Hospital-Acquired Bacterial 
Pneumonia and Ventilator-
Associated 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 
 
   
Hospital-Acquired Bacterial 
Pneumonia and Ventilator-
Associated 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 ....................................................................................................1 
III.  DEVELOPMENT PROGRAM ............................................................................2 
A.  General Considerations .................................................................................................... 2 
1. Nonclinical Development Considerations ........................................................................... 2 
2. Drug Development Population ............................................................................................ 2 
3. Efficacy Considerations ...................................................................................................... 3 
4. Safety Considerations .......................................................................................................... 3 
5. Clinical Microbiology Considerations ................................................................................ 3 
B.  Specific Efficacy Trial Considerations ............................................................................ 4 
1. Trial Design ......................................................................................................................... 4 
2. Trial Population .................................................................................................................. 4 
3. Inclusion and Exclusion Criteria......................................................................................... 4 
a.  Inclusion criteria ........................................................................................................... 4 
b.  Exclusion criteria .......................................................................................................... 5 
4. Randomization and Blinding ............................................................................................... 5 
5. Specific Populations ............................................................................................................ 6 
6. Dose Selection ..................................................................................................................... 6 
7. Choice of Comparators and Concomitant Antibacterial Drugs .......................................... 6 
8. Prior Antibacterial Drug Therapy....................................................................................... 7 
9. Efficacy Endpoints ............................................................................................................... 7 
a.  Primary endpoints ......................................................................................................... 7 
b.  Secondary endpoints ..................................................................................................... 8 
10.  Trial Procedures and Timing of Assessments ................................................................. 8 
a.  Entry visit ..................................................................................................................... 8 
b.  On-therapy and end-of-therapy visits ........................................................................... 8 
c.  Visits after completion of therapy ................................................................................ 8 
11.  Statistical Considerations ............................................................................................... 8 
a.  Analysis populations ..................................................................................................... 9 
b.  Noninferiority margins ................................................................................................. 9 
c.  Sample size considerations ........................................................................................... 9 
C.  Other Considerations ...................................................................................................... 10 
1. Pharmacokinetic/Pharmacodynamic Considerations ....................................................... 10 
2. Labeling Considerations ................................................................................................... 10 
REFERENCES .................................................................................................................11 
APPENDIX .......................................................................................................................13 
 
  Contains Nonbinding Recommendations 
Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated 
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 staff 
responsible for this guidance as listed on the title page. 
 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors and investigators in the clinical development of 
drugs for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-
associated bacterial pneumonia (VABP).2  Specifically, this guidance addresses the FDAs 
current thinking about the overall development program and clinical trial designs for drugs to 
support an indication for treatment of HABP/VABP. 
 
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. 
 
 
II.  BACKGROUND 
                                                 
1 This guidance has been prepared by the Division of Anti-Infectives in the Center for Drug Evaluation and 
Research at the Food and Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
1  Contains Nonbinding Recommendations 
 
HABP/VABP occurs in hospitalized patients and in patients who have been recently discharged 
from the hospital.  A hospital stay of 48 hours or more places patients at risk for infection with a 
variety of organisms, including gram-positive bacteria such as methicillin-resistant 
Staphylococcus aureus and gram-negative bacteria such as Klebsiella pneumoniae, Pseudomonas 
aeruginosa, and Acinetobacter species. 
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Nonclinical Development Considerations 
 
In addition to the expected nonclinical pharmacology/toxicology studies (see Section III. C. 1, 
Pharmacokinetic/Pharmacodynamic Considerations), sponsors should provide nonclinical data 
from in vitro studies and in vivo animal studies4 demonstrating activity against one or more of 
the commonly implicated pathogens for HABP/VABP.5 
 
2.  Drug Development Population 
 
HABP is an acute infection of the pulmonary parenchyma that is associated with clinical signs 
and symptoms such as fever or hypothermia, chills, rigors, cough, purulent sputum production, 
chest pain, or dyspnea, accompanied by the presence of a new or progressive infiltrate on a chest 
radiograph in a patient hospitalized for more than 48 hours or developing within 7 days after 
discharge from a hospital.6  Patients with HABP may or may not require intubation and 
mechanical ventilation. 
 
