One of the challenges in planning the HABP/VABP pilot study is determining which patients to approach for early enrollment. A group of patients at risk for pneumonia is required, but selecting criteria based on existing literature will involve a tradeoff between sensitivity and specificity. Approaching only the highest risk patients (e.g., those on a ventilator for a pre-specified length of time) would likely yield a relatively high percentage of patients who go on to develop pneumonia. The drawbacks of this approach include 1) not including a mix of VABP and non-VABP HABP; 2) exclusion of a large group of other patients who go on to develop pneumonia in the hospital in absence of the highest risk factors; and 3) increased likelihood of exclusion due to current use of antibiotics. Using a more inclusive approach, such as enrolling patients with a history of aspiration or with chronic lung disease, would increase the total number of patients who ultimately develop pneumonia, but would decrease the proportion of enrolled patients that develop pneumonia. If the proportion of patients developing pneumonia is too low, it is possible that the time, effort, and money required to conduct a study using an early enrollment strategy would not result in a meaningful increase in the number of patients enrolled who ultimately meet study criteria for antibacterial therapy for HABP/VABP.

A risk factor study was conducted to better define the population at highest risk for developing HABP/VABP. These results, in combination with CTTI’s Recommendations for Streamlining HABP/VABP Clinical Trials, which include a proposal for early consent to increase enrollment, have informed the development of an early enrollment strategy. Resources for those planning to implement an early enrollment strategy are being developed.

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ABDD Program: ABDD HABP/VABP Studies (Ongoing)

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• Better define the population that is at highest risk for developing pneumonia
• Conduct early enrollment study to show that consenting patients at the time they are identified as being high risk will yield a better recruitment rate than using traditional enrollment strategies

The ABDD Program will facilitate the development of new antibacterial drugs for HABP/VABP. Specifically, CTTI’s HABP/VABP studies will provide evidence for new enrollment techniques in HABP/VABP clinical trials. Evidence that an innovative enrollment approach will work can lead to more HABP/VABP clinical trials, which will eventually lead to more available antibiotics.

• Cost analysis
• Analysis of inclusion/exclusion criteria
• Expert meeting
• Prospective observational study
• Formative Research:  
  • Acceptability of an early enrollment strategy 
  • Consensus on Language for Advance Informed Consent in Health Care–Associated Pneumonia 

The related CTTI Streamlining HABP/VABP Trials Project included a number of collaborative efforts to better understand and address the challenges of conducting HABP/VABP trials. A data gathering and mapping project conducted in collaboration with the Tufts Center for the Study of Drug Development found that the cost of screen failures, as well as screen failure rates, are the main drivers of cost for a phase 3 HABP/VABP trial. HABP/VABP phase 3 trials are generally non-inferiority trials.

To address the concern of bias toward non-inferiority, FDA Draft Guidance recommends that 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 be excluded from HABP/VABP clinical trials. In a guided discussion with experienced research coordinators conducted by CTTI, this recommended exclusion criteria was noted as a significant challenge to enrollment as care standards in the intensive care unit often lead to antibacterial drugs being administered as soon as pneumonia is suspected. In addition, patients are often quite ill and unable to provide informed consent themselves, so legally authorized representatives must be identified and contacted for enrollment in a clinical trial. Other necessary enrollment procedures such as laboratory tests and other procedures to meet inclusion/exclusion criteria, randomization, and obtaining study drug from the pharmacy can add to the time between administration of antibacterial drugs and study enrollment. Strategies to address these feasibility concerns while ensuring that trial interpretability will not be limited by a bias toward non-inferiority are needed.

As part of the Streamlining HABP/VABP Trials Project, CTTI identified a network of U.S. and European sites for conducting HABP/VABP studies. A working group was convened and included key stakeholders, such as infectious diseases and pulmonary/critical care medicine experts, those experienced in designing clinical studies, and patient representatives. Site contracts were negotiated to minimize potential future delays. The network is being used to conduct a prospective observational study that examines the risk factors associated with HABP/VABP. Results from this study will inform the development of a randomized interventional pilot trial to test an early enrollment strategy that could make HABP/VABP trials more feasible. An expert meeting was held to gather input on design of the planned pilot study.

CTTI, together with the Tufts Center for the Study of Drug Development, conducted an analysis of cost drivers for phase 3 HABP/VABP trials to identify ways to make these trials more feasible. Key findings included:

• The cost of a phase 3 HABP/VABP clinical trial averages $89.6 million, which is over double the average cost of a phase 3 oncology trial
• Per patient, phase 3 HABP/VABP clinical trials were $2,300 more expensive than oncology clinical trials and $31,900 more expensive than endocrine trials
• Screening failure rates and the cost of screening failures were the biggest drivers of cost, suggesting sponsors and research sites should consider ways to increase the number of potentially eligible patients

• Guidance for Industry: Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment, by the FDA, June 2020
• Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections, Revision 2 by the EMA, December 2011
• Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections by the EMA, October 2013

Organization affiliations are listed as active affiliations during the project.

*Indicates former project manager, team leader, or team member.