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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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 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, at 301-796-

1400. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2009 

Clinical Antimicrobial 

Revision 1 

I:\8610dft.doc 

03/10/09
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 

E-mail: druginfo@fda.hhs.gov 

Fax: 301-847-8714 

(Tel) 301-796-3400 

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

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2009 

Clinical Antimicrobial 

Revision 1 
TABLE OF CONTENTS 

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

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

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

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

1. Definition of CABP...........................................................................................................................3

2. Drug Development Population.........................................................................................................4

3. Pharmacokinetic and Pharmacodynamic Considerations ...............................................................4

4. Dose Selection ..................................................................................................................................5

5. Efficacy Considerations ...................................................................................................................6

6. Safety Considerations.......................................................................................................................7

B. Specific Efficacy Trial Considerations .........................................................................................7

1. Trial Design......................................................................................................................................7

2. Trial Population ...............................................................................................................................7

3. Inclusion and Exclusion Criteria......................................................................................................7

a. Clinical, radiographic, and microbiologic criteria.....................................................................7

b. Exclusion criteria ....................................................................................................................10

4. Randomization, Stratification, and Blinding..................................................................................10

5. Special Populations........................................................................................................................11

6. Choice of Comparators ..................................................................................................................11

7. Prior Antibacterial Drug Use.........................................................................................................11

8. Concomitant Medications...............................................................................................................11

9. Efficacy Endpoints..........................................................................................................................11

a. Primary endpoints ...................................................................................................................11

b. Secondary endpoints ...............................................................................................................12

c. Patient-reported outcome instruments.....................................................................................12

10. Trial Visits and Timing of Assessments .....................................................................................13

a. Entry visit ................................................................................................................................13

b. On-therapy visits.....................................................................................................................13

c. End-of-therapy visit.................................................................................................................14

d. Test-of-cure visit.....................................................................................................................14

e. Follow-up assessment .............................................................................................................15

11. Endpoint Adjudication...............................................................................................................15

12. Statistical Considerations..........................................................................................................15

a. Analysis populations ...............................................................................................................15

b. Noninferiority margins............................................................................................................16

c. Sample size..............................................................................................................................16

d. Missing data ............................................................................................................................17

e. Interim analyses and data monitoring committee....................................................................17

f. Other analyses of interest and secondary endpoints ................................................................17

g. Statistical analysis plan ...........................................................................................................17

13. Risk-Benefit Considerations ......................................................................................................18

C. Other Considerations...................................................................................................................18

1. Labeling Considerations ................................................................................................................18

2. Antimicrobial Resistance Claims ...................................................................................................18

APPENDIX: NONINFERIORITY MARGIN JUSTIFICATION FOR CABP................... 19 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

Guidance for Industry1 1 

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Community-Acquired Bacterial Pneumonia: 

Developing Drugs for Treatment 

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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. 

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

development program and clinical trial designs for drugs to support an indication for treatment of 

CABP.2

 This guidance is intended to serve as a focus for continued discussions among the 

Division of Anti-Infective and Ophthalmology Products and the Division of Special Pathogen 

and Transplant Products and pharmaceutical sponsors, the academic community, and the public.3 

This guidance revises the draft guidance for industry Community-Acquired Pneumonia — 

Developing Antimicrobial Drugs for Treatment published in 1998. Once final, this guidance will 

be considered the FDA’s current thinking regarding the development of drugs for the treatment 

of CABP. It also supersedes, with regard to the development of drugs to treat CABP, more 

general guidance issued many years ago (i.e., Clinical Evaluation of Anti-Infective Drugs 

(Systemic) and Clinical Development and Labeling of Anti-Infective Drug Products,

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 as well as 

1

 This guidance has been prepared by the Office of Antimicrobial Products in the Center for Drug Evaluation and 

Research (CDER) at the Food and Drug Administration. 

2

 For the purpose 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 divisions to discuss specific issues that 

arise during the development of antimicrobial drug products. 

4

 See http://www.fda.gov/cder/guidance/old047fn.pdf and http://www.fda.gov/cder/guidance/old043fn.pdf, 

respectively. 

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the joint FDA/Infectious Disease Society of America’s (IDSA’s) General Guidelines for the 

Clinical Evaluation of Anti-Infective Drug Products.

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) 

For the purpose of this guidance, we assume that the majority of hospitalized patients will be 

initially treated with intravenous (IV) antibacterials and ambulatory patients will be treated with 

oral antibacterial drugs. However, this does not preclude the enrollment of hospitalized patients 

in oral drug trials. Additionally, patients in IV antibacterial trials may need to be enrolled in an 

emergency room setting to preclude use of prior antibacterial therapies. 

This guidance does not address the development of drugs for other purposes or populations, such 

as treatment of patients with viral infections or atypical bacterial pathogens (e.g., Legionella 

pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae), hospital-acquired 

pneumonia, or ventilator-associated pneumonia. If sponsors wish to develop drugs with activity 

against these pathogens, they should discuss the trial designs with the FDA. As the science of 

this indication evolves and new information accumulates, this guidance may be revised. 

This guidance does not contain discussion of the general issues of clinical trial designs or 

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

Considerations for Clinical Trials and E9 Statistical Principles for Clinical Trials.

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 This 

guidance focuses on specific drug development and trial design issues that are unique to the 

study of CABP. 

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

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

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

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

recommended, but not required. 

II. BACKGROUND 

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. It is 

estimated that approximately one million episodes of CAP occur annually in adults 65 years of 

age and older in the United States. Overall mortality remains relatively high, ranging from 5.1 

percent for patients hospitalized or treated in an ambulatory setting to 36.5 percent for patients 

treated in an intensive care unit.7

 Common etiologic agents of CAP include Streptococcus 

pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and M. pneumoniae. Certain 

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 Beam, TR, DN Gilbert, and CM Kunin, 1992, General Guidelines for the Clinical Evaluation of Anti-Infective 

Drug Products, Infectious Disease Society of America and the Food and Drug Administration, Clin Infect Dis, Nov 

15 (Suppl 1): S5-S32. 

6

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

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

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 Fine, MJ, MA Smith, CA Carson, SS Mutha, SS Sankey, LA Weissfeld, and W Kapoor, 1996, Prognosis and 

Outcomes of Patients with Community-Acquired Pneumonia: A Meta-Analysis, JAMA, 275:134-141. 

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respiratory viruses, and atypical bacterial pathogens such as C. pneumoniae and L. pneumophila, 

also cause CAP. 

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

treatment of CAP in 1998, there have been public discussions regarding clinical trial designs to 

study CAP, including an FDA-IDSA workshop and a meeting of the Anti-Infective Drugs 

Advisory Committee.8

 These discussions have focused on clinical trial designs for CAP and 

other important issues such as the following: 

• Noninferiority versus superiority design 

• Justification of an appropriate noninferiority margin 

• Classification of severity of illness 

• Classification of CAP based on hospitalization (inpatient versus outpatient) 

• Enrollment criteria 

• Application of appropriate diagnostic criteria, including microbiologic diagnosis 

• Use of appropriate definitions of clinical outcomes 

• Timing of outcome assessments 

• Use of prior antibacterial drugs 

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

incorporated into the appropriate sections below. 

III. DEVELOPMENT PROGRAM 

A. General Considerations 

1. Definition of CABP 

The FDA’s previous clinical definition of CAP in an immunocompetent adult patient was an 

acute infection of the pulmonary parenchyma associated with at least some symptoms of acute 

infection and accompanied by the presence of an acute infiltrate on a chest radiograph or 

auscultatory findings consistent with pneumonia (such as altered breath sounds and/or localized 

rales). The patient should not have been hospitalized or resided in a long-term care facility for 

14 or more days before the onset of symptoms. 

To better identify individuals most likely to have bacterial pneumonia and hence benefit from 

antimicrobial therapy, this guidance defines CABP in an adult patient as an acute infection of the 

pulmonary parenchyma associated with symptoms such as fever or hypothermia, chills, rigors, 

cough, chest pain, or dyspnea, accompanied by the presence of a new lobar or multilobar 

infiltrate on a chest radiograph. 

8

 See http://www.fda.gov/ohrms/dockets/ac/cder08.html#AntiInfective. 

