The objective of a clinical study is to answer pre-defined research questions. Goal setting involves the main parameters of the study, such as: subjects to be included, data management (including missing data), and the method of statistical analysis. The ICH represents a framework for estimators, which is useful in precisely defining the treatment effect.
Study planning should proceed according to a sequential method. The objective of the trial must determine the choice of estimands, and those estimands must determine the choice of estimators, not the other way around. The construction of the estimand must take into account what is of clinical relevance to the particular treatment in the relevant therapeutic setting. Underlying considerations include:
- Pathology under study;
- Clinical context (e.g., whether alternative treatments are available);
- Type of treatment administration;
- Goal of treatment (e.g., for preventive purposes, or symptom control…).
GOAL AND METHOD OF THE ESTIMAND
Each individual investigation objective, or endpoint, must be matched by an appropriate estimand (what is to be estimated). More specifically, the addendum to ICH E9, suggests aligning the estimand using sensitivity analysis, for each given endpoint of the trial. Identifying such cascading steps allows us to have a reliable and more effective statistical methodological approach, but more importantly it allows both Sponsors and regulatory reviewers to communicate on a common substrate.
Defining the study objectives should be an iterative process, directly predicting how the events intercurrent with the treatment effect of interest will be handled.
INTERCURRENT EVENTS AND MISSING DATA
Intercurrent events are events that occur subsequent to the onset of treatment and that affect or may affect both the interpretation and the very reliability of the measurements related to the question under interest. Therefore, it is necessary to consider potential intercurrent events precisely when describing the question under investigation in order to accurately define the treatment effect that is to be estimated.
Intercurrent events result from various patient pathways during the course of the study. For example, if we are interested in a patient reported outcome (PRO) endpoint at month 6, some patients will still be on treatment and their PRO results will reflect the 6 months of treatment, others may stop treatment because of an adverse event and start a new therapy.
Taking another example: imagine an end-of-life study in cancer patients, in which drugs are developed and administered to maintain weight, clinical status, and quality of life for the patient’s remaining lifespan.
Thus, measures to assess efficacy will be items such as body composition (DEXA), body weight, hand grip strength, and quality of life (QoL) rating scales. The intervening event here will be that a nonnegligible percentage of patients may not survive and must be considered in defining the treatment effect of interest.
In the absence of an indication of the estimand (effect of the treatment of interest) within the clinical protocol, deaths will be treated as missing data and therefore it will be difficult to interpret the results of the survey; therefore, it is essential to consider missing data in addition to intercurrent events, i.e., those data that would be significant for the analysis of a given estimand but have not been collected, which should be distinguished from data that do not exist or from data that are missing due to an intercurrent event.
THE NEW TRIALS.
The application of the E9 guideline is growing in studies conducted different therapeutic areas. Authorities have already recognized value in providing a common language to facilitate discussions with all stakeholders in clinical trials. For example, the FDA guideline called “Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision Making” includes a discussion of estimands and presents an example of application in breast cancer, considering not only clinical variables, but also and especially patient-reported outcomes (PROs).
This new approach to measuring therapeutic effects, linked to study objectives, will radically change the way clinical trials are designed, analyzed and interpreted, as well as the data collection strategy. In the context of PROs (patient reported-outcomes), there is an emerging opportunity to specify more precisely the rationale for patient-centered objectives. By developing precise objectives, especially considering the patient’s perspective of the treatment, and adopting appropriate estimands, it will be possible to ensure the collection of data that possess real clinical significance and provide a clear interpretation. Such an approach enables interpretative uniformity and clear assessment of the effect of patient-centered treatments, contributing to the rapid approval of effective therapies.
Edited by Dr. Monica Tocchi, medical director.
 Estimandi (Estimand): The word estimand used here refers to a specific statistical technical term used in clinical research, namely estimand, for which ICH E9 defines the scope and meaning.