Exploration of a Potential Desirability of Outcome Ranking Endpoint for Complicated Intra-Abdominal Infections Using 9 Registrational Trials for Antibacterial Drugs

Tori Kinamon, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
Ramya Gopinath, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
Ursula Waack, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
Mark Needles, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
Daniel Rubin, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
Deborah Collyar, Patient Advocates in Research, Danville, CA, USA.
Sarah B. Doernberg, Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, CA, USA.
Scott Evans, Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, District of Columbia.
Toshimitsu Hamasaki, Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Washington, District of Columbia.
Thomas L. Holland, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Jessica Howard-Anderson, Antibiotic Resistance Leadership Group, Durham, NC, USA.
Henry Chambers, Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, CA, USA.
Vance G. Fowler, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Sumati Nambiar, Antibiotic Resistance Leadership Group, Durham, NC, USA.
Peter Kim, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA.
Helen W. Boucher, Antibiotic Resistance Leadership Group, Durham, NC, USA.

Document Type

Journal Article

Publication Date

8-22-2023

Journal

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

Volume

77

Issue

4

DOI

10.1093/cid/ciad239

Keywords

DOOR; antimicrobial therapy; clinical trials; endpoints; intra-abdominal infection

Abstract

BACKGROUND: Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI). METHODS: Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator. RESULTS: Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator. CONCLUSIONS: We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease-specific DOOR endpoints.

Department

Biostatistics and Bioinformatics

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