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113 2. Drug Development Population 

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The intended trial population should be patients 18 years of age and older with CABP. In 

addition to the clinical syndrome of bacterial pneumonia previously described, bacteriological 

confirmation of the etiologic agent (discussed later in this guidance) should be provided in at 

least 30 to 40 percent of enrolled patients. 

3. Pharmacokinetic and Pharmacodynamic Considerations 

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

activity against the most commonly implicated pathogens for CABP (i.e., S. pneumoniae, H. 

influenzae, S. aureus, and Moraxella catarrhalis). 

Evaluation of the pharmacokinetic and pharmacodynamic characteristics of an antibacterial drug 

being developed for CABP can provide useful data to inform dose selection and dosing regimens 

that should be evaluated in subsequent clinical trials. 

Investigation of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of an 

antibacterial drug can begin in nonclinical studies. Dose fractionation studies, often conducted 

in a thigh infection model, can be useful in determining the PK/PD index best associated with 

activity for a new antibacterial drug. There are also other models such as in vitro hollow-fiber 

models and in vivo animal infection models (other than the thigh infection model) that can be 

used to identify or explore the PK/PD index best associated with antibacterial effect as well as 

the magnitude of the PK/PD index necessary to achieve the desired endpoint. Ideally, animal 

models of infection exploring antibacterial drug activity should be conducted in neutropenic and 

immunocompetent mice to evaluate antibacterial drug effect in the setting of either a 

compromised or intact immune system. Information regarding the pharmacokinetics and lung 

distribution of the test drug in the species being studied is important in interpreting 

pharmacodynamic data derived from the animal model. 

In addition to thigh infection models, animal models of acute pneumonia have been developed in 

both mice and rats, particularly for S. pneumoniae infection for evaluation of antibacterial 

therapy.9,10 The majority of pneumonia models initiate infection by direct instillation into nares 

and/or trachea, but lung infection also has been initiated using an aerosolization procedure.11 

Reproducible invasive lung infections are more difficult to induce with organisms such as H. 

influenzae.

12 Differences in the effect of animal lung secretions versus human lung secretions on 

9

 Tessier, PR et al., 2002, Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal 

Pneumonia, Antimicrob Agents Chemother, 46:1425-1434. 

10 Gavalda, J et al., 1997, Treatment of Experimental Pneumonia due to Penicillin-Resistant Streptococcus 

pneumoniae in Immunocompetent Rats, Antimicrob Agents Chemother, 41:795-801. 

11 Legget, J, 1999, Murine Models of Pneumonia Using Aerosol Infection, In: Zak O, Sande MA, eds., Handbook of 

Animal Infections: San Diego, Academic Press, 533-538. 

12 Miyazaki, S et al., 1997, New Murine Model of Bronchopneumonia due to Cell-Bound Haemophilus influenzae, J 

Infect Dis, 175:205-209. 

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the activity of the antibacterial should be evaluated.13 Although animal models may contribute 

to providing early proof of concept in the treatment of CABP (or for comparing in vivo activity 

of different antimicrobials), the results should be carefully interpreted when used to help design 

subsequent human trials. Animal models also can be used to explore antimicrobial activity 

against resistant bacteria or specific bacterial serotypes that occur less commonly in clinical 

trials.

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14 Animal studies cannot, however, substitute for the clinical trials in patients with CABP 

that must be conducted to evaluate drug safety and efficacy because clinical studies can be 

conducted in patients with CABP.15 

The results of PK/PD assessments in animals should be integrated with the findings from phase 1 

pharmacokinetic studies to help identify the appropriate dosing regimens for evaluation in phase 

2 and phase 3 clinical trials. A dose-response trial design should be considered as it allows 

weighing the benefits and risks of various doses and can ensure that excessive doses (beyond 

those that add to efficacy) are not used, offering some protection against unexpected and 

unrecognized dose-related toxicity.16

Consideration should be given to obtaining blood samples from all patients in phase 2 and phase 

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

retrospective exposure-response analysis based on the population pharmacokinetic model should 

be performed to assess the relationship between exposure and observed clinical and 

microbiologic outcomes. The relationship between drug exposure and clinically relevant adverse 

events also should be explored to identify potential risks with different dosing regimens (if 

applicable) and specific patient populations. 

4. 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. Studies 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. In addition, the pharmacokinetics of the 

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

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

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

trials. 

13 Silverman, JA, LI Mortin, AD Vanpraagh, T Li, and J Alder, 2005, Inhibition of Daptomycin By Pulmonary 

Surfactant: In Vitro Modeling and Clinical Impact, J Infect Dis, 191:2149-2152. 

14 Bender, JM, K Ampofo, K Korgenski et al., 2008, Pneumococcal Necrotizing Pneumonia in Utah: Does Serotype 

Matter?, Clin Infect Dis, 46:1346-1352. 

15 21 CFR 314.600 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=314.600) 

16 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

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

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5. Efficacy Considerations 

Either noninferiority or superiority trial designs can be used for this indication, but we do not 

believe that placebo-controlled trials can be ethically conducted for this indication, because 

placebo-treated patients would be exposed to serious risks.17 The goal of CABP clinical trials 

should be to demonstrate an effect of antibacterial therapy on the clinical course of CABP caused 

by bacterial pathogens such as S. pneumoniae, H. influenzae, S. aureus, or M. catarrhalis. If 

sponsors wish to include additional organisms in clinical trials for this indication, they should 

provide data sufficient to substantiate the clinical relevance of the particular organism as a 

pathogen in CABP. Patients with risk factors for infection with drug-resistant organisms such 

as methicillin-resistant S. aureus can be enrolled if the spectrum of activity of both the 

investigational drug and comparator includes the specific organism. 

The number of clinical trials needed to support a CABP indication depends on the overall 

development plan for the drug under consideration. If the development plan for the drug has 

CABP as the sole indication, then it would be expected that two adequate and well-controlled 

trials would support effectiveness. If a drug is being developed for other respiratory infections, 

sponsors should discuss with the FDA whether other trials might lend support to a CABP 

indication. A trial in which most patients have documented bacterial pathogens (e.g., S. 

pneumoniae, H. influenzae, S. aureus, or M. catarrhalis) generally will provide the strongest 

evidence of efficacy. Although a documented bacterial etiology is important for all trial designs, 

it is particularly critical for noninferiority trials, because the noninferiority margin is based on 

the evidence from patients with microbiologically documented infections, primarily S. 

pneumoniae. Microbiological confirmation also permits analysis of treatment response by 

individual pathogen. 

For drugs that have only an IV formulation available, we recommend that sponsors conduct trials 

with the IV formulation alone, without switching to an oral antibacterial drug, to allow for proper 

assessment of both the efficacy and safety of the test drug. If two adequate and well-controlled 

trials are being conducted for the indication of CABP, it may be appropriate to allow oral switch 

in one of the trials, provided adequate safety data are available from other indications. If this 

approach is taken, the IV antibacterial should be administered for a minimum length of time 

(e.g., 72 to 96 hours) before switching to oral therapy. Objective criteria that allow for oral 

switch should be specified in the protocol and captured on the case report form. Clinical 

assessment should be performed at the time of IV to oral switch. 

For drugs that have both an IV and oral formulation, appropriate criteria that allow for IV to oral 

switch should be specified in the protocol. The pharmacokinetics of the oral formulation should 

have been adequately evaluated to ensure comparable exposure and to determine an appropriate 

dosing regimen. These criteria should be listed on the case report form. If practice patterns 

allow, it may be appropriate to enroll hospitalized CABP patients in oral antibacterial trials. 

17 See the ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials

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

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Currently, we do not recognize any surrogate markers as a substitute for clinical outcomes in 

CABP trials. Sponsors who wish to propose a surrogate marker for clinical outcome or the 

initial diagnosis of CABP should discuss this with the FDA early in the drug development 

process. 

6. Safety Considerations 

The protocol should specify the methods to be used to obtain safety data during the course of the 

trial. Both adverse event information and safety laboratory data should be collected. All patients 

should be evaluated for safety at the time of each visit or assessment, regardless of whether the 

test drug has been discontinued. All adverse events should be followed until resolution, even if 

time on trial would otherwise have been completed. 

