Incorporating estimands into clinical trial statistical analysis plans

Abstract

Background: International Council for Harmonisation (ICH) E9 Statistical Principles for Clinical Trials was developed as a consensus guidance document to encourage worldwide harmonization of the principles of statistical methodology in clinical trials. Addendum E9 (R1) clarified and extended ICH E9 with a focus on estimands and sensitivity analyses. Since the release of E9 (R1), clinical trial protocols have included estimands, but there is variation in how they are presented. Statistical analysis plans (SAPs) are increasingly becoming publicly available (e.g. posting on ClinicalTrials.gov) and present an opportunity to link estimands with planned analyses to present the alignment of trial objectives, design, conduct, and analysis. Methods: A table format was used to create a template for inclusion in SAPs that satisfies ICH E9 (R1) guidance to align statistical analysis to the estimand. The template provides a consistent structure for presentation of estimands and the associated analysis, and is applicable to a wide range of trial designs. We illustrate use of the template with a hypothetical clinical trial in HIV-1. Results: The estimand-to-analysis table template starts with the study objective describing the clinical question of interest as written in the trial protocol. The remainder of the table describes each attribute of the estimand (treatment, target population, variable, intercurrent events, and population-level summary) in the left column (ESTIMAND), while the right column describes how each attribute will be handled using the data collected in the clinical trial (ANALYSIS). The template was applied to a hypothetical, early-phase single-arm trial, modeled after a pediatric trial in HIV, where the objective was to determine the safety of a new antiretroviral drug as part of a combination antiretroviral treatment regimen in the pediatric population. Three intercurrent events were illustrated in the table: death, premature treatment discontinuation before 24 weeks, and pregnancy. An estimand-to-analysis table from a grant application that addresses the primary objective of a placebo-controlled randomized trial is also presented to demonstrate an alternative usage. Conclusion: We found the template to be useful in study design, providing a snapshot of the objective, target population, potential intercurrent events, analysis plan, and considerations for missing data in one place and facilitating discussion among stakeholders. The proposed standardized presentation of estimand attributes and analysis considerations in SAPs will provide guidance to SAP authors and consistency across studies to facilitate reviews.

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“…A per-protocol analysis will also be conducted accounting for possible cross-over patients. A description of the planned intention-to-treat and per-protocol analyses for outcome PRWE conform to the estimands framework is provided as a supplementary file [ 42 , 43 ]. Baseline patient characteristics will be analysed using simple descriptive statistics.…”

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“…It encompasses specifying the population, the intervention, the variable of interest or outcome, the summary measure to be used, and the handling of intercurrent events. 9,15 The estimator is a mathematical function that takes the observed data and produces an estimate of the target estimand. 15 Common estimators include regression models, propensity score matching, and inverse probability weighting.…”

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“… 56 , 57 , 58 While this guidance is helpful, assessing uptake of these guidelines is left to secondary studies, such as suggestions for updates to trial protocols or assessing the use of new ICH standards. 57 , 58 …”

“…Other initiatives, such as guidance from non-profit trials group TransCelerate (tranceleratebiopharmainc.com) and the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use (ich.org), provide guidelines, data and protocol standards, and models for quality in trials. [56][57][58] While this guidance is helpful, assessing uptake of these guidelines is left to secondary studies, such as suggestions for updates to trial protocols or assessing the use of new ICH standards. 57,58 On an implementation side, the Accrual to Clinical Trials network aims to support trial conduct by identifying potentially trial-eligible patients across multiple sites in the United States.…”

“…[56][57][58] While this guidance is helpful, assessing uptake of these guidelines is left to secondary studies, such as suggestions for updates to trial protocols or assessing the use of new ICH standards. 57,58 On an implementation side, the Accrual to Clinical Trials network aims to support trial conduct by identifying potentially trial-eligible patients across multiple sites in the United States. 59 The National Patient-Centered Clinical Research Network (PCORnet) has also piloted electronic health record (EHR) based strategies to improve the conduct of pragmatic trials.…”