Intent-to-treat vs non-intent-to-treat analyses under treatment non adherence in mental health randomized trials.

The intent-to-treat (ITT) principle has long been mandated by the Food and Drug Administration (FDA) as the primary design and analysis strategy for industry clinical trials and also has been adopted widely in government-funded randomized clinical trials. Intent-to-treat analysis aims to estimate the effect of treatment as offered, or as assigned. This analysis entails comparisons of randomized groups and include outcome data for all randomized participants regardless of their status regarding non-adherence to assigned treatment protocols and missed assessment encounters. Petkova and Teresi attributed the term “intent-to-treat” to Hill with a common refrain “once randomized, always analyzed.” FDA regulations emphasize this point in more formal language: “The intention-to-treat principle implies that the primary analysis should include all randomized subjects. Compliance with this principle would necessitate complete follow-up of all randomized subjects for study outcomes.” While the ITT principle has been the dominant design and analysis paradigm for clinical trials in a variety of contexts, other approaches, which we refer to as “Non-ITT analyses,” aim to estimate the effect of treatment as delivered or as received (as opposed to “as assigned” under the ITT approach) to account for treatment non-adherence. These Non- ITT analyses are commonly presented as secondary analyses in terms of as-treated or per-protocol treatment effects along with ITT results. Indeed, the FDA allows for such supplementary results: “Under many circumstances, it (use of the full analysis set) may also provide estimates of treatment effects that are more likely to mirror those observed in subsequent practice.” Such sentiments have been voiced not only about data analysis, but also the need to collect adherence data as outcomes in addition to clinical outcomes. PMC ID: PMC2921714 (December 2008)