VABP is an acute infection of the pulmonary parenchyma that is associated with clinical signs 
and symptoms such as fever or hypothermia, chills, rigors, purulent respiratory secretions, and 
increased oxygen requirements.  These signs and symptoms are in addition to laboratory 
abnormalities such as leukocytosis accompanied by the presence of a new or progressive 
infiltrate on a chest radiograph in a patient on mechanical ventilation for a minimum of 48 hours. 
 
                                                 
4 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
5 See the guidelines from the American Thoracic Society and the Infectious Diseases Society of America (Kalil et al. 
2016), or other relevant publications, for descriptions of bacterial pathogens commonly identified in patients with 
HABP/VABP. 
 
6 Oral and nasotracheal bacterial flora may not return to normal flora within 4 to 6 weeks or longer after 
hospitalization. 
 
2  Contains Nonbinding Recommendations 
3.  Efficacy Considerations 
 
A showing of superiority or noninferiority, using an acceptable noninferiority margin, to a 
control drug in the treatment of HABP/VABP is readily interpretable as evidence of 
effectiveness (see the Appendix).7 
 
The Agency generally expects sponsors to conduct two adequate and well-controlled trials in 
HABP/VABP to establish substantial evidence of effectiveness.  Alternatively, a single adequate 
and well-controlled trial in HABP/VABP with confirmatory evidence (e.g., the results of a trial 
in another infectious disease indication) can provide substantial evidence of effectiveness.8  
Sponsors should discuss with the FDA the confirmatory evidence that would be used to support 
the efficacy findings from a single trial in HABP/VABP. 
 
4.  Safety Considerations 
 
If the same or greater dose and treatment duration for HABP/VABP were used in clinical trials 
for other infectious disease indications, safety data from these indications can be used to support 
safety for HABP/VABP.  Sponsors should discuss with the FDA the appropriate size of the 
premarketing safety database during clinical development. 
 
5.  Clinical Microbiology Considerations 
 
An adequate sputum specimen should be processed by a laboratory according to recognized 
methods for Gram stain, culture, and in vitro antibacterial susceptibility testing.9 
 
Use of rapid diagnostic or nonculture tests may help identify a patient for enrollment in an 
HABP/VABP trial.  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 
HABP/VABP as a means to also evaluate a diagnostic test are encouraged to discuss this with 
the Agency. 
 
                                                 
7 See section 505(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 
 
8 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. 
 
9 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. 
3  Contains Nonbinding Recommendations 
B.  Specific Efficacy Trial Considerations 
 
1.  Trial Design 
 
HABP/VABP trials should be randomized and double-blind when possible, comparing the 
investigational drug with an active control.  In general, HABP/VABP trials will be designed as 
noninferiority trials.  Another trial design is the add-on superiority design, in which patients 
receive either a placebo or an investigational drug added to standard-of-care antibacterial drug 
therapy. 
 
2.  Trial Population 
 
For an indication for the treatment of HABP/VABP, the trial population should consist of 
patients who have HABP (regardless of mechanical ventilation) or VABP.  The trial population 
should include at a minimum approximately 50 percent of patients who are on mechanical 
ventilation at enrollment (VABP/ventilated HABP).  Sponsors interested in seeking an indication 
for HABP only should discuss the trial design and trial population with the Agency. 
 
The protocol can specify the use of a clinical severity scoring system to identify a trial 
population consisting of patients who have a sufficient severity of illness to maintain assay 
sensitivity for the all-cause mortality endpoint in a noninferiority trial (e.g., at least a 15 percent 
mortality rate).  An example of a clinical severity scoring system is the Acute Physiology and 
Chronic Health Evaluation II. 
 
