Estimands and the Patient Journey: Addressing the Right Question in Oncology Clinical Trials

Degtyarev, Evgeny; Zhang, Yiyun; Sen, Kapildeb; Lebwohl, David; Akacha, Mouna; Bornkamp, Bjoern; Maniero, Antonella; Bretz, Frank; Zuber, Emmanuel

doi:10.1200/po.18.00381

Cited by 18 publications

(15 citation statements)

References 23 publications

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“…Experience with the estimand framework is growing in clinical research across various therapeutic areas [11,[14][15][16][17][18], as well as its value as a providing a common language to facilitate discussions with all relevant stakeholders in clinical trials. In the FDA's Patient Focused Drug Development (PFDD) workstream, the PFDD draft Guidance 4 focuses on "Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision Making" [19], and includes discussion of the estimand framework and a case study example considering the PRO of physical function in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

Lawrance

Degtyarev

Griffiths

et al. 2020

J Patient Rep Outcomes

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Background: Published in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example. Main: We describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement, "What is the effect of treatment X on patient's quality of life?", we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework. Conclusion: The use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

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Section: Discussionmentioning

confidence: 99%

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

Lawrance

Degtyarev

Griffiths

et al. 2020

J Patient Rep Outcomes

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“…The weights in (3) show that our proposal relies on a positivity assumption (see web appendix A.2 for details). In particular, we assume that if P(S 1 = s|L 1 , C) = 0 for certain L 1 and C and s = 0, 1, then also P(S 0 = s|L 1 , C) = 0.…”

Section: Identificationmentioning

confidence: 99%

“…2 Likewise, patients in oncology trials may sometimes start a new anticancer regimen before observing the endpoint of interest upon disease progression. 3 The use of rescue medication complicates the interpretation of trial results, especially when its use is imbalanced between treatment arms, in which case it typically reduces the observed treatment effect in an "intention-to-treat" or "treatment policy" analysis. Ignoring all data after switching to rescue medication is likely to deliver biased results since rescued patients or "switchers" form a highly selective group.…”

Section: Introductionmentioning

confidence: 99%

“…For example, in a trial of dietary intervention to reduce high blood pressure, a patient may be rescued by starting antihypertensive medication when his/her blood pressure fails to respond 2 . Likewise, patients in oncology trials may sometimes start a new anticancer regimen before observing the endpoint of interest upon disease progression 3 …”

Section: Introductionmentioning

confidence: 99%

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A novel estimand to adjust for rescue treatment in randomized clinical trials

Michiels

Sotto

Vandebosch

et al. 2021

Statistics in Medicine

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The interpretation of randomized clinical trial results is often complicated by intercurrent events. For instance, rescue medication is sometimes given to patients in response to worsening of their disease, either in addition to the randomized treatment or in its place. The use of such medication complicates the interpretation of the intention‐to‐treat analysis. In view of this, we propose a novel estimand defined as the intention‐to‐treat effect that would have been observed, had patients on the active arm been switched to rescue medication if and only if they would have been switched when randomized to control. This enables us to disentangle the treatment effect from the effect of rescue medication on a patient's outcome, while tempering the strong extrapolations that are typically needed when inferring what the intention‐to‐treat effect would have been in the absence of rescue medication. We propose a novel inverse probability weighting method for estimating this effect in settings where the decision to initiate rescue medication is made at one prespecified time point. This estimator relies on specific untestable assumptions, in view of which we propose a sensitivity analysis. We use the method for the analysis of a clinical trial conducted by Janssen Pharmaceuticals, in which patients with type 2 diabetes mellitus can switch to rescue medication for ethical reasons. Monte Carlo simulations confirm that the proposed estimator is unbiased in moderate sample sizes.

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“…Sensitivity analyses may be prespecified to explore the estimator’s robustness of inference to model assumptions (Degtyarev et al. 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials—Application of the Estimand Framework

Degtyarev

Rufibach

Shentu

et al. 2020

Statistics in Biopharmaceutical Research

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– Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

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Estimands and the Patient Journey: Addressing the Right Question in Oncology Clinical Trials

Cited by 18 publications

References 23 publications

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

A novel estimand to adjust for rescue treatment in randomized clinical trials

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials—Application of the Estimand Framework

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