A sufficient number of patients, including patients older than 65 years, should be studied at the 

dose and duration proposed for use to draw appropriate conclusions regarding drug safety. 

Safety evaluations and assessments should take into consideration the patient populations that are 

likely to be treated for CABP. Age- and sex-appropriate normal laboratory values should be 

included with clinical measurements when reporting laboratory data. Additional safety 

evaluations may be needed based on the nonclinical and clinical profile of the specific drug 

under investigation. Longer term assessment of adverse events after discontinuation or 

completion of the antimicrobial should be considered, depending on the specific drug’s potential 

for long-term or delayed adverse effects. 

B. Specific Efficacy Trial Considerations 

1. Trial Design 

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

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

2. Trial Population 

The trial population should include patients 18 years of age and older with CABP. The trials 

should enroll patients with either confirmed CABP or with a high likelihood of CABP. An 

adequate number of patients with bacteriologically confirmed infections should be enrolled to 

allow assessment of the drug’s effectiveness based upon the prespecified noninferiority margin, 

as described in section III.B.12., Statistical Considerations. 

3. Inclusion and Exclusion Criteria 

a. Clinical, radiographic, and microbiologic criteria 

The diagnosis of CABP should be based on the following clinical, radiographic, and 

microbiologic criteria. 

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273 • Clinical criteria. 

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− As part of the clinical picture of CABP, a patient should have at least three of the 

following symptoms and signs: 

 Cough with production of purulent sputum 

 Dyspnea or tachypnea 

 Chest pain 

 Fever, defined as body temperature greater than 38 degrees Celsius (100.4 

degrees Fahrenheit) taken orally, greater than 38.5 degrees Celsius (101.2 degrees 

Fahrenheit) tympanically, or greater than 39 degrees Celsius (102.2 degrees 

Fahrenheit) rectally; or hypothermia (less than 35 degrees Celsius)18

 Clinical findings of pulmonary consolidation (e.g., dullness on percussion, 

bronchial breath sounds, or egophony) 

− Additional criteria that may support the diagnosis of CABP but not needed for 

inclusion are as follows: 

 Chills or rigors 

 Hypoxemia with a PO2 < 60mm Hg while patient is breathing room air 

 An elevated total white blood cell count or leukopenia, or elevated immature 

neutrophils (bands) 

− We recommend using the Pneumonia Severity Index or Pneumonia Patient Outcomes 

Research Team (PORT) classification system for the purposes of enrollment and 

stratification.19 The criteria that are used to calculate the PORT score and determine 

the risk class for each patient should be included in the case report form and in the 

datasets. 

 IV antibacterials. All patients being enrolled in IV antibacterial trials should have 

PORT scores of II or greater. No more than 25 percent of the enrolled population 

should have a PORT score of II and at least 25 percent of the population should 

have PORT scores of IV or greater. 

18 Some patients develop hypothermia, especially the elderly and others who have risk factors such as alcoholism, 

malnutrition, and other comorbid illnesses. 

19 Fine, MJ, TE Auble, DM Yealy et al., 1997, A Prediction Rule to Identify Low-Risk Patients with CommunityAcquired Pneumonia, N Engl J Med, 336:243-50. 

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 Oral antibacterials. Patients being enrolled in oral antibacterial trials should have 

PORT scores of II or greater. At enrollment, at least 50 percent of these patients 

should have PORT scores of III or greater. 

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• Radiographic criteria. The chest radiograph should show the presence of new 

infiltrates in a lobar or multilobar distribution characteristic of bacterial pneumonia. The 

final full report of the pretreatment and subsequent chest radiograph by the radiologist 

should be included in the case report form. 

• Microbiologic criteria. At the time of enrollment, an adequate specimen of respiratory 

secretions should be obtained in all patients and sent to the laboratory for Gram stain, 

culture, and in vitro antibacterial susceptibility testing performed on appropriate 

organisms isolated from the specimen. Specimens should be processed according to 

recognized methods.20 Microscopic examination of Gram stained smears should be 

performed. Specimens that have fewer than 10 squamous epithelial cells and more than 

25 polymorphonuclear cells per low power field (100X magnification) are considered 

appropriate for inclusion in evaluation of respiratory culture results. Ten to twenty fields 

of the Gram stain smear also should be examined at 1000X magnification and the 

morphology of potential pathogens recorded. The Gram stain should be performed and 

the specimen plated for culture within 2 hours from the collection time, if the specimen is 

kept at room temperature. Alternatively, these tests can be performed within 24 hours of 

collection if the specimen is stored at 2 to 8 degrees Celsius before processing. 

The specimen of respiratory secretions can be obtained by any of the following means: 

− Deep expectoration 

− Endotracheal aspiration in intubated patients 

− Bronchoscopy with bronchoalveolar lavage or protected-brush sampling 

All isolates considered to be possible pathogens should be saved in the event that 

additional testing of an isolate is needed. For microbiological assessment, the 

investigator should collect the following information: 

− A description of how the sample was obtained, processed, and transported to the 

laboratory. 

− Identification of the bacterial isolate and serotype if S. pneumoniae. 

− In vitro susceptibility testing of the isolates to both the study drug and other 

antibacterials that may be used to treat CABP caused by the targeted pathogens. In 

vitro susceptibility should be performed by using standardized methods unless 

20 American Society for Microbiology, 2007, Manual of Clinical Microbiology, 9th edition. 

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otherwise justified.21 Sponsors should describe the exact methodology used for 

susceptibility testing if a standardized method was not used. 

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The following topics regarding detection of bacterial pathogens should be discussed with 

the FDA before trial initiation: 1) use of rapid diagnostic tests for bacterial pathogens 

(e.g., urinary antigen test for S. pneumoniae) or for respiratory viral pathogens; 2) 

microbiologic testing for bacterial pathogens associated with atypical pneumonia such as 

L. pneumophila, M. pneumoniae, or C. pneumoniae; and 3) use of biomarkers for 

detection of bacterial pathogens. 

b. Exclusion criteria 

Exclusion criteria include the following: 

• Atypical pneumonia 

• Viral pneumonia 

• Aspiration pneumonia 

• Hospital-acquired pneumonia, including ventilator-associated pneumonia 

• Receipt of prior antibacterials (see section III.B.7., Prior Antibacterial Drug Use) 

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

(this 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, Stratification, and Blinding 

Patients should be randomized to treatment groups at enrollment. All trials should be doubleblind unless there is a compelling reason for unblinding. 

We recommend stratification by age (e.g., younger than 50 years, 50 years of age or older) and 

PORT scores (as outlined for entry criteria in section III.B.3.a., Clinical, radiographic, and 

microbiologic criteria). 

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

Laboratory Standards Institute. 

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394 5. Special Populations 

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The trials should include patients 18 years of age and older, of both sexes, and all races. If 

sponsors wish to pursue CABP trials in pediatric patients, they should discuss the development 

plans with the FDA. Patients with renal or hepatic impairment can be enrolled provided 

pharmacokinetics of the drug have been evaluated in these patients and appropriate dosing 

regimens have been defined. 

6. Choice of Comparators 

Placebo-controlled trials are not appropriate for this indication. The active comparator should be 

an FDA-approved antibacterial that is considered standard of care for this indication (e.g., 

guidelines published by professional societies) at the recommended dosage. 

7. Prior Antibacterial Drug Use 

The use of prior antibacterial drugs effective against bacteria that cause CABP should be avoided 

in a noninferiority trial (except as described below) because such treatments will reduce the 

difference between treatment arms and allow an incorrect conclusion of noninferiority. 

However, patients who have received prior antibacterial therapy and who are considered clinical 

failures can be enrolled provided objective criteria for treatment failure are prespecified and 

documented on the case report form. Also, patients can be enrolled if they have received prior 

antibacterial therapy that lacks in vitro activity against the baseline pathogen. 

8. Concomitant Medications 

Concomitant antibacterial therapy for other infections should not be allowed during the trial until 

after the test-of-cure visit. Patients who receive such therapy should be excluded from the 

evaluable population and will be considered failures in the intent-to-treat (ITT) and the modified 

intent-to-treat (MITT) populations. Patients requiring rescue antibacterial therapy should be 

considered treatment failures and should be included in the ITT, MITT, and per-protocol 

populations. 