3.  Inclusion and Exclusion Criteria 
 
a.  Inclusion criteria 
 
Patients should have at least one of the following clinical features: 
 
  New onset or acute worsening pulmonary symptoms or signs, such as cough, 
dyspnea, tachypnea (e.g., respiratory rate greater than 25 breaths per minute), 
expectorated sputum production, or requirement for mechanical ventilation 
 
  Hypoxemia 
 
  Need for acute changes in the ventilator support system to enhance oxygenation, as 
determined by worsening oxygenation or needed changes in the amount of positive 
end-expiratory pressure 
 
  New onset of suctioned respiratory secretions 
 
In addition, patients should have at least one of the following signs/laboratory abnormalities: 
 
  Documented fever (e.g., body temperature greater than or equal to 38C) 
 
4  Contains Nonbinding Recommendations 
  Hypothermia (e.g., core body temperature less than or equal to 35C) 
 
  Total peripheral white blood cell count greater than or equal to 10,000 cells per cubic 
millimeter (mm3) 
 
  Leukopenia with total white blood cell count fewer than or equal to 4,500 cells per 
mm3  
 
  Greater than 15 percent immature neutrophils (e.g., bands) noted on peripheral blood 
smear 
 
Plus 
 
  A chest radiograph showing the presence of a new or progressive infiltrate suggestive 
of bacterial pneumonia 
 
b.  Exclusion criteria 
 
The following patients should be excluded from HABP/VABP clinical trials: 
 
  Patients who have known or suspected community-acquired bacterial pneumonia or 
viral pneumonia 
 
  Patients who have received effective antibacterial drug therapy for HABP/VABP for 
a continuous duration of more than 24 hours during the previous 72 hours (see section 
III. B. 8., Prior Antibacterial Drug Therapy) 
 
4.  Randomization and Blinding 
 
The protocol should specify randomization of patients to treatment groups at enrollment.  
Randomization strategies other than 1:1 (e.g., 2:1 or 3:1 randomization of investigational drug to 
active control) could be considered in certain situations (e.g., to enhance the size of the safety 
database of the investigational drug).  To the extent possible, the trial should be double-blinded.  
If there is a compelling reason for single-blind or open-label trial designs, sponsors should 
discuss with the Agency efforts to minimize bias before initiating the trial. 
 
Sponsors should consider methods to enhance the efficiency of the enrollment and randomization 
processes and enable prompt administration of antibacterial drug therapy within the context of 
the clinical trial, thus avoiding the potential confounding by effective antibacterial drug therapy 
before enrollment (see section III. B. 8., Prior Antibacterial Drug Therapy).  For example, it 
often may be the case that few HABP/VABP patients are enrolled at each clinical center.  In this 
case, sponsors may consider randomizing centers rather than individual patients to simplify 
enrollment, with appropriate adjustments to the statistical analysis plan and informed consent 
procedures to accommodate cluster randomization.  As another example, sponsors could give 
hospitalized patients at risk for developing HABP/VABP informed consent in anticipation of 
participating in a clinical trial if the patient develops HABP/VABP (Corneli et al. 2018). 
5  Contains Nonbinding Recommendations 
 
5.  Specific Populations 
 
The trials should include patients of both sexes, patients of all races, and geriatric patients.10  The 
FDA encourages sponsors to begin discussions about their pediatric formulation and clinical 
development plan early in development because pediatric studies are a required part of the 
overall drug development program and sponsors are required to submit pediatric study plans no 
later than 60 days after an end-of-phase 2 meeting.11  Extrapolation of adult efficacy findings in 
HABP/VABP to pediatrics is generally acceptable.  However, studies are typically needed to 
determine the appropriate dose and assess the safety of the drug in the pediatric population.  
Sponsors should evaluate the pharmacokinetic (PK) information of the drug in specific 
populations (e.g., geriatric patients, patients with renal or hepatic impairment) to determine 
whether dose adjustments are necessary. 
 
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 and oral formulations, sponsors should collect PK data in 
earlier phase studies to select the appropriate oral dose for the intravenous-to-oral switch. 
 
7.  Choice of Comparators and Concomitant Antibacterial Drugs 
 
The active comparator drug should reflect the current standard of care for the treatment of 
HABP/VABP.  When evaluating the current standard of care, the FDA considers the 
recommendations by authoritative scientific bodies (e.g., American Thoracic Society, Infectious 
Diseases Society of America) based on clinical evidence and other reliable information that 
reflects current clinical practice. 
 
Ideally, an investigational drug would have activity against most bacterial pathogens implicated 
in HABP/VABP and concomitant antibacterial drugs would not be necessary.  However, 
                                                 
10 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); see also the 
guidance for industry Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (July 1993). 
 
