Chair: Xiaofei Wang, PhD (Duke University)
Instructors:
Toshimitsu Hamasaki, PhD (George Washington University)
Scott Evans, PhD (George Washington University)
Daniel Rubin, PhD (FDA)
Course Description:
Randomized clinical trials are the gold standard for evaluating the benefits and harms of interventions but they often fail to provide the necessary evidence to inform medical decision-making (DeMets and Califf, JAMA 2011, 305:713-714). One primary reason for this is a lack of awareness of the nature of benefit:risk, which is the most important question when treating patients in clinical practice. This is the motivation for using a patient-centric, benefit:risk approach to the design, monitoring, analysis, interpretation and reporting of clinical trials and medical product development.
Standard approaches to benefit:risk evaluation synthesizing information obtained from separate marginal analysis of each outcome do not address the most important questions for clinical practice as they are not patient-centric. They fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities in the interpretation of component outcomes, and since efficacy and safety analyses are often conducted on different populations, generalizability to patient populations is unclear. Treatment effect heterogeneity is typically evaluated based on a single efficacy or safety endpoint, and rarely evaluated based on benefit:risk. These challenges can be addressed by placing increased emphasis on patient-centric benefit:risk evaluation and questions of a pragmatic origin to match their clinical importance.
These challenges can be addressed by placing increased emphasis on patient-centric benefit:risk evaluation and questions of a pragmatic origin to match their clinical importance. In this short course, we will discuss the patient-centered method of assessing benefit:risk, called the Desirability of Outcome Ranking (DOOR). The desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, interpretation and reporting of clinical trials and other research studies based on patient-centric benefit:risk evaluation (Evans SR, Rubin D, Follmann D et al. Clin Infect Dis. 2015; 61:800-806, Evans SR, Follmann D. Stat Biopharm Res. 2016;8:386-393). The DOOR methodology uses outcomes to analyze patients rather than patients to analyze outcomes by comparing the experiences of trial participants in different treatment arms by the desirability of the overall patient outcome. The motivation for DOOR is to address the above limitations, 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?
In this course, we present several ways to define a DOOR outcome, which represents a global patient response constructed on the basis of important clinical outcomes. We describe two complementary statistical approaches for analyzing clinical trial data using the DOOR methodology, with applications to clinical trials in infectious diseases and other disease areas. We present an interactive web-based tool for implementing the DOOR methodology that allows statisticians and clinical researchers to easily perform the analyses. We discuss methods for sizing clinical trials with the DOOR outcome as the primary endpoint. Finally, we briefly discuss further developments in design and analysis of randomized trials using the DOOR methodology, including (1) subgroup analyses, (2) benefit: risk evaluation in longitudinal and survival trials, (3) integrated benefit:risk analysis of multiple trials, and (4) group-sequential and adaptive designs for monitoring trials.
Instructors:
Toshimitsu Hamasaki, PhD
The Biostatistics Center and the Department of Biostatistics and Bioinformatics
Milken Institute School of Public Health
George Washington University
6110 Executive Boulevard, Suite 750, Rockville, MD 20852
Dr. Toshimitsu Hamasaki is a Professor of the George Washington University Biostatistics Center and the Department of Biostatistics and Bioinformatics. His research interests include the design, monitoring, analyses, and reporting of clinical trials. He is the author of more than 200 peer-reviewed publications and four textbooks on statistical methods in clinical trials. Dr. Hamasaki is the Editor-in-Chief of Statistics in Biopharmaceutical Research, an Official Publication of the American Statistical Association (ASA). He served on the Steering Committee for the Adaptive designs CONSORT Extension (ACE) Project, an extension to the CONsolidated Standards of Reporting Trials (CONSORT) Statement for adaptive clinical trials. He has served as an ad hoc grant reviewer and on data and safety monitoring boards for NIH-funded trials in antibacterial resistance and cardiovascular diseases. Dr. Hamasaki is an elected member of the International Statistical Institute and a fellow of the ASA and the Society for Clinical Trials (SCT). Dr. Hamasaki’s recent research has focused on the DOOR.
Scott Evans, PhD
Director, The Biostatistics Center
Professor and Founding Chair, Department of Biostatistics and Bioinformatics
Milken Institute School of Public Health
George Washington University
6110 Executive Boulevard, Suite 750, Rockville, MD 20852
Dr. Scott Evans is a Professor and Founding Chair of the Department of Biostatistics Bioinformatics and the Director of The Biostatistics Center at 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 Co-Chair of the Benefit-Risk Balance for Medicinal Products Working Group of the Council for International Organizations of Medical Sciences (CIOMS); Editor of a mini-Series on DSMBs for the NEJM Evidence; and the President-elect 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).He is an originator of the DOOR and has published several papers on DOOR.
Daniel Rubin, PhD
Statistician
Office of Biostatistics at the Center for Drug Evaluation
Food and Drug Administration
Dr. Daniel Rubin is a statistician in the Office of Biostatistics at the Center for Drug Evaluation and Research of the US Food and Drug Administration (FDA). His career has focused on the design, conduct, and analysis of clinical trials to evaluate the safety and efficacy of drugs for infectious diseases. He has worked on multiple FDA guidance documents, published extensively in statistical and medical journals, and co-authored several papers on the Desirability Of Outcome Ranking (DOOR) methodology.
