, 1943, Chemotherapy in the Bacteremia, Conn State Med J, 7:92100. 
18   
19  Finland, M, WC Spring Jr., and FC Lowell, 1940, Specific Treatment of the Pneumococcic 
20  Pneumonias; An Analysis of the Results of Serum Therapy and Chemotherapy at the Boston City 
21  Hospital From July 1938 Through June 1939, Annals of Internal Medicine, 13:15671593. 
22   
23  Flippin, HF, JS Lockwood, DS Pepper, and L Schwartz, 1939, The Treatment of Pneumococcic 
24  Pneumonia With Sulfapyridine: A Progress Report on Observations in 100 Cases, JAMA, 
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26   
27  Gavalda, J, JA Capdevila, B Almirante, J Otero, I Ruiz, M Laguarda, H Allende, E Crespo, C 
28  Pigrau, and A Pahissa, 1997, Treatment of Experimental Pneumonia due to Penicillin-Resistant 
29  Streptococcus Pneumoniae in Immunocompetent Rats, Antimicrob Agents Chemother, 
30  41(4):795801. 
31   
32  Higgins, K, M Singer, T Valappil, S Nambiar, D Lin, and E Cox, 2008, Overview of Recent 
33  Studies of Community-Acquired Pneumonia, Clin Infect Dis, 47 (Suppl 3) S150S156. 
34   
35  Kingston, JR, RM Chanock, MA Mufson, LP Hellman, WD James, HH Fox, MA Manko, and J 
36  Boyers, 1961, Eaton Agent Pneumonia, JAMA, 176(2):118123. 
37   
38  Legget, J, 1999, Murine Models of Pneumonia Using Aerosol Infection, In:  Zak O, Sande MA, 
39  eds., Handbook of Animal Models of Infections:  San Diego, Academic Press, 533538. 
40   
41  Mandell, LA, RG Wunderink, A Anzueto, JG Bartlett, GD Campbell, NC Dean, SF Dowell, TM 
42  File, Jr., DM Musher, MS Niederman, A Torres, and CG Whitney, 2007, Infectious Diseases 
43  Society of America/American Thoracic Society Consensus Guidelines on the Management of 
44  Community-Acquired Pneumonia in Adults, Clin Infect Dis, 44:S27S72. 
45   
11  Contains Nonbinding Recommendations 
46  Meakins, JC and FR Hanson, 1939, The Treatment of Pneumoccic Pneumonia With 
47  Sulfapyridine, The Canadian Medical Association Journal, April, 333336. 
48   
49  Miyazaki, S, T Nunoya, T Matsumoto, K Tateda, and K Yamaguchi, 1997, New Murine Model 
50  of Bronchopneumonia Due to Cell-Bound Haemophilus Influenzae, J Infect Dis, 175(1):205
51  209. 
52   
53  Pertel, PE, P Bernardo, C Fogarty, P Matthews, R Northland, M Benvenuto, GM Thorne, SA 
54  Luperchio, RD Arbeit, and J Alder, 2008, Effects of Prior Effective Therapy on the Efficacy of 
55  Daptomycin and Ceftriaxone for the Treatment of Community-Acquired Pneumonia, Clin Infect 
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58  Silverman, JA, LI Mortin, AD VanPraagh, T Li, and J Alder, 2005, Inhibition of Daptomycin by 
59  Pulmonary Surfactant:  In Vitro Modeling and Clinical Impact, J Infect Dis, 191(12):21492152. 
60   
61  Talbot, GH, JH Powers, and SC Hoffmann, 2016, Developing Outcomes Assessments as 
62  Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the 
63  Biomarkers Consortium of the Foundation for the National Institutes of Health; Clin Infect Dis. 
64  62 (5): 603607. 
65   
66  Tessier, PR, M-K Kim, W Zhou, D Xuan, C Li, M Ye, CH Nightingale, and DP Nicolau, 2002, 
67  Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal 
68  Pneumonia, Antimicrob Agents Chemother, 46(5):14251434. 
69   
70  Toerner, JG, L Burke, S Komo, and E Papadopoulos, 2012, A Collaborative Model for Endpoint 
71  Development for Acute Bacterial Skin and Skin Structure Infections and Community-Acquired 
72  Bacterial Pneumonia, Clin Infect Dis, 55(8):11221123. 
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74  Wilson, AT, AH Spreen, ML Cooper, FE Stevenson, GE Cullen, and AG Mitchell, 1939, 
75  Sulfapyridine in the Treatment of Pneumonia in Infancy and Childhood, JAMA, 112(15):1435
76  1439. 
