BiostatisticsGlossary Term
ICH E9(R1) Section 5.2
A statistical analysis that includes only participants who completed the study according to protocol requirements, without major protocol violations, adequate treatment exposure, and complete outcome assessments.
Per-protocol analysis restricts the analysis population to participants who adhered to the protocol as designed, excluding those with major protocol deviations, inadequate treatment exposure, or missing primary endpoint data. This approach aims to evaluate treatment efficacy under optimal conditions by focusing on participants who received treatment as intended. While per-protocol analysis may provide cleaner estimates of biological efficacy, it sacrifices the protection against bias that randomization provides.
The criteria defining the per-protocol population must be specified prospectively in the statistical analysis plan before unblinding occurs. Common exclusion criteria include receipt of prohibited concomitant medications, inadequate drug exposure or compliance below a specified threshold, major protocol violations affecting efficacy assessment, and missing primary endpoint data. The criteria should be clinically and scientifically justified and should not be influenced by knowledge of outcomes or treatment assignments.
Per-protocol analysis typically serves as a supportive or sensitivity analysis rather than the primary analysis in regulatory submissions, because exclusion of randomized participants may introduce selection bias. If treatment assignment influences the likelihood of protocol adherence, the per-protocol population may no longer be balanced with respect to prognostic factors, potentially confounding the treatment comparison. However, per-protocol analysis provides valuable complementary information, and concordance between ITT and per-protocol results strengthens confidence in trial findings.
Compliance threshold
"The per-protocol population included only participants with at least 80% treatment compliance as documented through pill counts and IWRS dispensing records, excluding 23 participants who fell below this threshold."
Supportive analysis
"While the primary ITT analysis showed a 12% treatment benefit, the per-protocol analysis restricted to compliant participants showed a 16% benefit, suggesting that efficacy was even greater among those who adhered to the prescribed regimen."
A range of values calculated from study data that is expected to contain the true treatment effect with a specified probability, typically 95%, providing information about both the estimated effect size and the precision of that estimate.
A statistical analysis strategy that includes all randomized participants in the groups to which they were originally assigned, regardless of whether they completed the study treatment or adhered to the protocol.
A planned statistical analysis conducted before all participants have completed the study, typically to evaluate accumulating data for evidence of efficacy, futility, or safety concerns that might warrant early termination of the trial.
The probability of obtaining results at least as extreme as those observed in the study, assuming that the null hypothesis of no treatment effect is true.
The primary endpoint is the main outcome measure used to evaluate whether the treatment hypothesis is supported and forms the basis for regulatory approval decisions, while secondary endpoints provide supportive evidence and characterize additional treatment effects.
ICH E9(R1) Section 5.2
A statistical analysis that includes only participants who completed the study according to protocol requirements, without major protocol violations, adequate treatment exposure, and complete outcome assessments.
Per-protocol analysis restricts the analysis population to participants who adhered to the protocol as designed, excluding those with major protocol deviations, inadequate treatment exposure, or missing primary endpoint data. This approach aims to evaluate treatment efficacy under optimal conditions by focusing on participants who received treatment as intended. While per-protocol analysis may provide cleaner estimates of biological efficacy, it sacrifices the protection against bias that randomization provides.
The criteria defining the per-protocol population must be specified prospectively in the statistical analysis plan before unblinding occurs. Common exclusion criteria include receipt of prohibited concomitant medications, inadequate drug exposure or compliance below a specified threshold, major protocol violations affecting efficacy assessment, and missing primary endpoint data. The criteria should be clinically and scientifically justified and should not be influenced by knowledge of outcomes or treatment assignments.
Per-protocol analysis typically serves as a supportive or sensitivity analysis rather than the primary analysis in regulatory submissions, because exclusion of randomized participants may introduce selection bias. If treatment assignment influences the likelihood of protocol adherence, the per-protocol population may no longer be balanced with respect to prognostic factors, potentially confounding the treatment comparison. However, per-protocol analysis provides valuable complementary information, and concordance between ITT and per-protocol results strengthens confidence in trial findings.
Compliance threshold
"The per-protocol population included only participants with at least 80% treatment compliance as documented through pill counts and IWRS dispensing records, excluding 23 participants who fell below this threshold."
Supportive analysis
"While the primary ITT analysis showed a 12% treatment benefit, the per-protocol analysis restricted to compliant participants showed a 16% benefit, suggesting that efficacy was even greater among those who adhered to the prescribed regimen."
A range of values calculated from study data that is expected to contain the true treatment effect with a specified probability, typically 95%, providing information about both the estimated effect size and the precision of that estimate.
A statistical analysis strategy that includes all randomized participants in the groups to which they were originally assigned, regardless of whether they completed the study treatment or adhered to the protocol.
A planned statistical analysis conducted before all participants have completed the study, typically to evaluate accumulating data for evidence of efficacy, futility, or safety concerns that might warrant early termination of the trial.
The probability of obtaining results at least as extreme as those observed in the study, assuming that the null hypothesis of no treatment effect is true.
The primary endpoint is the main outcome measure used to evaluate whether the treatment hypothesis is supported and forms the basis for regulatory approval decisions, while secondary endpoints provide supportive evidence and characterize additional treatment effects.