On Biostatistics and Clinical Trials: Should We Follow ICH E9 Addendum to Include the Estimands in all Clinical Trial Protocols?

ICH E9 "Statistical Principles for Clinical Trials" was issued in 1998 - more than 20 years ago. While the principles specified in ICH E9 are still being followed, a call for a revision or addendum has been there for many years. In 2017, the draft version of ICH E9 (R1) “Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials” was released and at the end of 2019, ICH E9 (R1) was finalized. The E9 (R1) guidelines are now gradually been adopted by various regulatory agencies. In terms of the implementation, EMA seems to be ahead of the US requiring the sponsors to include the concept of Estimands in the regulatory submissions.

Purpose and scope of the addendum to ICH E9:

Provides a framework for describing with precision a treatment effect of interest
Precision in describing a treatment effect of interest is facilitated by constructing the “estimand”
Estimand: 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
Clarity requires a thoughtful envisioning of “intercurrent events” such as discontinuation of assigned treatment, use of additional or alternative treatment, and terminal events such as death
Intercurrent Events: Events occurring after treatment initiation that affect either the interpretation of the existence of the measurements associated with the clinical question of interest
It is necessary to address intercurrent events when describing the clinical question of interest in order to precisely define the treatment effect that is to be estimated
Addendum introduces strategies to reflect different questions of interest that might be posed
Attributes used to construct the estimand are also introduced in the addendum
Addendum clarifies the definition and the role of sensitivity analysis
Sensitivity Analysis: A series of analyses conducted with the intent to explore the robustness of inferences from the main estimator to deviations from its underlying modeling assumptions and limitations in the data

Estimand attributes:

Treatment: The treatment condition of interest and, as appropriate, the alternative treatment condition to which comparison will be made
Population: Patients targeted by the clinical question
Variable (or endpoint): Obtained for each patient and required to address the clinical question
Population-level summary: Provides a basis for comparison between treatment conditions for the variable
Handling of intercurrent events

While FDA has not mandated the implementation of the ICH E9 (R1), there seems to be a trend in the industry that ICH E9 (R1) is gradually being adopted and the concept ‘estimands’ is being mentioned in the study protocols and statistical analysis plans (SAPs).

Looking at the clinical trial protocol and SAP templates developed by TransCelerate Biopharma, both contained a section about estimands and the estimands was listed together with endpoints.

In my previous post "Should Clinical Trial Protocol be Made Public While the Trial is still ongoing?", I mentioned that the protocols for three phase III studies for Covid-19 vaccine were all made public because of the demand for transparency. I examed all three protocols and they had described the 'estimands'. The concept of 'intercurrent events', 'principal stratum strategy', 'treatment policy' was also mentioned.

In Phase III study protocol by Moderna "A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older":

In the estimand of the primary analysis on the primary endpoint, a treatment policy strategy will be used to address the intercurrent events of 1) withdrawal from the study or death unrelated to COVID-19, where the time to COVID-19 will be censored at the date of withdrawal from the study or death; 2) early COVID-19, where the time to COVID-19 will be censored at the time of early infection. Principal stratum strategy will be used to address the other 2 types of intercurrent events in the primary analysis based on the PP Set. The details of intercurrent event description and estimand strategies are presented in Section 11.4.1.

In Phase III study protocol by AstraZeneca / Oxford "A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study in Adults to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 VectorVaccine, for the Prevention of COVID-19":

The primary estimand will be used for the analysis of the primary efficacy endpoint. It will be based on participants in the full analysis set, defined as all randomized participants who received at least 1 dose of study intervention excluding those participants who are seropositive at baseline, analyzed according to their randomized treatment. For participants with multiple events, only the first occurrence will be used for the primary efficacy endpoint analysis. The set of intercurrent events for this estimand consists of participants who withdraw from the study prior to having met the primary efficacy endpoint. The intercurrent events will be handled using the treatment policy strategy and the absence of data following these participants’ withdrawal will be treated as missing (ie, counted as not having met the criteria). Participants who withdraw before 15 days post second dose or who have a case prior to 15 days post second dose will be excluded from primary endpoint analysis.
Additional estimands will be specified for the primary efficacy endpoint to carry out sensitivity analyses for assessing the robustness of results. These sensitivity analyses will explore different methods for handling intercurrent events and different assumptions for missing data. Estimands will also be specified for the analysis of secondary endpoints. Full details will be provided in the SAP.

In Phase III study protocol by Pfizer/BioNtech "A Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-2 RNA Vaccine Candidates Against COVID-19 in Healthy Individuals":

It looks like that the concept of 'estimands' has not been widely accepted by the medical community - it is indeed a new concept and a new term for clinical trialists to digest. Using a most recent paper in the New England Journal of Medicine (Rabe et al 2020 "Triple Inhaled Therapy at Two Glucocorticoid
Doses in Moderate-to-Very-Severe COPD"), the main body of the article had no mention of the concept of 'estimands' even though the attached protocol and SAP contained a section about 'estimands':