9. Efficacy Endpoints 

a. Primary endpoints 

The following primary endpoints can be considered for CABP trials. 

• Primary clinical outcome based on complete resolution of signs and symptoms 

measured at a fixed time point 

− Clinical success. A patient who is alive and has resolution of disease-specific signs 

and symptoms present at enrollment and who has no new symptoms or complications 

attributable to CABP is defined as a clinical success.22 

22 Some patients may have a prolonged cough despite resolution of other signs and symptoms of CABP. Such patients can be 

considered clinical successes provided they are not given additional antibacterials and are followed until resolution of the cough.

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− Clinical failure. Patients designated as clinical failures at an early time point should 

be designated as clinical failures for all subsequent follow-up visits. Clinical failure 

is defined as follows: 

 All-cause mortality within 30 days of start of study drug 

 Lack of resolution of baseline CABP-specific signs and symptoms at the test-ofcure visit 

 Progression or development of new symptoms or radiologic findings attributable 

to CABP at any time point after enrollment 

 Development of complications of CABP such as empyema or lung abscess 

 Need for rescue therapy with nonstudy antibacterial drugs 

• Primary clinical outcome based on time to resolution of signs and symptoms 

Currently, endpoints based on time to resolution of signs and symptoms are only 

applicable to superiority trials because an appropriate noninferiority margin has not been 

defined. If a patient-reported outcome (PRO) tool is used, its content validity and other 

measurement properties should be demonstrated in the population represented in the 

clinical trial. Relevant details regarding the planned trial design, analysis, and 

interpretation of the PRO findings should be discussed with the FDA before trial 

initiation. 

b. Secondary endpoints 

Sponsors can present secondary analyses on endpoints such as time to resolution of signs and 

symptoms (where the primary endpoint is complete resolution) or other endpoints of interest. 

Sponsors should be aware that analyses of secondary and additional endpoints usually will be 

considered exploratory, because trials usually are not designed to address the multiplicity 

questions raised by these analyses. It is possible, however, to identify in the statistical analysis 

plan particular analyses and subsets of interest when the trial is successful on its primary 

endpoint, and, using sequential approaches or multiplicity corrections, reach statistically valid 

conclusions on secondary endpoints. Analyses of secondary and additional endpoints is often 

most helpful for identifying areas for study in future trials. 

c. Patient-reported outcome instruments 

A PRO instrument can be used to measure patient symptoms and self-reported signs. If a PRO 

instrument is used for measuring responses that will be based on a scaled score, then the score 

rather than an endpoint of complete symptom resolution should be used as the outcome variable. 

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

and failure) at each time point if the criteria for the categories have been well-developed and 

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validated. If an alternative to a PRO is used, the method of assessment should be a well-defined 

and reliable method of assessing patient response. Any tool used to assess time to resolution of 

signs and symptoms should be discussed with the FDA before trial initiation. 

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Because no PRO instrument has been recognized by the FDA for this indication, exploratory 

testing of a well-developed PRO instrument in clinical trials may justify its use to support 

primary or secondary study objectives in subsequent trials. Development of the new instrument 

should begin well in advance of phase 3 clinical trials so that the instrument can be ready for 

incorporation into the phase 3 protocol. If the PRO tool is not developed for assessment of the 

primary endpoint, it may be appropriate to evaluate its use for assessment of secondary 

endpoints. 

For more information regarding the development of such outcome measures, see the draft 

guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 

Development to Support Labeling Claims.

23

10. Trial Visits and Timing of Assessments 

a. Entry visit 

At the entry visit, the following information should be captured and recorded on the case report 

form: 

• History and physical examination 

• Baseline signs and symptoms including vital signs 

• Chest X ray 

• PORT score criteria and calculation 

• Microbiologic specimens: adequate sputum specimens as determined by Gram stain (see 

section III.B.3.a., Clinical, radiographic, and microbiologic criteria), sputum culture, 

blood cultures, other rapid diagnostic tests 

• Laboratory tests: hematology, chemistry, and others as appropriate 

b. On-therapy visits 

Each patient should have on-therapy assessments of signs and symptoms. The frequency of 

these visits depends on whether the endpoint is assessed at a fixed time point or a time-toresolution endpoint is used. The ability to detect differences between study therapies for a timeto-resolution endpoint may be increased if assessments are done more often. These assessments 

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

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

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can be performed by the investigator during a visit to the investigator’s office or by a validated 

PRO instrument. Patients should be clinically evaluated by the investigator at a 48- to 72-hour 

visit to ensure that there is no clinical worsening at this time. 

Assigning clinical failure and permitting use of rescue antibacterial therapy should be reserved 

for patients who are worsening or not improving on their assigned treatment arm; specific criteria 

to initiate rescue therapy in these patients should be included in the protocol. Appropriate 

specimens for microbiologic evaluation should be obtained in these patients before instituting the 

new antibacterial therapy. It is important that investigators distinguish between patients who are 

worsening or not improving (i.e., where antibacterial rescue therapy is appropriate) from patients 

who are slow to improve but may still remain on assigned therapy and thereby achieve clinical 

success. In the case of clinical failure, therapy should be changed to an appropriate alternative 

antibacterial treatment for CABP, with other therapeutic modifications as necessary. Patients 

who receive rescue therapy should continue to have protocol-specified assessments identical to 

patients who continue to receive their originally assigned treatment and will be considered 

treatment failures in both complete resolution and time to resolution endpoints. 

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

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

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

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

the case report form. If a validated diary is used to capture patient symptoms during this trial, 

this information should also be recorded on the patient case report form. 

c. End-of-therapy visit 

Patients should be evaluated clinically at the end of the prescribed therapy. Laboratory 

assessments for safety should be performed at this visit. If the study drug needs to be continued 

beyond the protocol-specified duration, objective criteria for extending the therapy should be 

prespecified in the protocol. Patients without clinical improvement or with progression of signs 

and symptoms should be considered failures and alternative antibacterial rescue therapy should 

be provided. 

d. Test-of-cure visit 

The test-of-cure visit should occur after completion of study drug at a time when the drug is 

expected to have cleared from the infection site. The test-of-cure visit should occur at a fixed 

time point relative to randomization (5 to 10 days after completing therapy). If the treatment 

durations in the test and control arms are different, the timing should be based on the longest 

treatment duration. For drugs with long half-lives, sponsors should discuss the timing of the 

visits with the FDA during protocol development. At this visit, the investigator should obtain 

medical history including adverse events, perform physical examination, and obtain appropriate 

laboratory and radiological measurements. 

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571 e. Follow-up assessment 

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The follow-up assessment should occur approximately 1 to 2 weeks after the test-of-cure visit. 

This assessment can be performed by a telephone contact with patients who were considered to 

be clinical successes and had no adverse events noted at the test-of-cure visit. For patients with 

adverse events occurring at or after the test-of-cure visit, investigators should perform an 

assessment that includes a medical history, a physical examination, appropriate laboratory 

evaluations, and identification of any new adverse events. All adverse events should be followed 

to resolution. It is important that all patients are followed for at least 30 days after enrollment to 

capture the 30-day mortality data. 

11. Endpoint Adjudication 

Generally in CABP trials, there is no need for endpoint adjudication. If a sponsor believes that 

adjudication or endpoint assessment committee is necessary, this should be discussed with the 

FDA before trial initiation. 

12. Statistical Considerations 

The trial hypotheses and the analysis methods should be stated in the protocol and/or the 

statistical analysis plan, and should be finalized before trial initiation. Changes in statistical 

analysis plans made later may be appropriate if made entirely blindly; however, documenting 

unequivocal maintenance of the blind can prove difficult. The trials should be adequately 

powered to detect differences between treatment arms if differences exist. If sponsors choose to 

test multiple hypotheses, they should address issues related to the potential inflation of false 

positive results (overall type I error rate) because of multiple comparisons. These issues should 

be discussed with the FDA during protocol development, and if any subsequent changes are 

considered they should be discussed with the FDA before incorporation into the statistical 

analysis plan.24 

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. 

• ITT population — All patients who were randomized. 