11 See the Pediatric Research Equity Act (Public Law 108-155; section 505B(e)(2)(A) of the FD&C Act; 21 U.S.C. 
355B) as amended by the Food and Drug Administration Safety and Innovation Act (Public Law 112-144).  See also 
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. 
 
 
6  Contains Nonbinding Recommendations 
investigational drugs with a narrow spectrum of antibacterial activity can be developed for the 
treatment of HABP/VABP.  Because concomitant antibacterial drugs can confound the 
interpretation of treatment effect in a noninferiority trial, the protocol should specify any use of 
concomitant antibacterial drugs that may be permitted for treating patients with HABP/VABP 
and address the impact these concomitant drugs may have on study conclusions. 
 
To the extent possible, the concomitant antibacterial drug should not have antibacterial activity 
similar to the spectrum of activity of the investigational drug.  After culture and in vitro 
susceptibility testing results are available, if there is a defined level of clinical improvement, 
sponsors should consider de-escalating concomitant therapy.12  Whenever possible, treatment 
should be completed as monotherapy with the investigational drug in patients randomized to the 
investigational drug group. 
 
8.  Prior Antibacterial Drug Therapy 
 
Ideally, patients enrolled in an HABP/VABP clinical trial would not have received prior 
antibacterial drug therapy.  Prior antibacterial drug therapy can have important consequences for 
a clinical trial.  Specifically, prior antibacterial drug therapy could 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 a finding of noninferiority; 
see, for example, Pertel et al. 2008).  However, excluding patients who have received prior 
antibacterial drug therapy also could have adverse consequences.  Specifically, certain trial sites 
may decline to participate in the clinical trial because of concerns that trial treatment would not 
represent standard of care and would place patients at risk. 
 
A pragmatic approach to these concerns is to (1) encourage prompt enrollment procedures (e.g., 
anticipatory informed consent offered to patients at risk for developing HABP/VABP) so that 
patients can receive the clinical trial treatment initially, with no need for other antibacterial drug 
therapy; and (2) allow enrollment of patients who have received no more than 24 hours of 
therapy before enrollment.  Patients who have objective documentation of clinical failure while 
receiving any duration of prior antibacterial drug therapy for treatment of HABP/VABP can be 
enrolled. 
 
9.  Efficacy Endpoints 
 
a.  Primary endpoints 
 
Sponsors should select one of the following two primary efficacy endpoints for clinical trials: 
 
  A primary endpoint based on survival: all-cause mortality can be evaluated at a fixed 
time point at any time between day 14 and day 28 (see the Appendix). 
 
                                                 
12 For example, see the recommendations for de-escalation of the initial empirical antibacterial drug therapy based 
on the culture results and in vitro susceptibility testing in the setting of clinical improvement at 48 to 72 hours 
(American Thoracic Society 2005). 
7  Contains Nonbinding Recommendations 
  A primary endpoint based on survival and no disease-related complications: all-cause 
mortality or disease-related complications (e.g., development of empyema, onset of acute 
respiratory distress syndrome, sepsis syndrome, other complications) can be evaluated at 
a fixed time point at any time between day 14 and day 28.  Sponsors should discuss with 
the Agency the disease-related complications before initiating the trial. 
 
In general, the primary efficacy analysis should be based on a comparison of the proportions of 
patients achieving the primary endpoint at a fixed time point from randomization. 
 
b.  Secondary endpoints 
 
Secondary endpoints can include the following: (1) an assessment of resolution of signs and 
symptoms of HABP/VABP at approximately 7 to 14 days after the completion of antibacterial 
drug therapy, (2) days spent in the hospital, and (3) days spent on mechanical ventilation (for 
VABP and ventilated-HABP patients). 
 
 
10.  Trial Procedures and Timing of Assessments 
 
a.  Entry visit 
 
At the entry visit, the protocol should specify the collection of baseline demographics, clinical 
information, sputum specimen for evaluation and culture, and baseline laboratory tests, as 
appropriate. 
 
b.  On-therapy and end-of-therapy visits 
 
The protocol should specify an evaluation of patients during therapy and at the end of therapy 
and should specify clinical and laboratory assessments for safety as appropriate. 
 
c.  Visits after completion of therapy 
 
The protocol should specify evaluations for continued clinical response or resolution of 
HABP/VABP and safety at approximately 7 to 14 days after patients complete antibacterial 
therapy.  Sponsors should assess and report mortality, including a mortality assessment at day 
28. 
 
