Principles and recommendations for incorporating estimands into clinical study protocol templates

Abstract

Clinical study protocols are the foundation of good clinical studies. Prospective and multidisciplinary collaboration that pays attention to the design of all components of the study protocol can ensure that a clinical study will answer the research questions posed in a reliable manner that is meaningful for decision-makers and patients. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials provides a framework for clinical study planning to ensure alignment between study objectives, design, conduct, and analysis. The estimand or clinical question posed can be regarded as the backbone of the study and the clinical study protocol should reflect estimands accordingly. In practice, stakeholders are still learning how to embrace the estimand framework and how it impacts studies and study documents. In this paper, we anticipate that a protocol structure centred around estimands, or objectives rather than endpoints alone will prevail for all types of studies. To assist sponsors during this paradigm shift, this paper provides discussion and guidance for implementing the estimand framework in protocol templates.

Enhancing quality and impact of early phase dose-finding clinical trial protocols: SPIRIT Dose-finding Extension (SPIRIT-DEFINE) guidance

“…All these aspects influence the statistical methods for design and analysis; hence this extension recommends providing comprehensive information on statistical methods covering these adaptive features and requiring clear definitions of analysis populations and plans for handling intercurrent events that occur after treatment initiation 51. Both analysis populations and intercurrent events relate to the estimands framework, which provides guidance on defining the treatment effect under investigation in a clinical trial (for details, see the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum on estimands910).…”

“…Estimands provide a structural framework to define the target of estimation for a particular clinical trial objective 910. They require to specify the treatment condition of interest, the population targeted by the clinical question, the variable of interest or endpoint used to answer that question, the handling strategies for intercurrent events (ie, events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question), and a population level summary of the variable or endpoint.…”

Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT Dose-finding Extension (CONSORT-DEFINE) guidance

“…Both analysis populations and intercurrent events are related to the estimands framework, which provides guidance on defining the treatment effect under investigation in a clinical trial (see the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum on estimands for further details 11 ). 12 …”

“…Estimands provide a structural framework to define the target of estimation for a particular clinical trial objective. 11 12 They require to specify the treatment condition of interest, the population targeted by the clinical question, the variable of interest or endpoint used to answer that question, the handling strategies for intercurrent events (ie, events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question), and a population level summary of the variable or endpoint.…”

Effectiveness of an anti-inflammatory diet versus low-fat diet for knee osteoarthritis: the FEAST randomised controlled trial protocol

“…Analysis will be performed according to the estimands framework 63 with a statistical analyst blinded to group allocation. All outcomes and analyses are prospectively categorised as primary, secondary or exploratory.…”