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

population) — All randomized patients who have a baseline bacterial pathogen known to 

cause CABP against which the test drug has antibacterial activity. This includes bacterial 

pathogens identified in blood, appropriate sputum specimen, or other test such as urinary 

antigen test. Patients should not be excluded from this population based upon events that 

occur postrandomization (e.g., loss to follow-up). 

24 See ICH E9 and ICH E10 (http://www.fda.gov/cder/guidance/index.htm). 

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

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

protocol. 

• Microbiologically evaluable populations — Patients who meet the definition for the 

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

protocol. 

Generally, ITT analyses are preferred for superiority trials, although use of the MITT population 

may greatly increase the chance of demonstrating effectiveness by excluding patients who do not 

have the disease under study. Although the ITT population is usually the primary analysis in a 

difference-showing trial, the inherent bias toward the null in noninferiority trials poses a 

significant problem, and in this case ITT may not be the preferred analysis.25 Particularly where 

the noninferiority margin is based primarily on microbiologically defined patients, the MITT 

population is preferred. Moreover, for similar reasons, the microbiologically evaluable 

population should be strongly considered. In addition, consistency of results should be evaluated 

in the ITT and clinically evaluable populations. 

b. Noninferiority margins 

Based on a review of the historical data, we believe that noninferiority trials are appropriate for 

the CABP indication (see Appendix). This issue was discussed at the Anti-Infective Drugs 

Advisory Committee meeting in April 2008. The noninferiority margins can be justified based 

on historical evidence of the treatment effect of antibacterial therapy on mortality in patients with 

lobar or pneumococcal pneumonia. Sponsors should justify the noninferiority margin for the 

proposed trial design and population enrolled. In the final trial report, sponsors should address 

issues relating to the noninferiority margin as it applies to the trial population. 

For drugs with an IV formulation, the MITT population will be considered as the primary 

analysis population and a 15 percent noninferiority margin is appropriate. However, as outlined 

in section III.B.3., Inclusion and Exclusion Criteria, no more than 25 percent of patients enrolled 

should have PORT scores of II and a minimum of 25 percent of patients should have a PORT 

score of IV or greater. 

For drugs with only an oral formulation, the MITT population will be considered as the primary 

analysis population and a 10 percent noninferiority margin is appropriate. As outlined in section 

III.B.3., Inclusion and Exclusion Criteria, patients with a PORT score of I should be excluded 

and at least 50 percent of the population should have a PORT score of III or greater. 

c. Sample size 

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

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

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

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

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

expected to be superior (for a superiority trial). The appropriate sample size should be estimated 

using a two-sided α=0.05. 

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d. Missing data 

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

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

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

patients who remain in the trial in both measured and unmeasured ways. The method of how 

missing data will be handled should be specified in the protocol. Sponsors also should present 

sensitivity analyses such as including all missing patients as failures or including all missing 

patients as successes. Interpretation of trial results may be affected if the rates of missing data 

are different across treatment arms. 

e. Interim analyses and data monitoring committee 

If interim effectiveness analyses for success or futility will be performed, they should be 

prespecified in the protocol and in the analysis plan along with a justification. Details on the 

operating procedures also should be provided before trial initiation. The purpose of the interim 

analysis should be stated along with the appropriate statistical adjustment to control the overall 

type I error rate (if any). It is important that the interim analysis not affect trial conduct and 

thereby compromise trial results. This can be accomplished by creating an independent data 

monitoring committee (DMC). Such a committee also might be created if there were safety 

concerns about the drug or the treatment approach. If a DMC is used, a detailed charter with the 

composition of the committee members, decision rules, details on the measures taken to protect 

the integrity of the trial, and the standard operating procedures should be provided for review.26 

f. Other analyses of interest and secondary endpoints 

Sponsors can present secondary analyses on other endpoints of interest such as: 

• Mortality and clinical response in bacteremic versus nonbacteremic patients 

• Response at earlier time points or at the end of therapy 

• Response based on patient demographics such as age, geographic region, underlying 

renal impairment, and microbiologic etiology 

g. Statistical analysis plan 

Before initiation of any phase 3 CABP trial, sponsors should provide a detailed statistical 

analysis plan to the FDA. 

26 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 

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

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18 

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13. Risk-Benefit Considerations 

Risk-benefit considerations depend on the population being studied and the safety profile of the 

drug being investigated. 

C. Other Considerations 

1. Labeling Considerations 

The labeled indication will be community-acquired bacterial pneumonia caused by the specific 

bacteria identified in patients in the clinical trials and will reflect the patient population enrolled 

in the clinical trials. 

2. Antimicrobial Resistance Claims 

To obtain a claim for resistant pathogens in CABP, the claim should be relevant to CABP and 

sponsors should present data from their clinical trials to demonstrate treatment effect with the 

drug against resistant organisms. Sponsors seeking resistance claims for CABP are encouraged 

to contact the review division regarding appropriate trial designs for resistant pathogens and to 

discuss the desired resistance claims. 
Contains Nonbinding Recommendations 

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723 APPENDIX: NONINFERIORITY MARGIN JUSTIFICATION FOR CABP 

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Background 

Conceptually, the selection of a noninferiority margin is a two-step process. The first step 

involves reliable estimation of the treatment effect of the active comparator (i.e., effect of the 

active comparator over placebo, referred to as M1) based upon placebo-controlled trials. When 

data from placebo-controlled trials are not available, an alternative means to estimate treatment 

effect is to use available data from trials of treated versus untreated disease, remaining conscious 

of the risks of cross-study comparisons. All use of such historical estimates of treatment effect 

relies on the constancy assumption, the assumption that the past effect of the active control is the 

effect it will have in the contemporary noninferiority trial. For example, if the present effect is in 

doubt because of changes in ancillary therapy, it may be necessary to discount the historically 

based estimate of the control effect. The estimate of M1 includes any such discounting. The 

second step involves clinical judgment regarding how much of the estimated treatment effect 

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

to as M2. 

Because no data from placebo-controlled trials in CAP are available, we reviewed results from 

historical comparative clinical trials of treated versus untreated controls and from observational 

studies that evaluated mortality in patients treated with antibacterial drugs or with no specific 

therapy to estimate the treatment effect of antibacterial drugs in CAP. Based on review of these 

data, we believe that noninferiority trials are appropriate for the specific indication of CABP, as 

described in this guidance. Historical studies and clinical trials of antibacterial treatment of 

pneumonia provide evidence that antibacterial drugs reduced mortality in patients with 

pneumococcal or lobar pneumonia. Although the treatment effect varied across studies and 

clinical trials, the effect of treatment on survival was consistently greater in older patients (older 

than 50 years) and in patients with bacteremia. 

Direct extrapolation of treatment effect from historical studies and clinical trials to contemporary 

CABP clinical trials is difficult. The historical-controlled clinical trials lacked blinding and 

randomization as currently defined. There is also considerable uncertainty regarding the 

similarity of patient populations from historical studies and clinical trials to populations in 

current clinical trials. For example, patients today may have different comorbidities and risk 

factors for pneumonia, or may have received pneumococcal vaccine. Additionally, improved 

standards of medical care today may result in improved outcomes (e.g., care in an intensive care 

unit, mechanical ventilation, hemodynamic support). 

Another area of uncertainty in extrapolating the treatment effect of antibacterial drugs from 

historical studies and clinical trials is the spectrum of bacterial pathogens that cause CABP today 

in comparison to the early mid-twentieth century. In most of the historical studies and historicalcontrolled clinical trials, CAP was considered synonymous with pneumococcal pneumonia, 

whereas in recent CAP clinical trials, less than 20 percent of patients enrolled had documented S. 

pneumoniae.

27 Although S. pneumoniae remains the most common cause of CAP, we know that 

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

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

19 
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CAP also can be caused by other pathogens such as H. influenzae or parainfluenzae, S. aureus, 

and M. catarrhalis; atypical bacteria such as M. pneumoniae and C. pneumoniae; and Legionella

species, as well as respiratory viruses. Limited information is available on antibacterial 

treatment effect in CAP caused by M. pneumoniae, whereas for pathogens such as C. 

pneumoniae, the size of the treatment effect remains unknown. 

