How do intention-to-treat (ITT) and per-protocol (PP) analyses differ, and how do they affect interpretation of trial results?

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Intention-to-treat and per-protocol analyses address what happens when participants don’t follow the assigned plan. Intention-to-treat includes every randomized participant in the analysis, regardless of adherence or dropouts. This preserves the randomization, so baseline balance is maintained, and the results reflect real-world effectiveness where patients may not fully comply. Because some participants may not follow the protocol, the difference between groups can be muted, making the overall effect estimate more conservative.

Per-protocol analysis, on the other hand, includes only those who fully adhered to the protocol. This can reveal how effective the treatment is under ideal conditions, but it introduces potential bias because adherence is not random—participants who stay compliant may differ in important ways (motivation, health status, risk factors) from those who do not, which can overstate the treatment’s effect and limit generalizability.

In practice, ITT is often favored for primary conclusions about effectiveness in a typical clinical setting, while PP is useful for exploring the potential efficacy with good adherence, with the caveat that its estimates should be interpreted with awareness of possible bias. Sensitivity analyses that report both perspectives help provide a fuller picture of how adherence impacts the results.