Title

Improving Traditional Registrational Trial Endpoints: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Complicated Urinary Tract Infection Clinical Trials

Authors

Jessica Howard-Anderson, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
Toshimitsu Hamasaki, Biostatistics Center and Department of Biostatics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, D.C.,USA.
Weixiao Dai, Biostatistics Center and Department of Biostatics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, D.C.,USA.
Deborah Collyar, Patient Advocates in Research, Danville, CA, USA.
Daniel Rubin, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Sumathi Nambiar, Johnson and Johnson, Raritan NJ, USA.
Tori Kinamon, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Carol Hill, Duke Clinical Research Institute, Durham, North Carolina, USA.
Steven P. Gelone, Nabriva Therapeutics US, Inc., Fort Washington, PA, USA.
David Mariano, Nabriva Therapeutics US, Inc., Fort Washington, PA, USA.
Takamichi Baba, Biostatistics Center, Shionogi & Co., Ltd, Osaka, Japan.
Thomas L. Holland, Duke Clinical Research Institute, Durham, North Carolina, USA.
Sarah B. Doernberg, Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, USA.
Henry F. Chambers, Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, USA.
Vance G. Fowler, Duke Clinical Research Institute, Durham, North Carolina, USA.
Scott R. Evans, Biostatistics Center and Department of Biostatics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, D.C.,USA.
Helen W. Boucher, Tufts University School of Medicine and Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA.

Document Type

Journal Article

Publication Date

8-29-2022

Journal

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

DOI

10.1093/cid/ciac692

Keywords

clinical trials; complicated urinary tract infections; desirability of outcome ranking; drug development

Abstract

BACKGROUND: Traditional endpoints used in registrational randomized controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience. METHODS: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience we developed a DOOR endpoint for infectious disease syndromes and demonstrated how this could be applied to three registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTI). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI cefiderocol to imipenem and DORI-05 doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug. RESULTS: In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR. CONCLUSIONS: DOOR can effectively be utilized in registrational cUTI trials. The DOOR endpoint presented here can be adapted for other infectious diseases syndromes and prospectively incorporated into future clinical trials.

Department

Biostatistics and Bioinformatics

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