Patient-Centric Pragmatic Clinical Trials: Opening the DOOR

Document Type

Journal Article

Publication Date

2-1-2026

Journal

Statistics in medicine

Volume

45

Issue

3-5

DOI

10.1002/sim.70328

Keywords

DOOR; DOOR probability; benefit:risk; partial credit; patient‐centric; pragmatic trials

Abstract

Randomized clinical trials are the gold standard for evaluating the benefits and harms of interventions, though they often fail to provide the necessary evidence to inform medical decision-making. Primary reasons are failure to recognize the most important questions for informing clinical practice, and that traditional approaches do not directly address these most important questions, and subsequently not using these most important questions as the motivation for the design, monitoring, analysis, and reporting of clinical trials. The standard approach of analyzing one outcome at a time 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-centric responses, and since efficacy and safety analyses are often conducted on different populations, benefit:risk estimands and generalizability are unclear. Cardiovascular event prevention trials typically utilize: (1) major adverse cardiovascular events (MACE), for example, stroke, myocardial infarction, and death as the primary endpoint, which fails to recognize multiple events or the differential importance of events, and (2) relative risk models which rely on robustness-challenging modeling assumptions and are contraindicated in benefit:risk and multiple outcome evaluation. The Desirability Of Outcome Ranking (DOOR) is a paradigm for the design, data monitoring, analysis, interpretation, and reporting of clinical trials based on comprehensive patient-centric benefit:risk evaluation, developed to address these issues and advance clinical trial science. The rationale and the methodology for the design and analyses for the DOOR paradigm are described. The methods are illustrated using an example. Freely available online tools for the design and analysis of studies implementing the DOOR are provided.

Department

Biostatistics and Bioinformatics

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