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This JAMA Guide to Statistics and Methods explains the intention-to-treat principle, which defines the study population included in the primary efficacy analysis and how the outcomes are analyzed, including why the intention-to-treat principle is used and its limitations.

The intention-to-treat (ITT) principle is a cornerstone in the interpretation of randomized clinical trials (RCTs) conducted with the goal of influencing the selection of medical therapy for well-defined groups of patients. The ITT principle defines both the study population included in the primary efficacy analysis and how the outcomes are analyzed. Under ITT, study participants are analyzed as members of the treatment group to which they were randomized regardless of their adherence to, or whether they received, the intended treatment.1-3 For example, in a trial in which patients are randomized to receive either treatment A or treatment B, a patient may be randomized to receive treatment A but erroneously receive treatment B, or never receive any treatment, or not adhere to treatment A. In all of these situations, the patient would be included in group A when comparing treatment outcomes using an ITT analysis. Eliminating study participants who were randomized but not treated or moving participants between treatment groups according to the treatment they received would violate the ITT principle.

Robertson et al conducted an RCT using a factorial design to compare transfusion thresholds of 10 and 7 g/dL and administration of erythropoietin vs placebo in 895 patients with anemia and traumatic brain injury.4 The primary outcome was the 6-month Glasgow Outcome Scale (GOS), dichotomized so a good or moderate score indicated success. The trial was conducted with high fidelity to the protocol, so only a few patients did not receive the intended treatment strategy. Two patients randomized to the 7-g/dL study group were managed according to the 10-g/dL threshold and an additional 2 patients randomized to the 7-g/dL study group received one transfusion not according to protocol. The authors implemented the ITT principle and the outcomes for these 4 patients were included in the 7-g/dL group.


Why Is ITT Analysis Used?

The effectiveness of a therapy is not simply determined by its pure biological effect but is also influenced by the physician's ability to administer, or the patient's ability to adhere to, the intended treatment. The true effect of selecting a treatment is a combination of biological effects, variations in compliance or adherence, and other patient characteristics that influence efficacy. Only by retaining all patients intended to receive a given treatment in their original treatment group can researchers and clinicians obtain an unbiased estimate of the effect of selecting one treatment over another.

Treatment adherence often depends on many patient and clinician factors that may not be anticipated or are impossible to measure and that influence response to treatment. For example, in the study ...

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