11.  Statistical Considerations 
 
In general, sponsors should provide, before trial initiation, a detailed statistical analysis plan 
stating the trial hypotheses and the analysis methods before trial initiation.  The primary efficacy 
analysis should be based on the difference between treatment groups in the proportions of 
success on the primary outcome measure, assessing either noninferiority or superiority. 
 
8  Contains Nonbinding Recommendations 
a.  Analysis populations 
 
The following definitions apply to various analysis populations: 
 
  Intent-to-treat (ITT) population  All randomized patients. 
 
  Safety population  All patients who received at least one dose of drug during the trial. 
 
  Microbiological intent-to-treat (micro-ITT) population  All randomized patients who 
have a baseline bacterial pathogen known to cause HABP/VABP that is susceptible to the 
investigational drug and active control, identified from an appropriate sputum or blood 
specimen. 
 
  Per-protocol populations  Patients who are not lost to follow-up and adhere to trial 
procedures as specified in the protocol. 
 
  Per-protocol microbiologically evaluable populations  Patients who are characterized 
in the per-protocol population and have a baseline bacterial pathogen identified as the 
cause of HABP/VABP. 
 
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 
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 data support the appropriateness of noninferiority trials for HABP/VABP (see the 
Appendix).  For example, with the use of a survival endpoint, a noninferiority margin of 10 
percent can be supported by the historical evidence, which supports a reduction in mortality by 
effective therapy of about 20 percent.  A 10 percent noninferiority margin supports a 
preservation of a meaningful fraction of that effect.  If a noninferiority margin >10 percent is 
selected, sponsors should discuss the rationale and justification with the Agency. 
  
c.  Sample size considerations 
 
In one example of a sample size calculation, approximately 268 patients per group is estimated 
for the ITT analysis population based on the rate of all-cause mortality of 15 percent in the test 
and control groups and a noninferiority margin of 10 percent.  The trial will rule out greater than 
10 percent inferiority of the investigational drug to the control drug (an upper bound of the two-
sided 95 percent confidence interval for the difference in the rates of all-cause mortality of the 
control drug minus the investigational drug). 
 
9  Contains Nonbinding Recommendations 
C.  Other Considerations 
 
1.  Pharmacokinetic/Pharmacodynamic Considerations 
 
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.13 
 
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. 
 
2.  Labeling Considerations 
 
Generally, the labeled indication should reflect the patient population (HABP, VABP, or 
HABP/VABP) enrolled in the clinical trials. 
                                                 
13 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). 
10  Contains Nonbinding Recommendations 
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11  Contains Nonbinding Recommendations 
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West, M, BR Boulanger, C Fogarty, A Tennenberg, B Wiesinger, M Oross, S-C Wu, C Fowler, 
N Morgan, and JB Kahn, 2003, Levofloxacin Compared With Imipenem/Cilastatin Followed By 
Ciprofloxacin in Adult Patients With Nosocomial Pneumonia:  A Multicenter, Prospective, 
Randomized, Open-Label Study, Clin Ther, 25(2):485506. 
 
Wunderink, RG, SK Cammarata, TH Oliphant, and MH Kollef, 2003, Continuation of a 
Randomized, Double-Blind, Multicenter Study of Linezolid Versus Vancomycin in the 
Treatment of Patients With Nosocomial Pneumonia, Clin Ther, 25(3):980992. 
12  Contains Nonbinding Recommendations 
APPENDIX 
 
Support for a Noninferiority Margin for Clinical Trials 
Evaluating Antibacterial Drugs for Treatment of HABP/VABP 
 
The usual source of information about the effect of the control drug, the basis for specifying a 
noninferiority margin, is placebo-controlled trials.  Such trials do not exist for hospital-acquired 
bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP).  This 
Appendix describes an approach to providing historical evidence of sensitivity to drug effect and 
support for the noninferiority margin by comparing trials using inadequate or delayed treatment 
and trials using effective antibacterial drug treatment. 
 