767 

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Most of the historical studies and clinical trials reported mortality as the clinical outcome. 

Mortality has not been used as a primary endpoint in recent CAP clinical trials, although it has 

been a part of the composite endpoint of clinical failure. For noninferiority trials, extrapolating 

quantitative estimates of treatment benefit from a mortality endpoint to a clinical failure endpoint 

raises questions regarding the applicability of the treatment effect for mortality to other outcome 

measures. In current clinical trials, patients who are not improving on therapy would be 

considered clinical failures, and alternative antibacterial treatment (i.e., rescue therapy) would be 

initiated before death occurs. The endpoint of clinical failure in a present-day clinical trial 

includes patients who would have progressed to death in a historical study or clinical trial, but it 

may include others who ultimately would not have died. Thus, it appears reasonable to include 

in current trials death, disease progression, and lack of clinical improvement as an appropriate 

endpoint that reasonably well reflects past effects on mortality. 

Although some of the historical studies and clinical trials attempted to grade severity of illness, 

descriptions of how severity was assessed were limited. The PORT score, which classifies 

patients by prognosis (risk of mortality) based on age and other criteria, is used for clinical 

decision making regarding hospitalization. Current treatment guidelines recommend 

hospitalization of patients who have a PORT score of III or greater.28 The PORT score is 

weighted heavily by age, and the majority of patients with PORT scores of III or greater will be 

over 50, have significant comorbidities, or have severe physiologic derangements upon 

presentation. 

Historical studies and trials 

798 Observational

799 

800 

801 

802 

803 

 

In several observational studies of pneumococcal pneumonia, a significant mortality benefit was 

shown among patients treated with antibacterial drugs compared to patients who received no 

specific therapy (untreated), as summarized in Table A1. 

28 Fine, MJ, TE Auble, DM Yealy, BH Hanusa, LA Weissfeld, DE Singer, CM Coley, TJ Marrie, and WN Kapoor, 

1997, A Prediction Rule to Identify Low-Risk Patients with Community-Acquired Pneumonia, N Engl J Med, 

336:243-50. 

20 
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Table A1. Mortality in Observational Studies of Pneumococcal Pneumonia1 804 

Publication Population Mortality (%) 

Untreated 

N 

(Study Years) 

Mortality (%) 

AntibacterialTreated 

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) 

18.5% (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) 

805 

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807 

808 

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810 

811 

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822 

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825 

826 

827 

828 

829 

830 

1

 Singer, M, S Nambiar, T Valappil, K Higgins, and S Gitterman, 2008, Historical and Regulatory Perspectives on the Treatment 

Effect of Antibacterial Drugs for Community-Acquired Pneumonia, Clin Infect Dis, 47 (Suppl 3): S216-S224. 2

 Finland, M, 1943, Chemotherapy in the Bacteremia, Conn State Med J, 7:92-100. 3

 Dowling, HG and MH Lepper, 1951, The Effect of Antibiotics (Penicillin, Aureomycin and Terramycin) on the Fatality Rate 

and Incidence of Complications in Pneumococcic Pneumonia: A Comparison with other Methods of Therapy, AM J Med Sci, 

222:396-402. 4

 Austrian, R and J Gold, 1964, Pneumococcal Bacteremia with Especial Reference to Bacteremic Pneumococcal Pneumonia, 

Ann Intern Med, 60:759-776. 

* Historical controls 

Despite the many limitations of these historical studies, such as observational study design and 

use of historical controls, the mortality benefit demonstrated with antibacterials was substantial. 

The lower limit of the 95 percent confidence interval (CI) for the treatment difference 

(antibacterials minus placebo) from the Finland study was 21 percent. In the Dowling and 

Lepper study, the lower limit of the 95 percent CI for the treatment difference (antibacterials 

minus placebo) was 15 and 22 percent for patients who received sulfonamides or penicillins and 

tetracyclines respectively; the latter group seems more likely to reflect the effect of modern 

antibacterial treatments. In the Austrian and Gold study, which only evaluated patients with 

bacteremic pneumococcal pneumonia, the lower limit of the 95 percent CI was 41 percent. In 

these studies of pneumococcal pneumonia, the mortality difference between antibacterial-treated 

and untreated groups was largest in patients older than 50 years, in patients treated with 

penicillin or tetracyclines rather than sulfonamides, and in patients with pneumococcal 

bacteremia. 

The mortality associated with pneumonia is greatest at the extremes of age. Persons over the age 

of 50 years exhibit the greatest mortality, and correspondingly antibacterial therapy has its 

21 
Contains Nonbinding Recommendations 

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831 

832 

833 

834 

835 

greatest effect in reducing mortality in these populations. This observation is apparent from 

looking at the data from Dowling and Lepper in patients with pneumococcal pneumonia, as 

shown in Table A2. 

Table A2. Mortality By Age from Dowling and Lepper (1951)1

Age 

(Years) 

Untreated Sulfa-Treated Penicillin, 

Tetracycline-Treated 

Serum-Treated 

N Deaths 

(%) 

N Deaths 

(%) 

N Deaths 

(%) 

N Deaths 

(%) 

10 to 49 725 139 

(19.2) 

988 79 (8.0) 684 18 (2.6) 710 74 (10.4) 

50 to > 

70 

362 192 

(53.0) 

286 78 (27.3) 236 20 (12.3) 179 76 (42.5) 

Total 1,087 331 

(30.5) 

1,274 157 

(12.3) 

920 47 (5.1) 889 150 (16.9) 

836 

837 

838 

839 

840 

841 

842 

843 

844 

845 

1

 Dowling, HG and MH Lepper, 1951, The Effect of Antibiotics (Penicillin, Aureomycin and Terramycin) on the 

Fatality Rate and Incidence of Complications in Pneumococcic Pneumonia: A Comparison with other Methods of 

Therapy, AM J Med Sci, 222:396-402. 

As shown in Table A3, an approximate doubling of the size of the treatment effect with 

antibacterial drugs is noted in patients older than 50 years compared to patients younger than 50 

years. 

Table A3. Treatment Difference By Age in Patients with Pneumococcal 

Pneumonia from Dowling and Lepper (1951)1

Treatment Age Treatment Difference 

(% Death Untreated-

% Death Treated) 

Sulfa < 50 11.2 (7.8, 14.5) 

≥ 50 25.8 (18.5, 33.1) 

Penicillin, tetracycline < 50 16.5 (13.4, 19.6) 

≥ 50 44.6 (38.3, 50.8) 

Serum < 50 8.7 (5.1, 12.4) 

≥ 50 10.6 (1.7, 19.5) 

846 

847 

848 

849 

1

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

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

Pneumonia: A Comparison with other Methods of Therapy, AM J Med Sci, 222:396-402. 

850 

851 

852 

853 

854 

855 

856 

857 

858 

859 

860 

Controlled trials

In the historical-controlled clinical trials in patients with lobar pneumonia, the point estimates for 

the treatment difference for mortality in patients treated with sulfapyridine or no specific therapy 

varied from 10 to 19 percent for all ages combined, as shown in Table A4. The CI for each of 

the trials (or subtrials) are wide, as the number of patients enrolled in most of these trials was 

small. A high proportion of the population in these trials was younger than 50 years of age, a 

group in which the treatment effect was smaller in the observational studies. The numbers of 

patients in these trials was not sufficient to provide informative estimates of the effect of age on 

mortality. 

