Methods: Intention-to-treat

In JAMA, Michelle Detry and Roger Lewis explain the “intention-to-treat” (ITT) principle:

[I]n 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.

Why do this?

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.

Why not do this?

[1] Noninferiority trials, which are designed to demonstrate that an experimental treatment is no worse than an established one, require special considerations. […] The intervention in group A may incorrectly appear noninferior to the intervention in group B, simply as a result of nonadherence rather than because of similar biological efficacy. […]

[2] Although the ITT principle is important for estimating the efficacy of treatments, it should not be applied in the same way in assessing the safety (eg, medication adverse effects) of interventions. […]

[3] [I]t would be unfortunate to falsely conclude, based on the ITT analysis of a phase 2 clinical trial, that a novel pharmaceutical agent is not effective when,in fact, the lack of efficacy stems from too high a dose and patients’ inability to be adherent because of intolerable adverse effects. In that case, a lower dose may yield clinically important efficacy and a tolerable adverse effect profile.

In these cases, one may be more interested in an estimate of the effect of treatment-on-the-treated (TOT), or a per-protocol analysis.

If you’re aware of good papers that explain the use and interpretation of common research methods, let me know in the comments, which are open for one week after this post’s time stamp, or by email or Twitter.


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