The detailed clinical objectives approach to designing clinical trials and choosing estimands

Bell, J. Simon; Hamilton, Alan; Sailer, Oliver; Voß, Florian

doi:10.1002/pst.2129

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…It should instead be possible to merge the information they contain into more precise and well-written study objectives to avoid repetition and facilitate engagement with non-statisticians, e.g. using detailed clinical objectives as proposed by [12].…”

Section: Discussionmentioning

confidence: 99%

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Principles and recommendations for incorporating estimands into clinical study protocol templates

Lynggaard

Bell²,

Lösch

et al. 2022

Trials

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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.

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Section: Discussionmentioning

confidence: 99%

“…There are different ways to define objectives so that they can serve as a starting point for specifying estimands: They can be stated in great detail (e.g. detailed clinical objectives (DCOs) [12]) or in less detail (e.g. reflected in ICH E8(R1) [13]), or anywhere in between:…”

Section: How To Write Objectivesmentioning

confidence: 99%

Principles and recommendations for incorporating estimands into clinical study protocol templates

Lynggaard

Bell²,

Lösch

et al. 2022

Trials

Self Cite

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“…This paper describes an interdisciplinary process for implementing the estimand framework proposed by the ISCTM Estimand WG, a group that represents both clinical and statistical functions. Building on Bell et al 35 and Ratitch et al 36,37 , we expand the "thinking process" outlined in the ICH E9(R1) o cial training material 38 by considering the trial stakeholder(s), the decisions they need to make and the questions that would support their decision making. Study teams are encouraged to justify how answering the proposed questions of interest would support stakeholder decision making.…”

Section: Discussionmentioning

confidence: 99%

Defining Clinical Trial Estimands: A Practical Guide for Study Teams with Examples Based on a Psychiatric Disorder

Polverejan

O’Kelly

Hefting

et al. 2022

Preprint

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While the ICH E9(R1) Addendum on “Estimands and Sensitivity Analysis in Clinical Trials” was released in 2019, the widespread implementation of defining and reporting estimands across all clinical trials is still in progress and the engagement of non-statistical functions in this process is still to be fully experienced. Case studies are sought after, especially those with documented clinical and regulatory feedback. This paper describes an interdisciplinary process for implementing the estimand framework, devised by the Estimands and Missing Data Working Group (a group with clinical, statistical, and regulatory representation) of the International Society for CNS Clinical Trials and Methodology. This process is illustrated by specific examples using various types of hypothetical trials evaluating a treatment for major depressive disorder. Each of the estimand examples follows the same template and features all steps of the proposed process, including identifying the trial stakeholder(s), the decisions they need to make and the questions that would support their decision making. Each of the five strategies for addressing intercurrent events are addressed in at least one example; the featured endpoints are also diverse, including continuous, binary and time to event. Several examples are presented that include specifications for a potential trial design, key trial implementation elements needed to address the estimand, and main and sensitivity estimator specifications. Ultimately this paper highlights the need to incorporate multi-disciplinary collaborations into implementing the ICH E9(R1) framework.

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“…The ICH E9(R1) Addendum discusses the importance of objectives in setting estimands but does not provide guidance on how best to write objectives. Clinical trial objectives can be broad and high level [ 9 ], or detailed and specific [ 24 ]. More detailed objective specification assists the choice of estimand, yet when writing a protocol containing detailed objectives, estimands and clinical questions of interest may lead to unnecessary repetition.…”

Section: The Implementation Experience So Farmentioning

confidence: 99%

“…To bring the framework out of the statistics corner, the detailed clinical objectives approach [ 24 ] described in Sect. 3.2 could act as a role model and facilitate discussions with key stakeholders such as clinicians, ethic committees, investigators, and patients on estimands of interest aligned to trial objectives.…”

Section: Continuing the Estimand Journeymentioning

confidence: 99%

Marking 2-Years of New Thinking in Clinical Trials: The Estimand Journey

Fletcher

Hefting

Wright

et al. 2022

Ther Innov Regul Sci

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The ICH E9(R1) addendum on Estimands and Sensitivity Analyses in Clinical Trials has introduced a new estimand framework for the design, conduct, analysis, and interpretation of clinical trials. We share Pharmaceutical Industry experiences of implementing the estimand framework in the first two years since the final guidance became available with key lessons learned and highlight what else needs to be done to continue the journey in embedding the estimand framework in clinical trials. Emerging best practices and points to consider on strategies for implementing a new estimand thinking process are provided. Whilst much of the focus of implementing ICH E9(R1) to date has been on defining estimands, we highlight some of the important aspects relating to the choice of statistical analysis methods and sensitivity analyses to ensure estimands can be estimated robustly with minimal bias. In particular, we discuss the implications if complete follow-up is not possible when the treatment policy strategy is being used to handle intercurrent events. ICH E9(R1) was introduced just before the start of the COVID-19 pandemic, but a positive outcome from the pandemic has been an acceleration in the adoption of the estimand framework, including differentiating intercurrent events related or not related to the pandemic. In summary, much has been learned on the estimand journey and continued sharing of case studies will help to further advance the understanding and increase awareness across all clinical researchers of the estimand framework.

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The detailed clinical objectives approach to designing clinical trials and choosing estimands

Cited by 8 publications

References 17 publications

Principles and recommendations for incorporating estimands into clinical study protocol templates

Principles and recommendations for incorporating estimands into clinical study protocol templates

Defining Clinical Trial Estimands: A Practical Guide for Study Teams with Examples Based on a Psychiatric Disorder

Marking 2-Years of New Thinking in Clinical Trials: The Estimand Journey

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