22 
Contains Nonbinding Recommendations 

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Table A4. Mortality in Historical-Controlled Trials of Lobar Pneumonia1 861 

Publication Population Mortality (%) 

Untreated 

N 

Mortality (%) 

AntibacterialTreated 

Treatment 

Difference 

UntreatedTreated (95% 

Confidence 

Interval) 

Evans and 

Gaisford (1938)2

8-68 years old, 

86% < 50 years 

old; specific 

serotypes 

identified in 

22%, 

bacteriology in 

remainder not 

described 

27/100 (27%) 8/100 (8%) 19% (8.8, 29.2) 

Graham (1938)3 86% had 

pneumococcal 

pneumonia, 29% 

bacteremic, 70% 

< 50 years old 

7/30 (23%) 3/50 (6%) 17% (0.1-36.4) 

Agranat 

(Europeans 

substudy, 1938)4

97% < 50 years 

old, frequency of 

bacteremia not 

reported 

6/27 (22%) 2/22 (7%) 15% (-6.2, 35.5) 

Agranat (NonEuropeans 

substudy, 1938)4

81% < 50 years 

old, frequency of 

bacteremia not 

reported 

16/86 (19%) 6/71 (9%) 10% (-0.3, 20.6) 

862 

863 

864 

865 

866 

867 

868 

869 

870 

871 

872 

873 

874 

875 

876 

877 

878 

879 

880 

881 

882 

1

 Singer, M, S Nambiar, T Valappil, K Higgins, and S Gitterman, 2008, Historical and Regulatory Perspectives on the 

Treatment Effect of Antibacterial Drugs for Community-Acquired Pneumonia, Clin Infect Dis, 47 (Suppl 3): S216-

S224. 2

 Evans, GM and WF Gaisford, 1938, Treatment of Pneumonia with 2-(aminobenzenesulphonamido) pyridine, Lancet, 

2:14-19. 3

 Graham, D, WP Warner, JA Dauphinee, and RC Dickson, 1939, The Treatment of Pneumococcal Pneumonia with 

Dagenan (M. & B. 693), Can Med Assoc J, 40:325-332. 4

 Agranat, AL, AO Dreosti, and D Ordman, 1939, Treatment of Pneumonia with 2-( aminobenzenesulphonamido) 

pyridine (M. & B. 693), Lancet, 1:309-317. 

Estimation of M1 

The estimate of the treatment effect should take into consideration several sources of uncertainty 

while relying upon the data from previously conducted studies and clinical trials as discussed 

below: 

• The first source of uncertainty is the precision of the estimate of the treatment effect from 

the historical data. The 95 percent CIs have been used to estimate the range within which 

the true treatment effect is likely to fall. 

23 
Contains Nonbinding Recommendations 

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• The second source of uncertainty arises from the issue of whether the magnitude of the 

treatment effect that was observed in previously conducted studies and clinical trials will 

be different from that which would be seen in a future clinical trial (i.e., constancy 

assumption). 

883 

884 

885 

886 

887 

888 

889 

890 

891 

892 

893 

894 

895 

896 

897 

898 

899 

900 

901 

902 

903 

904 

905 

906 

907 

908 

909 

910 

911 

912 

913 

914 

915 

916 

917 

918 

919 

920 

921 

922 

923 

924 

925 

926 

927 

• The third source of uncertainty is type I error (concluding that the test drug is noninferior 

when it is not). The issue of type I error in a present-day CABP trial is controlled 

through choosing an alpha of two-sided 0.05 (i.e., one-sided 0.025) as a means to control 

for alpha error. 

Acknowledging the uncertainties inherent in the historical data, an estimate of the treatment 

effect from the observational studies, based on the lower bound of the 95 percent CI, is 22 

percent for penicillins and tetracycline in patients with pneumococcal pneumonia and 15 percent 

for sulfa drugs in treating pneumococcal pneumonia. For the three controlled trials, we 

performed a meta-analysis using a random effects model to control for intratrial variability. The 

point estimate for the treatment difference and the corresponding 95 percent CI was 15.1 percent 

(8.8 percent, 21.4 percent). Several factors should be considered in interpreting the lower bound 

of 8.8 percent derived from this meta-analysis when estimating the treatment effect for a presentday CABP trial with designs as described in this guidance. 

This estimate of the treatment effect may be an underestimate for the following reasons: 

• The vast majority (at least 70 percent) of patients in the controlled trials were younger 

than 50 years of age. Based on data from observational studies in pneumococcal 

pneumonia, it is evident that mortality increases with age and the treatment effect in 

patients 50 years of age and older is much larger than that seen in patients younger than 

50 years of age. The design for present-day CABP trials as described in this guidance 

will enroll patients with a set distribution of PORT scores and hence enroll an adequate 

number of patients 50 years of age or older. 

• All patients in the controlled trials were treated with oral sulfonamides, which were dosed 

sub-optimally in some patients in at least two of the trials in Table A2. In the 

observational studies of pneumococcal pneumonia, the treatment effect based on 

mortality was greater with penicillins than with sulfonamides (see Table A1). For a 

present-day CABP trial, the treatment effect is likely to be larger considering that more 

effective therapies and optimal dosage regimens are used in the clinical trials. 

• The treatment effect for an endpoint such as clinical failure would likely be larger than 

that seen with a mortality endpoint. It is reasonable to assume that some of the patients in 

present-day trials would progress to death in the absence of rescue therapy. If the 

definition of clinical failure (including death) were applied to a historically conducted 

study or clinical trial, the clinical failure endpoint would be at least as great as the 

observed mortality. Thus, the treatment effect based on mortality in historical studies or 

clinical trials can be extrapolated to a composite endpoint in a present-day trial that 

includes both mortality and clinical failure. It is important to note that any differential 

24 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

effect on mortality should be assessed independent of its inclusion in the composite 

endpoint. 

928 

929 

930 

931 

932 

933 

934 

935 

936 

937 

938 

939 

940 

941 

942 

943 

944 

945 

946 

947 

948 

949 

950 

951 

952 

953 

954 

955 

956 

957 

958 

959 

960 

961 

962 

963 

964 

965 

966 

967 

968 

 

This estimate of the treatment effect may be an overestimate for the following reasons: 

• Predominance of data in the historical studies and clinical trials was derived from patients 

with pneumococcal disease compared to the mixture of microbial etiologies that would 

likely be present in a present-day CABP trial. 

• Advances in supportive care such as mechanical ventilation, blood pressure support, and 

other intensive care interventions may reduce the mortality observed in a present-day trial 

compared to what was seen in the 1930s and 1940s. 

• The general health status of patients may be somewhat better in a present-day CABP 

trial. Factors such as improved nutritional status, use of pneumococcal vaccine, 

underlying comorbidities such as diabetes, or immunocompromise may affect the 

outcome of pneumococcal disease. 

Contemporary CAP clinical trials 

In a review of previously conducted clinical trials of oral antibacterial drugs for CAP the median 

and mean ages were 45 and 46 years of age, respectively.29 Ninety to ninety-five percent of 

patients in these CAP trials had PORT scores of I or II and 5 to 10 percent had a PORT score of 

III. In trials of intravenous drugs for CAP, enrolled patients were somewhat older with a mean 

age of 56 years; the corresponding PORT scores for these trials were 55 percent PORT I or II, 20 

percent PORT III, 20 percent PORT IV, and less than 5 percent PORT V. 

Because of the differences in historical studies and clinical trials and present-day CAP trials, we 

also examined data from a more recent daptomycin trial that provide some insight into the 

treatment effect of antibacterial drugs in CAP.30 We present some analyses discussed in the 

paper and discuss results of additional analyses performed by the FDA. 

Two clinical trials were conducted comparing daptomycin to ceftriaxone in the treatment of 

patients with CAP caused by Gram-positive organisms. The second trial was terminated early 

based on failure of the first trial to demonstrate noninferiority. Data presented are aggregate data 

from the two trials. The data provide useful information on the questions of the effect of prior 

antimicrobial therapy on treatment outcomes and whether these effects vary by PORT score. 

The mean age was 55 years and the distribution of PORT scores was approximately 42 percent 

PORT II, 30 percent PORT III, and 28 percent PORT IV. 

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

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

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

and Ceftriaxone for the Treatment of Community-Acquired Pneumonia, Clin Infect Dis, 46:1142-51. 

25 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

969 

970 

971 

972 

973 

974 

975 

976 

977 

978 

979 

980 

981 

982 

983 

984 

985 

986 

987 

988 

989 

In these trials, prior antibacterial therapy was defined as any potentially effective antibacterial 

drug received within 72 hours of starting study drug. Patients were excluded if they had received 

potentially effective antibacterial therapy for more than 24 hours within 72 hours of enrollment. 

In the published post-hoc analysis of these trials, prior effective therapy was defined as 

antibacterial drugs with both greater potency and longer half-lives (such as levofloxacin, 

ceftriaxone, azithromycin, and clarithromycin). Patients who had received no antibacterial drugs 

or only drugs with lesser potency or shorter half-lives (such as penicillins, tetracyclines, or 

trimethoprim-sulfamethoxazole) were classified as having received no prior effective therapy. 

