10.2 - Intention-to-Treat

Intention-to-treat (ITT) is the principle that patients in a randomized clinical trial should be analyzed according to the group to which they were assigned, even if they did not

  1. receive the intended treatment,
  2. did not adhere to the treatment regimen, or
  3. comply with the protocol in any manner.

The ITT Principle is a generalization of the pragmatic approach while the Treatment received (TR) or a protocol analysis is the principle that patients should be analyzed according to the treatment they actually received.

Most statisticians favor the ITT principle because it yields the best properties for the test of the null hypothesis of no treatment difference. "If randomized, then analyzed" is the view widely held among clinical trial statisticians and considered a critical component of the ITT Principle to avoid biases due to post-randomization exclusions. ITT also is favored by the federal agencies because a clinical trial is a test of treatment policy, not a test of treatment received. After a meeting to discuss clinical trials methodology, which included US FDA representatives, the International Conference on Harmonization (ICH) published a document entitled "Statistical Principles for Clinical Trials (E9)" that discusses the ITT Principle under various circumstances.

According to the E9 document there are a limited number of circumstances in which randomized patients can be excluded from the full analysis set. Patients who failed to satisfy an entry criterion may be excluded from the full analysis set only under the following circumstances:

  1. The entry criterion was measured prior to randomization
  2. The detection of the relevant eligibility violations can be objectively determined
  3. All patients underwent similar scrutiny for eligibility violations
  4. All patients with detected violations of the eligibility criterion are excluded

Although the ITT principle generally is preferred, it can be misleading in some circumstances. For example, consider a situation in which a new therapy is compared to placebo. Suppose that a patient undergoing treatment failure is provided emergency medications for safety purposes. If the placebo group has a higher failure rate, it actually could appear to be more beneficial than the new therapy in an ITT analysis because of the emergency medications (even though this may seem to be a design flaw of the trial). In such a situation, the statistical analysis would be better served with time to treatment failure as the primary endpoint. This analysis would still include all patients, but using time to failure as the primary endpoint eliminates the problem of misleading results from the ITT analysis.

Many factors can contribute to a patient's failure to complete the intended therapy, including severe adverse reactions, disease progression, patient or physician preference for an alternative treatment, and a change of mind. In nearly all of these circumstances, failure to complete the assigned therapy is partially a trial outcome. Patients cannot be eliminated from analysis for such reasons without introducing bias.