A literature search identified seven trials that evaluated patients who had HABP/VABP.  Two 
trials evaluated patients who received inadequate or delayed treatment and five trials were 
prospective, controlled trials of effective antibacterial drug treatment.  Patients in the seven trials 
had similar baseline demographic characteristics.  Clinical responses were not provided in a 
standardized or consistent manner in any of these trials, so only all-cause mortality was 
identified in these trials as a well-defined and reliable clinical endpoint.  The all-cause mortality 
reporting time period for these evaluations was variable (e.g., 30 days after completion of 
therapy, 28 days after onset of HABP/VABP, 12 days after completion of therapy) or was not 
reported at all.  Tables 1 and 2 provide the results of all-cause mortality observed in each arm of 
the trials. 
 
 
Table 1.  Nonrandomized Evaluations Involving Inadequate or Delayed Treatment in 
Hospitalized Patients With HABP/VABP 
Trial  Number of Patients  Inadequate or Delayed  Appropriate Treatment  
(% Ventilator- Treatment  All-Cause Mortality 
Associated)  All-Cause Mortality n/N  n/N (%) 
(%) 
Kollef and Ward  102* (100%)  31/51 (61%)  17/51 (33%) 
1998   
Luna et al. 2006  76 (100%)  33/52 (64%)  7/24 (29%) 
*
The trial evaluated 130 patients who were receiving mechanical ventilation, 28 of whom did not have evidence to 
support a diagnosis of VABP. 
 
 
A random effects meta-analysis (DerSimonian and Laird 1986) for the estimate of mortality in 
patients who received inadequate or delayed treatment was 62 percent (95 percent confidence 
interval, 52 percent to 71 percent).  An all-cause mortality rate was lower in patients who 
received appropriate treatment in these nonrandomized trials. 
 
13  Contains Nonbinding Recommendations 
Table 2.  Prospective, Controlled Clinical Trials Using Effective Antibacterial Drug 
Therapy in Patients With HABP/VABP  
Trial  Number of Patients  Effective Treatment  Effective Treatment 
(% Ventilator- Group 1*   Group 2*  
Associated)  All-Cause Mortality  All-Cause Mortality 
n/N (%)  n/N (%) 
Alvarez-Lerma et al.  124 (85.5%)  P/T/A  Cef/A 
2001  27/88 (31%)  8/36 (22%) 
Fink et al. 1994  402 (75.6%)  Imi  Cip 
38/200 (19%)  43/202 (21%) 
Rubinstein et al.  396 (57.3%)  Lin/Az  Van/Az 
2001  36/203 (18%)  49/193 (25%) 
West et al. 2003  438 (10.7%)  Imi/Cip  Lev/Lev PO 
32/218 (15%)  38/220 (17%) 
Wunderink et al.  623 (50.6%)  Lin/Az  Van/Az 
2003  64/321 (20%)  61/302 (20%) 
* The data in the table are presented by the treatment groups (1 and 2) for these active-controlled trials; A = 
amikacin; Cef = ceftazidime; Cip = ciprofloxacin; Imi = imipenam/cilastatin; Lev = levofloxacin; P/T = 
piperacillin/tazobactam; Lin = linezolid; Az = Aztreonam; Van = vancomycin. 
 
 
The estimate of mortality based on a random effects meta-analysis (DerSimonian and Laird 
1986) in patients who received effective antibacterial drug treatment (all 10 treatment groups 
from the 5 trials) was 20 percent (95 percent confidence interval, 18 percent to 23 percent).  The 
meta-analyses yielded a lower bound estimate of all-cause mortality for inadequate or delayed 
treatment of HABP/VABP of 52 percent and an upper bound estimate of all-cause mortality 
among effective antibacterial drug treatment of 23 percent.  An estimate of the treatment effect 
of an antibacterial drug over inadequate or delayed treatment is approximately 29 percent (52 
percent minus 23 percent).  Allowing for some uncertainty of the results from these 
nonrandomized comparisons, the Agency considers an acceptable effectiveness margin of the 
active-control drug relative to placebo (M ) to be 20 percent.  Therefore, the Agency considers a 
1
noninferiority margin (M ) of 10 percent to be reasonable both clinically and statistically.  
2
Sponsors can discuss with the Agency the selection of a noninferiority margin that is greater than 
10 percent. 
14