As shown in Table A5, in subgroup analyses in the clinically evaluable population of the 

aggregated daptomycin CAP trials, it appears that prior antibacterial therapy of 24 hours or less 

duration within the 72-hour period before enrollment has an effect on clinical response and could 

lessen the treatment effect that an experimental drug could demonstrate. Prior antibacterial 

therapy had a greater effect on the cure rates in the daptomycin arm compared to the ceftriaxone 

arm. Similar results were seen in the ITT and MITT populations. Although these are post hoc 

analyses of subgroups from the aggregate trial data, they suggest the importance of limiting or 

avoiding prior antibacterial therapy and that prior antibacterial therapy may reduce the treatment 

effect of an antibacterial drug under study. 

Table A5. Effect of Prior Antibacterial Therapy on Clinical Response By Treatment Arm 

(Clinically Evaluable Populations)1

Clinical 

Response 

Prior Antibacterial 

Therapy

Treatment 

Difference 

(95% 

Confidence 

Interval) 

No Prior Antibacterial 

Therapy 

Treatment 

Difference 

(95%Confidence 

Interval) 

Daptomycin 

N=97 

n (%) 

Ceftriaxone 

N=92 

n (%) 

Daptomycin 

N=272 

n (%) 

Ceftriaxone 

N=279 

n 

Cure rate 88 (90.7) 81 (88) 2.7 (-6.1%, 

11.5%) 205 (75.4) 245 (87.8) -12.4% (-18.8, -6.0) 

990 

991 

992 

993 

994 

995 

996 

997 

998 

999 

1000 

1001 

1

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

Ceftriaxone for the Treatment of Community-Acquired Pneumonia, Clin Infect Dis, 46:1142-51. 

The question of whether patients with higher PORT scores are less likely to show an effect of 

prior antibacterial therapy than patients with lower PORT scores was also explored. For 

example, in more severely ill patients, do 24 hours or less of prior antibacterial therapy affect 

clinical response? Analyses of the daptomycin trials revealed that prior antibacterial therapy 

affects the observed treatment effect even in patients with PORT scores of III or IV. 

Future CABP trials 

1002 

1003 

1004 

1005 

Patient population

This guidance recommends inclusion and exclusion criteria (section III.B.3.) designed to enroll 

patients with CAP of a bacterial etiology (i.e., CABP) with a set distribution of PORT scores. 

26 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

1006 

1007 

1008 

This increases the likelihood that the patient population in CABP trials is comparable to that 

studied historically (pneumococcal or lobar pneumonia). 

1009 

1010 

1011 

1012 

1013 

1014 

1015 

1016 

1017 

1018 

1019 

1020 

1021 

1022 

1023 

1024 

1025 

1026 

1027 

1028 

1029 

Age

Age is a strong predictor of mortality in CAP, and from the historical studies and clinical trials of 

patients with pneumococcal pneumonia there was a larger treatment effect in patients older than 

50 years of age. As noted in Table A3, the point estimate for treatment effect approximately 

doubles in the patient population older than 50 years of age compared to the population younger 

than 50 years of age. Age is also a large factor in the PORT score, and specifying a population 

with this distribution of PORT scores as outlined in the guidance will lead to enrollment of a 

population that is largely older than 50 years of age. Based on these factors, we anticipate the 

following: 

• For an IV drug trial, approximately 75 percent of the population will be 50 years of age 

or older 

• For an oral drug trial, approximately 50 percent of the population will be 50 years of age 

or older 

Thus, CABP trials as described in this guidance should enroll a patient population with lobar 

disease on chest X ray along with other cardinal signs of pneumonia, a population with the 

aforementioned distribution of PORT scores, and an age distribution of approximately 75 percent 

(in IV drug trials) or 50 percent (in oral drug trials) older than 50 years of age. 

1030 Comparator agents

1031 

1032 

1033 

1034 

1035 

1036 

1037 

1038 

1039 

1040 

1041 

1042 

1043 

1044 

1045 

1046 

Present-day CABP trials should use comparator agents that are FDA-approved for CAP and that 

are recommended by guidelines to achieve a comparator with a high degree of efficacy. Based 

upon the finding that prior antimicrobial therapy affected the cure rates in the daptomycin trials, 

it is critical that the use of prior antibacterial therapy be minimized in the present-day CABP 

trials. Drug trials for CABP should exclude patients who have received any prior antibacterial 

therapy. 

Most of the available data on treatment effect are data from many years ago and there have been 

advances in medical care over this time period. Nevertheless, this information provides evidence 

of treatment effect with antibacterials and allows for reasonable judgments regarding expected 

treatment effect in a present-day CABP trial. The patient characteristics and trial design factors 

that are described above are chosen to design a trial that has the capacity to achieve an expected 

treatment effect. 

27 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

1047 Noninferiority margin 

1048 

1049 

1050 

1051 

1052 

1053 

1054 

1055 

1056 

1057 

1058 

1059 

1060 

1061 

1062 

1063 

1064 

1065 

1066 

1067 

IV antibacterial drugs

In a patient population enrolled in a present-day CABP trial for an IV formulation as described in 

this guidance, the treatment effect is likely to exceed that which was observed for the trials 

described in Table A4 with a lower bound of 8.8 percent, because of: 1) the inclusion criteria; 2) 

the distribution of PORT scores; 3) the proportion of patients older than 50 years of age; 4) the 

exclusion of patients with prior antibacterial therapy; and 5) the use of an approved and 

guideline-recommended comparator antibacterial therapy. The observation that the lower 

bounds of the 95 percent CI for the treatment effect varied from 15 to 22 percent in the 

observational studies in patients with pneumococcal pneumonia (Table A1) suggests that there is 

a larger treatment effect when a bacteriologic diagnosis is made. 

The MITT population will be considered the primary analysis population. Use of the MITT 

population provides reasonable assurance that most of the patients in the trial have a documented 

microbiologic diagnosis. Thus, based on the evidence discussed in this Appendix, a reasonable 

estimate of M1 for the MITT population for the endpoint of clinical outcome in a CABP trial is 

at least 15 percent for patients enrolled in IV antibacterial trials and an M2 of up to 15 percent is 

considered appropriate in the MITT population. 

1068 

1069 

1070 

1071 

1072 

1073 

1074 

1075 

1076 

1077 

1078 

1079 

1080 

1081 

1082 

1083 

1084 

1085 

1086 

1087 

1088 

1089 

1090 

1091 

1092 

Oral antibacterial drugs

Oral antibacterial drug trials generally enroll patients with less severe disease than IV 

antibacterial drug trials, introducing additional uncertainly regarding the antibacterial treatment 

effect. As described above, the MITT population will be considered the primary analysis 

population. Use of the MITT population provides reasonable assurance that most of the patients 

in the trial have a documented microbiologic diagnosis. 

In oral antibacterial drug trials, there are greater uncertainties in the treatment effect. Because 

patients enrolled in such trials can have illness of lesser severity, the magnitude of treatment 

effect may be smaller. Thus, based on the evidence discussed in this Appendix, a reasonable 

estimate of M1 for the MITT population for the endpoint of clinical outcome in a CABP trial of 

oral antibacterial drug is at least 10 percent and an M2 of up to 10 percent is considered 

appropriate for the MITT population. 

For both IV and oral antibacterial drug trials, results in the ITT, clinically evaluable, and 

microbiologically evaluable populations should be examined for consistency with the results in 

the MITT population. 

Summary 

Based on data from historical studies and clinical trials, appropriate noninferiority margins for 

CABP trials for IV drugs and oral drugs have been described. To arrive at these margins from 

the available data a series of judgments were required. In addition, the recommended design of 

28 
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

29 

1093 

1094 

1095 

1096 

1097 

the CABP trials includes a number of provisions to select and evaluate populations that are 

appropriate for the proposed margins. These provisions include defining CABP as a clinical 

syndrome consistent with bacterial pneumonia and limiting enrollment to an appropriate patient 

population based on age, severity of illness, making the MITT the primary analysis population, 

and excluding patients who received prior antibacterial therapy.