Table 1.

Summary of Foundation for the National Institutes of Health Analyses and Interim Conclusions for Conduct of Registrational Trials in the Community-Acquired Bacterial Pneumonia, Acute Bacterial Skin and Skin Structure Infection, Hospital-Acquired Bacterial Pneumonia, and Ventilator-Associated Bacterial Pneumonia Indications

Indication	Methodology	Major Findings, Conclusions, and Recommendations	Date [Reference]
CABP	Review of literature; analysis of modern-day clinical trial data submitted in-kind by pharmaceutical sponsors	“Progressive improvement in four symptoms (cough, dyspnea, chest pain, and sputum production) during the first 4 d of therapy was sufficiently well documented that an early response endpoint measure could be proposed. To assess durability of response and other late events, supportive information should be obtained by assessing outcomes at a fixed timepoint after therapy has been completed. Such information could include a late response endpoint similar to the traditional test-of-cure endpoint. Although based on limited data and requiring further research, an early response endpoint can be used to anchor a non-inferiority trial for this indication. The early response endpoint is thus suggested for possible use by FDA in review of registrational trials and approval of applications in CABP while further research into this area is conducted.”	2011 [11]
ABSSSI	Review of literature; analysis of modern-day clinical trial data submitted in-kind by pharmaceutical sponsors	“Control of lesion spread at 48 to 72 h after randomization was sufficiently well documented that an early response endpoint measure could be proposed. To assess sustained response and other late events, supportive information should be obtained by assessing outcomes at a fixed time point after therapy has been completed. Such information could include a late response endpoint similar to the traditional test-of-cure (TOC) endpoint but more clearly defined. Although incompletely validated under the proposed conditions of use and requiring further research, an early response endpoint can be used to anchor a non-inferiority hypothesis in a trial for this indication. Thus, the Project Team supports a primary endpoint based on early response in review of registrational trials and approval of applications in ABSSSI while further research into outcomes at later time points in this area is conducted.”	2011 [12]
HABP	Review of literature	“A clinically meaningful endpoint of symptom improvement plus survival for non-ventilated patients could be based on the historical data for community-acquired bacterial pneumonia, for which there is a large treatment effect to day 7 of antibacterial drug therapy.” “There was some concern  …  that mortality and other differences between HABP and VABP suggest these are different diseases, meaning that combining both in a single trial could raise methodological issues.”	2013 [14]
VABP	Review of literature	“Despite the potential clinical trial implementation feasibility issues that have been raised with current FDA HABP/VABP Guidance, including an all-cause mortality (ACM) endpoint, most [FNIH] participants are comfortable with ACM as an endpoint, especially for VABP, if trial feasibility could be addressed by changing other parameters of study design.” “The outstanding questions for use of ACM relate to timing of its assessment, as well as to whether there are suitable intermediate clinical endpoints. One concern with ACM is its lower incidence in registrational trials versus “real life.” It is hypothesized that making exclusion criteria less restrictive, and thereby increasing the severity of illness in the enrolled population, has the potential to facilitate enrollment.” “A number of candidate changes to other aspects of trial design (eg, primary analysis set) were identified as promising potential approaches to improving feasibility, while maintaining scientific validity.”	2013 [14]

Abbreviations: ABSSSI, acute bacterial skin and skin structure infection; ACM, all-cause mortality; CABP, community-acquired bacterial pneumonia; FDA, US Food and Drug Administration; FNIH, Foundation for the National Institutes of Health; HABP, hospital-acquired bacterial pneumonia; VABP, ventilator-associated bacterial pneumonia.