October 2, 2018 — Bacterial infections acquired in hospitals are a major concern for healthcare providers and their patients. In particular, hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are severe infections that cause patient deaths. As bacterial resistance to antibiotics increases, new treatments to combat these infections are desperately needed. Yet, measuring the effectiveness of new treatments continues to be a challenge due to a lack of well-defined clinical trial endpoints (outcomes measured to determine whether a therapy being studied is beneficial to patients). The Foundation for the NIH (FNIH) Biomarkers Consortium (BC) is tackling this challenge by refining the criteria for how new antibiotic treatments are developed through the “Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia Clinical Endpoint Development” (HABP/VABP) project. The project team includes a broad array of clinical trial design experts and academic scientists from the National Institute of Allergy and Infectious Diseases (NIAID), the Infectious Diseases Society of America (IDSA), the U.S. Food and Drug Administration (FDA), not-for-profit organizations and industry. In the following Q&A, George H. Talbot, M.D., HABP/VABP Project Principal Investigator and Project Team Co-Chair, discusses the project’s history and significant achievements to-date that will help design more efficient clinical trials and facilitate the antibiotic approval process. Click here to learn more about the project.

1. Why is the HABP/VABP project needed?

Due to increasing antibiotic resistance, many bacterial infections are very difficult to treat, and new antibiotics are urgently needed to save patient lives. The traditional measures of treatment success in clinical trials of antibiotics for skin infections and pneumonia have not kept pace with the evolving standards of regulatory science, which has led to substantial uncertainty and delays for companies developing these important drugs. The lack of antibiotic development is a worldwide public health concern that is well suited to the BC’s approach in which multidisciplinary scientific experts collaborate to find solutions.

2. What are the origins of the project and its accomplishments to-date?

In 2010, the FDA asked the BC to provide input on measures to determine the effectiveness of treatments for serious skin infections and community-onset bacterial pneumonia. In response, the BC established a project team of experts in antibiotic development from all relevant disciplines. I served as Co-Chair alongside my colleague Dr. Joe Toerner from the FDA. A primary focus of the project was leveraging the historical literature and results from modern clinical trials to select the best, quantifiable and reproducible measures of treatment success for each type of infection. The team submitted scientific recommendations to the FDA in 2011; those recommendations subsequently were incorporated into the FDA Guidance for Industry for both skin infections and community-onset pneumonia. This was a major accomplishment for the project because FDA Guidance for Industry represent FDA’s current thinking on the design, process, content and evaluation of regulatory submissions for drug approval. Based on this success, the FDA asked the BC to expand the project scope to include analysis of improvements in study design and clinical trial endpoints for HABP/VABP. In June 2017, the BC submitted scientific recommendations to the FDA to help guide drug development for HABP and VABP.

3. Has the FDA used the BC’s recommendations to help approve new drugs?

The initial BC work informed new FDA Guidance for Industry documents and helped the regulatory agency approve several new antibiotics for the treatment of skin infections and community-onset pneumonia. The BC’s subsequent work in HABP/VABP also has been reflected in FDA Guidance for Industry, with recent studies of new antibiotics incorporating key elements of the recommendations. Overall, seven antibacterial drugs have been approved, or approved for expanded use, based on clinical studies incorporating recommendations from these BC projects.

4. What are Patient-Reported Outcome (PRO) instruments and how are they useful?

The BC has partnered with ICON plc. to develop PRO questionnaires for skin infections and pneumonia to directly assess how patients “feel and function” over the course of their infection. PROs capture the “patient voice” and measure how patients describe and quantify their symptoms of illness. For pneumonia, these could include painful or difficult breathing, social isolation and the inability to perform the tasks of daily living. Having the patient record these data directly avoids the “middle man” of a healthcare provider, who could unconsciously and unintentionally bias the patient’s perspective. The FDA seeks to capture how patients “feel and function,” and PRO instruments achieve this imperative by capturing the patient voice reproducibly and verifiably. As a result, the use of PRO questionnaires is continuing to gain adherents in many fields. The BC project team is currently working directly with the FDA to validate these questionnaires for use in clinical studies and pharmaceutical trials.

5. How will this project help patients in the future?

Giving the FDA and clinical researchers better tools to measure the impact of new treatments helps spur the development of new therapies and ensures that these therapies are effective: an obvious benefit to patients, their families and their healthcare providers. The contributions of these projects are particularly important at a time when the incidence of treatment-resistant pathogens, such as methicillin-resistant Staphylococcus aureus and many gram-negative bacteria, are increasing. The outcome measures and PRO questionnaires developed in these projects will be made broadly available to clinicians and the research community; their application in research and practice will clarify the similarities and differences between therapies, thereby enhancing patient care.