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JAMA Guide to Statistics and Methods
August 3, 2021

Interpreting the Results of Intention-to-Treat, Per-Protocol, and As-Treated Analyses of Clinical Trials

Author Affiliations
  • 1Department of Population Health Sciences, Duke University, Durham, North Carolina
  • 2Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham VA Medical Center, Durham, North Carolina
  • 3Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
  • 4Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
JAMA. 2021;326(5):433-434. doi:10.1001/jama.2021.2825

Nonadherence in a randomized clinical trial (RCT) occurs when study participants do not follow the randomly assigned treatment protocol. Reasons for nonadherence may include the study participant not taking trial medications, crossing over to the other intervention being studied, or accessing treatment outside of the trial. Nonadherence also may occur when the clinician is unable to complete the assigned therapy (eg, a surgical procedure) as intended.

The CABANA clinical trial published in JAMA by Packer et al1 was difficult to interpret because of nonadherence with the treatment protocol that resulted from substantial crossover between groups. In this trial, patients with atrial fibrillation were randomized to either undergo catheter ablation or receive conventional medical therapy. Of the 1108 participants randomized to ablation, 102 (9%) did not receive the procedure. Of the 1096 patients randomized to drug therapy, 301 (27%) underwent ablation during the follow-up period, resulting in nonadherence to assigned treatment in both groups of the study. Interpretation of the effect of catheter ablation on atrial fibrillation differed based on alternate ways of analyzing the trials results. Intention-to-treat (ITT), per-protocol (PP), and as-treated (AT) approaches to analysis differ in how the included patient population and treatment assignments are defined, with important implications for interpretation of treatment effects in clinical trials.

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