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To address the concern of bias toward non-inferiority, FDA Draft Guidance recommends that patients who have received effective antibacterial drug therapy for HABP/VABP for a continuous duration of more than 24 hours during the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
