TITLE: The DOOR is Open: Patient-centric, Pragmatic Benefit-Risk Evaluation in Clinical Trials
SPEAKER: Scott Evans and Toshimitsu Hamasaki, George Washington University
Moderator: Alfred H. Balch
Abstract:
Randomized clinical trials (RCTs) are the gold standard for evaluating the benefits and harms of interventions. However commonly used design and analysis approaches to RCTs often are not suited to answer the most important research questions to inform medical decision-making. Typically efficacy and safety are evaluated in silos, one outcome at a time. However this approach: fails to incorporate associations between or the cumulative nature of multiple outcomes in individual patients, suffers from competing risk complexities during interpretation of individual outcomes, fails to recognize important gradations of patient responses, suboptimally evaluates treatment effect heterogeneity based on a single endpoint rather than benefit:risk considerations, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear.
The Council for International Organizations of Medical Sciences (CIOMS) released “Benefit-risk balance for medicinal products” in 2025. Included within the report are two new points of emphasis: (1) transitioning benefit-risk evaluation as a post-hoc exercise to incorporating benefit-risk considerations into clinical trial design, and (2) a pragmatic patient-centric approach to benefit-risk assessment reflecting how benefits and harms are experienced by patients to better align with the goals of informing clinical practice.
The desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials and other research studies based on patient-centric benefit-risk evaluation, developed to address these issues and advance clinical trial science. In this paradigm outcomes are used to analyze patients rather than patients being used to analyze outcomes. The experiences of trial participants in different treatment arms are compared by the desirability of the overall patient outcome, increasing pragmatism and addressing the most important “real world” question to aid clinical decision-making: how do resulting patient experiences, when comprehensively considering benefits and harms, compare between therapeutic alternatives? We describe the DOOR paradigm; define guiding principles to maximize replicability, robustness, objectivity, transparency, and pragmatism; outline a recommended statistical analysis plan; illustrate application with examples; and demo a freely-available online application for implementing the recommended DOOR analyses and the design of studies implementing DOOR.
Instructors’ Biography:
Dr. Scott Evans is a Professor and Founding Chair of the Department of Biostatistics and Bioinformatics and the Director of the Biostatistics Center at Milken Institute School of Public Health of the George Washington University. He is the: Director of the Statistical and Data Management Center for the Antibacterial Resistance Leadership Group (ARLG) funded by NIAID/NIH; the PI of the Coordinating Center for the Exercise and Nutrition Interventions to Improve Cancer Treatment-Related Outcomes (ENICTO) in Cancer Survivors Consortium funded by the NCI/NIH, and the co-PI of the Data Coordinating Center of the Clamp OR Delay among neonates with Congenital Heart Disease (CORD-CHD) clinical trial funded by the NHLBI/NIH. He is the author of more than 250 publications and four books on clinical trials. He served as: the Guest Editor of a mini-Series on DSMBs for the NEJM Evidence; a member of an FDA Advisory Committee; and the past-President of the Society for Clinical Trials (SCT). He is a recipient of the Mosteller Statistician Award, the Zackin Distinguished Collaborative Statistician Award, the Founders Award from the American Statistical Association (ASA), an elected member of the International Statistical Institute (ISI), and is a Fellow of the ASA, SCT, and the Infectious Disease Society of America (IDSA).
Dr. Toshimitsu Hamasaki is a Professor of Biostatistics at the Biostatistics Center and the Department of Biostatistics and Bioinformatics at the Milken Institute School of Public Health, George Washington University. His research focuses on the design, monitoring, analysis, and reporting of clinical trials. He has authored more than 200 peer-reviewed publications and four textbooks on statistical methods in clinical trials. Dr. Hamasaki served as Editor-in-Chief of Statistics in Biopharmaceutical Research, an Official Publication of the American Statistical Association (ASA), from 2000 to 2025. He was also a member of the Steering Committee for the Adaptive designs CONSORT Extension Project, an initiative to extend the CONSORT Statement for adaptive clinical trials, and participated in the ICH-E5 Guideline Implementation Working Group as a representative of the Japan Pharmaceutical Manufacturers Association. Dr. Hamasaki is an elected member of the International Statistical Institute and a Fellow of the ASA and the Society for Clinical Trials.