New ICH E9 Addendum reaches Step 2b of the ICH Process

The International Council for Harmonisation (ICH) informed on September 4, 2017, that the E9(R1) Addendum Estimands and Sensitivity Analysis in Clinical Trials reached Step 2b of the ICH Process and now enters the consultation period. The deadline for comments for EC (Europe) is February 28, 2018.

"The ICH E9(R1) Addendum promotes harmonized standards on the choice of estimand in clinical trials and describes an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data", the council says.

The 24 page addendum was proposed to provide clarification on E9. It presents an update on the choice of estimand in clinical trials to describe an agreed framework for planning, conducting and interpreting sensitivity analyses of clinical trial data. The addendum is proposed to focus on statistical principles related to estimands and sensitivity analysis, not on the use or acceptability of specific statistical procedures or methods. "The statistical analysis, aligned to the estimand, will be associated with assumptions and data limitations, the impact of which can be investigated through sensitivity analysis". While a variety of mid-stage and late-stage clinical trials may be in scope, the primary focus of the addendum will be on confirmatory clinical trials. Furthermore, the addendum clarifies and extends the current ICH E9 of 1998 in a number of aspects.

Background
An estimand is that which is to be estimated in a statistical analysis, i.e. the target of estimation for a particular trial objective (“what is to be estimated”), through specification of:

• the population of interest,
• the variable (or endpoint) of interest,
• the handling of intercurrent events (events that occur after treatment initiation and either preclude observation of the variable or affect its interpretation),
• the population-level summary for the variable.

A suitable method of estimation can then be selected. An estimand is closely linked to the purpose or objective of an analysis. It describes what is to be estimated based on the question of interest. This is in contrast to an estimator (= analytic approach to compute an estimate from observed clinical trial data), which defines the specific rule according to which the estimand is to be estimated. The main estimator will be underpinned by certain assumptions. To explore the robustness of inferences from the main estimator to deviations from its underlying modelling assumptions and limitations in the data, a sensitivity analysis should be conducted, in form of one or more analyses, targeting the same estimand with differing assumptions.

The framework enables proper trial planning that clearly distinguishes between the target of estimation (estimand), the method of estimation (resulting in an estimate = numerical value computed by an estimator based on the observed clinical trial data), and a sensitivity analysis. "This will assist sponsors in planning trials, regulators in their reviews, and will enhance the interactions between these parties when discussing the suitability of clinical trial designs, and the interpretation of clinical trial results, to support drug licensing", ICH notes. In general, it is important to proceed sequentially, and not for the choice of an estimator to determine the estimand, and hence the scientific question that is being addressed. The specification of appropriate estimands will usually be the main determinant for aspects of trial design, conduct and analysis.

Comments on the ICH E9(R1) draft Addendum document can be provided by e-mailing the ICH Secretariat. More details can be found under ICH´s Public Consultation page. Please note that stakeholders from ICH Regions are encouraged to submit their comments to their respective regulatory authorities.