Program: Antibacterial Drug Development (ABDD)

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HABP/VABP Pilot Study

overview icon Overview

Prospective Observational Study of the Risk Factors for Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) and Early Enrollment Study

Clinical trials to evaluate the efficacy and safety of new antibacterial drugs for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are challenging to conduct and expensive, and there are a very limited number of clinical trials of new drugs for this indication in progress or planned. Evaluating new antibacterial drugs for efficacy in HABP/VABP is important, as a number of antibacterial drugs with demonstrated efficacy in the treatment of other serious bacterial infections have demonstrated limitations when studied in HABP/VABP. In addition, patients with infections caused by multi-drug resistant Gram-negative bacteria often present with HABP/VABP.

A HABP/VABP pilot study, incorporating many of the recommendations from the CTTI Streamlining HABP/VABP Trials Project, is planned. The primary objective is to conduct a study that will lead to improved HABP/VABP clinical trial feasibility. The proposed design of the future pilot study is a randomized trial comparing early enrollment and traditional enrollment strategies. The early enrollment strategy (treatment arm) will include approaching AND consenting patients at high risk for developing pneumonia, many before pneumonia symptoms develop. The rationale of this early enrollment strategy is to identify and enroll high-risk patients at the time they meet criteria for a diagnosis of HABP/VABP and before they have received more than 24 hours of effective antibacterial therapy.

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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 number of patients enrolled who ultimately meet study criteria for antibacterial therapy for HABP/VABP. Therefore, a risk factor study will be conducted to better define the population at highest risk for developing HABP/VABP.

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ABDD Program: Prospective Observational Study of the Risk Factors for Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) and Early Enrollment Study (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 hospital and ventilator acquired pneumonia.

Specifically, the results from the Streamlining HABP/VABP project will inform better processes and practices to employ in a pilot HABP/VABP protocol to be tested at participating clinical sites.

  • A pilot protocol using the recommendations developed from the workstreams will show that an innovative approach will work, leading to more ABDD clinical trials, which will eventually lead to more available antibiotics.
  • Streamlining data collection and recording will help accelerate study conduct and reduce the cost associated with excess data collection.

Convened experts and held a series of meetings and workshops to address the following:

  • Identify inefficiencies of current protocol elements and data collection processes in ABDD trial conduct.
  • Explore novel ideas and issue recommendations on designing scientifically valid, feasible, and clinically meaningful trials to establish the efficacy of antibacterial drugs for the treatment of HABP/VABP.
  • Build a pilot network of 45 sites globally (30 US and 15 OUS) with a capability of conducting HABP/VABP studies and implement the planned HABP/VABP pilot protocol.

The CTTI Streamlining HABP/VABP Trials Project includes a number of collaborative efforts to better understand the challenges of conducting HABP/VABP trials and address these challenges through streamlining the operational processes and building efficiencies for data collection in 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. 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.

Another aspect of this project is dedicated to identifying trial sites for the HABP/VABP pilot study. A working group has been convened to include key stakeholders, such as Infectious Diseases and Pulmonary/Critical Care medicine experts, those experienced in designing clinical studies, and patient representatives. A network of sites has been identified, and, simultaneously, efforts are underway to negotiate site contracts to minimize potential future contract negotiation delays so that the HABP/VABP pilot protocol can be implemented immediately. There has been outreach to the Innovative Medicines Initiative’s Combacte and New Drugs for Bad Bugs projects and their CLIN-net site network to expand the site list.

Project Team Members

Rolesort descending Name Affiliation
Project Manager Sara Calvert Clinical Trials Transformation Initiative
Team Leader Vance Fowler Duke University
Team Member Carisa DeAnda Merck & Co, Inc
Team Member Helen Donnelly Northwestern University
Team Member Beth Evans Duke University
Team Member John Farley Food and Drug Administration
Team Member Karen Fusaro The Medicines Company
Team Member Peidi Gu Duke University
Team Member Karen Higgins Food and Drug Administration
Team Member Thomas Holland Duke University
Team Member Kristen Miller Food and Drug Administration
Team Member Christina Murphy Duke University
Team Member John Powers National Institutes of Health
Team Member Daniel Rubin Food and Drug Administration
Team Member Jonas Santiago Food and Drug Administration
Team Member Simone Shurland Food and Drug Administration
Team Member David Sigel National Institutes of Health
Team Member Pamela Tenaerts Clinical Trials Transformation Initiative
Team Member Joshua Thaden Duke University
Team Member Rose Tiernan Food and Drug Administration
Team Member Joseph Toerner Food and Drug Administration
Team Member Daniel White The Medicines Company
Team Member Elizabeth Alexander The Medicines Company
Team Member Steve Barriere Theravance
Team Member Stephen Bergin Duke University
Team Member Deborah Collyar Individual Patient/Caregiver
Team Member Heather Cross Duke University