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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'.
    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.
    Grouped by theme

    Primary references

    3 sources
    Link health: 3 verified· last checked 2026-06-20
    ICH·2NIH·1
    1. 1
      ICH E9
      Verified
      ICHich.org
    2. 2
      ClinicalTrials.gov
      Verified
      NIHclinicaltrials.gov
    3. 3
      ICH Guidelines
      Verified
      ICHich.org

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