12  Contains Nonbinding Recommendations 
77  APPENDIX: 
78  NONINFERIORITY MARGIN JUSTIFICATION FOR CABP 
79   
80  Background 
81   
82  Selecting a noninferiority margin depends on a reliable estimate of the treatment effect of the 
83  active comparator (i.e., effect of the active comparator over placebo, referred to as M ), usually 
1
84  based upon placebo-controlled trials, that can be assumed to hold for the noninferiority trial.  
85  After M  is established, clinical judgment determines how much of the estimated treatment effect 
1
86  (M ) should be preserved in determining a clinically acceptable noninferiority margin, referred to 
1
87  as M . 
2
88   
89  Historical studies and clinical trials of antibacterial drug therapy for bacterial pneumonia provide 
90  evidence that antibacterial drugs have the following treatment effects: 
91   
92    Achieving a greater proportion of patients with favorable clinical responses at time points 
93  earlier in the course of antibacterial drug therapy (i.e., at day 3 to day 5) 
94   
95    Reducing mortality in patients with pneumococcal or lobar pneumonia 
96   
97  An area of uncertainty in evaluating historical data is the spectrum of bacterial pathogens that 
98  cause community-acquired bacterial pneumonia (CABP) today.  In most of the historical studies 
99  and historical controlled clinical trials, CABP was considered synonymous with pneumococcal 
100  pneumonia because Streptococcus pneumoniae was regularly identified.  A review of recently 
101  conducted trials showed that less than 20 percent of the total patient populations had documented 
102  S. pneumoniae (Higgins et al. 2008).  CABP is also caused by other pathogens such as 
103  Haemophilus influenzae, Haemophilus parainfluenzae, Staphylococcus aureus, and Moraxella 
104  catarrhalis, as well as atypical bacteria such as Mycoplasma pneumoniae, Chlamydophila 
105  pneumoniae, and Legionella species.  Limited information is available on a treatment effect of 
106  antibacterial drugs in CABP caused by M. pneumoniae (Kingston et al. 1961).  A fundamental 
107  assumption is that historical response rates in infections such as S. pneumoniae CABP are 
108  relevant to response rates in modern infections with sensitive organisms. 
109   
110  The steps taken to determine a noninferiority margin for the primary outcome measure based on 
111  the outcome assessments of chest pain, frequency or severity of cough, amount of productive 
112  sputum, and difficulty breathing at day 4 after enrollment is as follows: 
113   
114  Primary Endpoint Based on Clinical Outcome Assessments at Day 4 after Enrollment 
115   
116  Studies conducted around the time of the introduction of antibacterial drug therapy described 
117  clinical responses among untreated patients and patients treated with antibacterial drugs.  These 
118  observational studies provide an estimate of the effect of antibacterial drugs on clinical response 
119  endpoints other than mortality. 
120   
121  Several papers described the clinical course of patients with pneumococcal pneumonia in a 
122  similar way; patients were recorded as having a successful clinical result by demonstrating fever 
13  Contains Nonbinding Recommendations 
123  resolution and accompanying improvement and resolution of other signs and symptoms of 
124  pneumonia.  For example, a description in one of the papers stated, This fall in temperature was 
125  in all cases accompanied by a conspicuous reduction in the pulse and respiratory rates, and the 
126  patients were improved subjectively (Meakins and Hanson 1939).  One study described the 
127  clinical course of 663 patients who did not receive antibacterial drug therapy (Bullowa 1937), 
128  whereas two other studies included patients who received antibacterial drug therapy.  One study 
129  described the clinical course over the first 4 days after therapy in 100 patients with 
130  pneumococcal pneumonia (Flippin et al. 1939) and another study described the clinical course 
131  over 7 days in 30 patients with pneumococcal pneumonia (Meakins and Hanson 1939).  Figure 1 
132  compares the three studies in the rates of clinical recovery, defined generally as the improvement 
133  in both clinical signs and symptoms. 
134   
135  Figure 1.  Rates of Clinical Recovery Recorded at Each Day (Meakins and Hanson 1939; 
136  Bullowa 1937; Flippin et al. 1939) 
Sample sizes:  Bullowa: N = 663; Flippin: N = 100; Meakins: N = 30 
100%
Untreated (Bullowa)
90% Sulfapyridine (Flippin) 
Sulfapyridine (Meakins) 
80%
70%
60%
%)
y (
r
e 50%
v
o
c
e
R
40%
30%
20%
10%
0%
1 2 3 4 5 6 7
Days
137   
138  The difference in clinical recovery rates at day 4 between patients in the two treatment studies 
139  and patients in the study without treatment were 72 percent and 77 percent. 
