ICH E9 Addendum adopted

Recommendation

5-7 November 2024
Hamburg, Germany

GMP meets Development
GMP and FDA Compliance in Pharmaceutical Development and IMP Manufacturing

The ICH E9(R1) Addendum to defining the appropriate Estimand for a Clinical Trial / Sensitivity Analyses reached Step 4 of the ICH Process. The topic was endorsed by the ICH Steering Committee in 2014 and reached Step 2b of the ICH Process in September 2017.

According to ICH, the Addendum is published to provide clarification on E9 and to give an update on the choice of estimand in a clinical trial (CT), with a focus on statistical principles related to estimands and sensitivity analysis (mainly used in confirmatory clinical trials). According to ICH, the Addendum is meant to strengthen the dialogue between disciplines, "as well as between sponsor and regulator regarding the treatment effect(s) of interest that a clinical trial should address".

What is an Estimand?

According to the definition in the document, an estimand is a "precise description of the treatment effect reflecting the clinical question posed by the trial objective. It summarises at a population-level what the outcomes would be in the same patients under different treatment conditions being compared". The targets of estimation are to be defined in advance of a CT. The following Estimand Attributes are used to construct the estimand:

• The treatment condition of interest,
• The population of patients targeted by the clinical question,
• The variable (or endpoint), and 
• A population-level summary for the variable as a basis for comparison between treatment conditions.

Documenting Estimands and Sensitivity Analysis

According to the Addendum, a CT protocol / report should:

• Define and specify explicitly a primary estimand that corresponds to the primary trial objective,
• Pre-specify the main estimator that is aligned with the primary estimand and leads to the primary analysis, together with a suitable sensitivity analysis to explore the robustness under deviations from its assumptions,
• Document an estimand  - for each exploratory objective - However, this is not a regulatory requirement,
• Report results from the main, sensitivity and supplementary analyses systematically in the CT report,
• Report summaries of the number and timings of each intercurrent event in each treatment group,
• Reflect a change to the estimand through amendment to the protocol.

More information can be found in the final E9 Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the GUIDELINE ON STATISTICAL PRINCIPLES FOR CLINICAL TRIALS.