Estimands in a Chronic Pain Trial: Challenges and Opportunities

Callegari, Francesca; Akacha, Mouna; Quarg, Peter; Pandhi, Shaloo; Raison, Florian von; Zuber, Emmanuel

doi:10.1080/19466315.2019.1629997

Cited by 15 publications

(18 citation statements)

References 10 publications

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“…We have limited our scope to the treatment-policy strategy for handling treatment discontinuation. We acknowledge that estimands that employ other strategies might also be informative-for example, the long-term effect in patients who tolerate treatment or a strategy that handles differentially treatment discontinuation depending on the reason (Callegari et al 2020). However, this strategy has a special place in a regulatory context (e.g., as mentioned in EMA 2018a, 2018b, 2018c), and in clinical practice as ultimately prescribers will make a decision of treatment assignment, and noncompliance occurs not only in clinical trials but also in practice (Sansone and Sansone 2012).…”

Section: Discussionmentioning

confidence: 99%

The Use of a Variable Representing Compliance Improves Accuracy of Estimation of the Effect of Treatment Allocation Regardless of Discontinuation in Trials with Incomplete Follow-up

Guizzaro

Pétavy

Ristl

et al. 2020

Statistics in Biopharmaceutical Research

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In Clinical Trials, not all randomized patients follow the course of treatment they are allocated to. The potential impact of such deviations is increasingly recognized, and it has been one of the reasons for a redefinition of the targets of estimation ("Estimands") in the ICH E9 draft Addendum. Among others, the effect of treatment assignment, regardless of the adherence, appears an Estimand of practical interest, in line with the intention-to-treat principle. This study aims at evaluating the performance of different estimation techniques in trials with incomplete post-discontinuation follow-up when a "treatment-policy" strategy is implemented. To achieve that, we have (i) modeled and visualized as directed acyclic diagram a reasonable data-generating model; (ii) investigated which set of variables allows identification and estimation of such effect; (iii) simulated 10,000 trials in Major Depressive Disorder, with varying real treatment effects, proportions of patients discontinuing the treatment, and incomplete follow-up. Our results suggest that, at least in a "Missing at Random" setting, all studied estimation methods increase their performance when a variable representing compliance is used. This effect is more pronounced the higher the proportion of post-discontinuation follow-up is.

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Section: Discussionmentioning

confidence: 99%

The Use of a Variable Representing Compliance Improves Accuracy of Estimation of the Effect of Treatment Allocation Regardless of Discontinuation in Trials with Incomplete Follow-up

Guizzaro

Pétavy

Ristl

et al. 2020

Statistics in Biopharmaceutical Research

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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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“…Having the study objective and estimand drive the design, conduct, and analysis of the trial leads to substantial clarity in its interpretation. The International Conference on Harmonization E9 Addendum 100 provides excellent guidance and examples regarding choices of estimands; examples specific to clinical trials in pain are provided by Callegari et al 19 and Cai et al 18 …”

Section: Missing Data and Trial Estimandsmentioning

confidence: 99%

“… 138 Given its flexibility, the approach is particularly useful for performing sensitivity analyses to examine the robustness of the results of the primary analysis to assumptions concerning the missing data mechanism, 8 , 21 , 138 , 151 but it might also be appropriate for the primary analysis of a clinical trial depending on the primary estimand of interest. 18 , 19 The method should be used with caution when the clinical trial does not include a control group that is expected to be either comparable with or inferior to the active treatment groups under study with respect to outcomes. 151 …”

Section: Missing Data and Trial Estimandsmentioning

confidence: 99%

Essential statistical principles of clinical trials of pain treatments

Dworkin

Evans

Mbowe

et al. 2020

PR9

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This article presents an overview of fundamental statistical principles of clinical trials of pain treatments. Statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating efficacy and safety are discussed, including (1) research design; (2) endpoints and analyses; (3) sample size determination and statistical power; (4) missing data and trial estimands; (5) data monitoring and interim analyses; and (6) interpretation of results. Although clinical trials of pharmacologic treatments are emphasized, the key issues raised by these trials are also directly applicable to clinical trials of other types of treatments, including biologics, devices, nonpharmacologic therapies (eg, physical therapy and cognitive-behavior therapy), and complementary and integrative health interventions.

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Estimands in a Chronic Pain Trial: Challenges and Opportunities

Cited by 15 publications

References 10 publications

The Use of a Variable Representing Compliance Improves Accuracy of Estimation of the Effect of Treatment Allocation Regardless of Discontinuation in Trials with Incomplete Follow-up

The Use of a Variable Representing Compliance Improves Accuracy of Estimation of the Effect of Treatment Allocation Regardless of Discontinuation in Trials with Incomplete Follow-up

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

Essential statistical principles of clinical trials of pain treatments

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