140   
141  Figure 2 shows the rates of clinical recovery in an observational study of patients with 
142  pneumococcal pneumonia who received antibacterial drug therapy (sulfapyridine) and a group of 
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143  patients who received no specific therapy.  Clinical recovery was defined as a permanent drop 
144  in oral temperature below 100F, with subsidence of other symptoms of acute infection 
145  (Finland et al. 1940).  Time points at 36 to 48 hours and 48 to 72 hours after therapy initiation 
146  show the greatest treatment effect on clinical recovery.  The treatment difference is 
147  approximately 30 percent (95 percent confidence interval:  22 percent, 37 percent) at the 48- to 
148  72-hour time point.  Clinical observations that were reported at any time after the 48- to 72-hour 
149  assessment are displayed as 72+ in Figure 2.  The time points after 72 hours (i.e., 72+) included 
150  recovery time points out to several weeks following therapy completion. 
151   
152  Figure 2.  Rates of Clinical Recovery of Acute Bacterial Pneumonia (Finland et al. 1940)  
90%
79%
80% Sulfapyridine (N=225)
No Therapy (N=472)
71%
70%
69%
63%
60%
55%
%)
( 50%
y 
r
e
v
o
c
e 40%
R 33% 41%
30% 31%
28%
20% 16% 21%
10% 12%
0%
12 12--24 24--36 36--48 48--72 72+
Hours
153   
154  Another paper described the outcomes among pediatric patients with pneumococcal pneumonia 
155  and provides additional support for a treatment effect of antibacterial drugs relatively early in 
156  therapy.  The mean time to clinical recovery was 4.7 days among patients who received 
157  antibacterial drug therapy whereas patients who did not receive antibacterial drug therapy had a 
158  mean time to clinical recovery of 8.9 days (Wilson et al. 1939). 
159   
160  The clinical response endpoints that were evaluated in each of these studies were not well 
161  defined.  The studies evaluated both signs and symptoms together.  A large treatment effect was 
162  observed at the early time point in the course of therapy (i.e., day 3 to day 5 after therapy 
15  Contains Nonbinding Recommendations 
163  initiation) for an endpoint that included improvement in both signs and symptoms.  The studies 
164  show that the treatment differences become smaller at times beyond day 3 to day 5 of therapy.  
165  Features of these studies that support their use as an estimate of M  at day 4 include the 
1
166  following: 
167   
168    The studies documented bacterial pneumonia, all as S. pneumoniae. 
169   
170    The estimate of the treatment difference appears to be large and is consistent across 
171  studies. 
172   
173    Some patients included in the no therapy group in Figure 2 were patients who had signs 
174  and symptoms of milder pneumonia.  Even after the availability of antibacterial drugs, 
175  the clinician chose not to treat such patients with antibacterial drug therapy because of the 
176  likelihood of spontaneous recovery.  Including patients more likely to experience 
177  spontaneous recovery of pneumonia in the no-therapy group led to an underestimate of 
178  the true treatment difference among patients with more serious disease. 
179   
180    The clinical response measurements are plausible consequences of treating an infection. 
181   
182  The limitations of these studies include the following: 
183   
184    The studies were not randomized 
185   
186    Historically controlled studies created a greater level of uncertainty in estimating 
187  treatment differences 
188   
189    The clinical response evaluations were not defined 
190   
191    The clinical response evaluations included improvement in both signs and symptoms 
192  together and did not separately evaluate improvement in chest pain, frequency or severity 
193  of cough, amount of productive sputum, and difficulty breathing 
194   
195  The treatment difference appears to be large for an endpoint based on clinical outcome 
196  assessments earlier in the course of therapy for CABP.  However, the results are variable, 
197  ranging from the point estimate of 30 percent treatment difference at a 48- to 72-hour time point 
198  noted in Figure 2 to a point estimate of 77 percent treatment difference at day 3 noted in Figure 
199  1. 
200   
201  It is difficult to provide a precise numerical value for the treatment effect of a proposed primary 
202  endpoint of symptom improvement at day 3 to day 5.  However, an M  of at least 20 percent 
1
203  appears to be a reasonably appropriate and conservative estimate, accounting for the 
204  uncertainties with clinical recovery in the historical literature.  A conservative estimate of M  at 
1
205  20 percent is still large enough to support selecting a noninferiority margin (M ) of 12.5 percent 
2
206  for the endpoint of symptom improvement at day 4.  Selecting the noninferiority margin (M ) is 
2
207  a matter of clinical judgment and should be justified by the sponsor. 
208   
16  Contains Nonbinding Recommendations 
209  The Agency also evaluated the literature from just before and just after the introduction of 
210  antibacterial drug therapy in the mid-twentieth century (Finland 1943; Dowling and Lepper 
211  1951; Austrian and Gold 1964).  The Agency found support for a treatment effect of antibacterial 
212  drug therapy on the endpoint of all-cause mortality. 
213   
214  Summary 
215   
216  The available data provide a basis for a noninferiority margin specification for primary efficacy 
217  outcome assessments based on symptom improvement at day 4 compared with baseline. 
17