Improving traditional intention-to-treat analyses: A new approach

BACKGROUND: Drop-out, often accompanied by treatment non-compliance, is common in psychiatric trials. Methodologists have criticized the use of a traditional intention-to-treat (ITT) approach in such cases, and have proposed alternative methods. We set out to describe and assess methods for estimation of a treatment effect when the trial is 'broken'. METHOD: We describe a stratified method of moments (SMOM) estimator that assesses treatment effects on subjects who are willing to comply with all the treatments under study. A simulation study and a re-analysis of data from an antipsychotics trial are used to compare SMOM to ITT, as-treated, and adequate estimators. RESULTS: The new estimator retains good statistical properties under different levels of non-compliance and drop-out mechanisms. The re-analysis indicates that SMOM yields more precise results. CONCLUSIONS: Although the traditional ITT approach provides a valid method to estimate treatment effects, it can be biased in the presence of treatment non-compliance and drop-out. It is critical that researchers move beyond traditional approaches when trials are broken. A key first step is to consider non-compliance and drop-out as two independent phenomena, tracking and reporting rates separately. (July 2005)