Biomarkers Consortium - Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia Clinical Endpoint Development (HABP/VABP)

Creating breakthrough tools for clinical trials to assess antibacterial drugs
 

The Problem
Researchers lack tools to assess the effectiveness of treatments for serious bacterial infections, such as hospital-acquired bacterial pneumonia.
The Solution
This project will improve researchers’ ability to measure tangible benefits for patients with serious bacterial infections in clinical trials, ultimately accelerating development of effective treatments for these conditions.

Overview

The Biomarkers Consortium’s Hospital-Acquired Bacterial Pneumonia (HABP) and Ventilator-Associated Bacterial Pneumonia (VABP) Project developed clinically relevant endpoints to improve the feasibility of antibacterial drug trials for HABP and VABP. The project results helped to address one of the biggest hurdles in the field of drug development for HABP and VABP indications – the lack of well-defined endpoints. Previously, the approaches to quantitatively assess the effects of antibacterial drug treatments vs. no treatment or placebo were quite limited, as was the ability to compare between active agents. The HABP VABP project developed reliable, well-defined, clinically meaningful endpoints that measure tangible benefits for HABP/VABP patients in terms of how they feel, function and survive. In addition, the project created new design components that would improve the ability to conduct rigorous antibacterial drug trials. The project conducted a retrospective analysis of data from several industry-sponsored clinical trials and submitted the results to the FDA in order to provide recommendations to update the endpoints used in future HABP/VABP clinical trials. An additional key deliverable from the project was the development of an HABP Patient-Reported Outcome (PRO) draft instrument.

Goals

  • Develop reliable and well-defined clinically relevant endpoints for use in clinical trials of antibacterial drugs for HABP and/or VABP that measure tangible benefits for patients in terms of how they feel, function and survive.
  • Identify potential changes to study design and analysis that could improve the feasibility of HABP/VABP registrational clinical trials based on a non-inferiority (NI) design.
  • Complete the content validity phase of a Patient-Reported Outcome (PRO) measure.

Results & Accomplishments

Developed Novel Outcome Measures

  • The FNIH HABP/VABP Project Team confirmed relevant outcome measures for use in both HABP and VABP clinical trials via retrospective analysis and synthesis of data from past trials. These data were used to prepare a briefing package that was submitted to the FDA docket on HABP and VABP to include symptomatic endpoints in the FDA Guidance. 

Partners

Public-Sector Partners

  • National Institute of Allergy and Infectious Diseases (NIAID)
  • U.S. Food and Drug Administration (FDA)

Private-Sector Partners

  • Achaogen, Inc.*
  • Actelion Pharmaceuticals Ltd.*
  • American Thoracic Society
  • AstraZeneca Pharmaceuticals LP*
  • Basilea Pharmaceutica International Ltd.*
  • Bayer HealthCare Pharmaceuticals Inc.*
  • Cubist Pharmaceuticals, Inc.*
  • ICON plc.
  • InClin
  • Infectious Diseases Society of America
  • The Medicines Company*
  • Melinta Therapeutics*
  • Merck Sharp & Dohme Corp.*
  • Nabriva Therapeutics AG*
  • Pfizer Inc.*
  • Roche*
  • Shionogi Inc.*
  • Tetraphase Pharmaceuticals*
  • Theravance Biopharma*

Academic Partners

  • Universitat de Barcelona
  • *Provided financial or in-kind support for this program.

FNIH Contacts

  • Stephanie Cush, Ph.D., Senior Project Manager, Inflammation and Immunity, scush@fnih.org;
  • Steve Hoffmann, Director, Inflammation and Immunity, shoffmann@fnih.org

Patient Reported Outcome

  • The FNIH HABP/VABP Project Team built on the work from the CABP/ABSSSI Project to assess the overlap in symptoms between CABP and HABP patients to support the development and use of a unified PRO instrument to aid the evaluation of new treatments for both disease areas. The results support the use of PNEUMO PRO© instrument in both CABP and HABP indications as detailed in the posters below.  The PRO instruments are intended to measure tangible benefits for patients in clinical trials of antibacterial drugs for both CABP and HABP.
  • PNEUMO PRO© https://eprovide.mapi-trust.org/instruments/community-acquired-bacterial-pneumonia-symptom-diary

Poster Presentations

  • Signs, Symptoms, and Existing Patient-Reported Outcome (PRO) Measures in Hospital-Acquired Bacterial Pneumonia (HABP): A Comprehensive Literature Review  Read more
  • Hospital-Acquired Bacterial Pneumonia: Development of a New Patient Reported Outcome Instrument  Read more
  • Content Validation of a New Patient-Reported Outcome (PRO) Instrument in Hospital-Acquired Bacterial Pneumonia (HABP)  Read more
  • Alternatives to the All-cause Mortality Endpoint for Studies of Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Read more

Resulting FDA Guidance Documents

  • Submission to the FDA Docket: Considerations for Clinical Trial Design for the Study of Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia. Read more
  • Guidance for Industry: Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (2014). Read more

Scientific Publications

  • Evolution and current status of United States Food and Drug Administration and European Medicines Agency regulatory guidance for studies of nosocomial pneumonia. Talbot GH. Curr Opin Crit Care. 2018. 24:379-384 DOI: 10.1097/MMC.0000000000000524 Read more 
  • Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia. Talbot G, Das A, Cush S, Dane A, Wible M, Echols R, Torres A, Cammarata S, Rex JH, Powers JH, Fleming T, Loutit J, Hoffmann S, FNIH Biomarkers Consortium HABP/VABP Project Team. Journal of Infectious Disease., jiy578. 2019 Jan 11. Read more
  • Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases. Powers JH, Howard K, Saretsky T, Clifford S, Hoffmann S, Llorens L, Talbot G. Clin Infect Dis. 2016 Aug 15;63 Suppl 2:S52-6. doi: 10.1093/cid/ciw317. PMID: 27481954 Read more.
  • Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health. Talbot GH, Powers JH, Hoffmann SC; Biomarkers Consortium of the Foundation for the National Institutes of Health CABP-ABSSSI and HABP-VABP Project Teams. Clin Infect Dis. 2016 Mar 1;62(5):603-7. doi: 10.1093/cid/civ927. PMID: 26668337 Read more.

Media

  • FNIH Web Announcement (October 2, 2018): Q&A with George H. Talbot, M.D.: Improving Antibacterial Drug Development Tools. Read more
  • FNIH Web Announcement (July 20, 2017): FNIH Biomarkers Consortium Provides Recommendations to FDA to Facilitate Drug Development for Serious Bacterial Infections Read more
  • Editorial Commentary: A Collaborative Model for Endpoint Development: Advancing the Science of Antibacterial Drug Clinical Trials. Toerner JG, Cox E. Clin Infect Dis. 2016 Mar 1;62(5):608-9. doi: 10.1093/cid/civ1007. No abstract available Read more
  • ICON Press Release (Feb. 20, 2017): ICON Selected by the FDA to Validate Patient-Reported Outcome Endpoints for Antibacterial Drug Trials Read more