When is Per-Protocol (PP) analysis typically preferred as the primary analysis?

Per-Protocol analysis is typically preferred as the primary analysis in non-inferiority trials. This is because ITT analysis in non-inferiority trials may dilute the true treatment effect, potentially leading to an erroneous conclusion of non-inferiority when there is a meaningful difference.

Why is it important to compare ITT and PP results in MedTech clinical trials?

Comparing ITT and PP results is crucial for a comprehensive understanding of treatment effects and to assess the robustness of the trial findings. Significant discrepancies between these analyses can indicate issues such as differential dropout rates or non-adherence, which regulators will scrutinize.

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Clinical & TrialsClinical EvidenceITT / PP

Intent-to-Treat vs Per-Protocol

Two analysis populations: ITT analyzes everyone randomized; PP analyzes only those compliant with protocol.

Reviewed by Christian Espinosa, Founder, Blue Goat CyberLast reviewed May 5, 2026

Definition

ITT preserves randomization and is the primary analysis for superiority trials. Per-Protocol analyses are typically supportive - and primary in non-inferiority trials, where ITT can bias toward 'no difference'. ITT analyzes all randomized subjects in their assigned group, whatever happened next, while per-protocol excludes subjects with major protocol deviations. Modified ITT variants, such as subjects who received the device, are common in device trials and must be defined in advance. The ICH E9(R1) estimand framework now encourages sponsors to state exactly which treatment effect they are estimating.

What the regulation says

The FDA and other regulatory bodies emphasize the importance of both Intent-to-Treat (ITT) and Per-Protocol (PP) analyses in clinical trials, particularly for MedTech devices. Regulators typically expect ITT to be the primary analysis for superiority trials to maintain the benefits of randomization. For non-inferiority trials, PP analysis is often considered primary, as ITT can sometimes obscure important treatment differences and bias towards a finding of non-inferiority, as outlined in FDA guidance documents on non-inferiority clinical trials.

What this means in practice

Non-inferiority device trials require pre-specified analysis populations and consistent ITT/PP results; mismatch is a frequent reason for FDA panel debate.

Examples

A superiority trial for a new cardiac stent uses ITT analysis as the primary endpoint to assess whether the new stent is statistically significantly better than an existing one, including all randomized patients regardless of whether they received the assigned stent.
A non-inferiority trial for a diagnostic imaging device primarily uses PP analysis to demonstrate that the new device is not clinically worse than the current standard, focusing on patients who completed the study according to protocol.
During an FDA review of an orthopedic implant trial, a significant divergence between ITT and PP results prompts the agency to request further justification from the manufacturer regarding patient adherence and dropout rates.

Common pitfalls

•Misinterpreting an ITT analysis that shows no significant difference as a definitive lack of treatment effect, when a PP analysis might reveal otherwise.
•Failing to pre-specify the analysis populations for both ITT and PP analyses in the clinical trial protocol.
•Not adequately addressing discrepancies between ITT and PP results in regulatory submissions, leading to questions or objections from regulatory bodies.
•Applying ITT analysis as the primary endpoint in a non-inferiority trial without careful consideration of its potential to bias the results toward equivalence.
•Excluding participants from the ITT analysis who dropped out or did not adhere to the protocol, thereby compromising the integrity of randomization.

Frequently asked questions

The primary advantage of ITT analysis is that it preserves the integrity of randomization, preventing bias that can arise from participant dropout or non-adherence. It provides a more conservative estimate of treatment effect in superiority trials, reflecting real-world effectiveness.

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Sources

3 sources

Every citation below opens the original document. Each is graded against our source-tier hierarchy so you can see what rests on binding law versus commentary.

Tier 2Regulator guidance and consensus· 2Tier 3Peer-reviewed and registry evidence· 1

Link health: 3 verified· last checked 2026-06-20

ICH·2NIH·1

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Category: Clinical & Trials
Acronym: ITT / PP
Sources: 3
Updated: 5/5/2026

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Learn in 60 seconds

Two analysis populations: ITT analyzes everyone randomized; PP analyzes only those compliant with protocol.

·Non-inferiority device trials require pre-specified analysis populations and consistent ITT/PP results; mismatch is a frequent reason for FDA panel debate.
·Per-Protocol analyses are typically supportive - and primary in non-inferiority trials, where ITT can bias toward 'no difference'.
·ITT analyzes all randomized subjects in their assigned group, whatever happened next, while per-protocol excludes subjects with major protocol deviations.

Remember this

Watch out: Misinterpreting an ITT analysis that shows no significant difference as a definitive lack of treatment effect, when a PP analysis might reveal otherwise.

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