Estimands and their Estimators for Clinical Trials Impacted by the COVID-19 Pandemic: A Report from the NISS Ingram Olkin Forum Series on Unplanned Clinical Trial Disruptions

Lancker, Kelly Van; Tarima, Sergey; Bartlett, Jonathan; Bauer, Madeline; Bharani-Dharan, Bharani; Bretz, Frank; Flournoy, Nancy; Michiels, Hege; Parra, Camila Olarte; Rosenberger, James L.; Cro, Suzie

doi:10.1080/19466315.2022.2094459

Cited by 14 publications

(10 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The impacts of COVID-19 will be investigated in sensitivity analyses that include examination of participant Open access event rates by whether their randomisation occurred pre-pandemic, peri-pandemic or post-pandemic, and consider COVID-19 vaccination status (which will be an intercurrent event for those randomised pre-pandemic and a baseline covariate for those randomised postpandemic), following emerging guidance on analytical approaches and estimand definitions. 52 Trial status Recruitment commenced in November 2015 and was expected to be completed in 2021. However, COVID-19 public health directives and work restrictions resulted in reduced access to general practices across Australia such that recruitment had to be extended for further 18 months.…”

Section: Discussionmentioning

confidence: 99%

“…The impacts of COVID-19 will be investigated in sensitivity analyses that include examination of participant event rates by whether their randomisation occurred pre-pandemic, peri-pandemic or post-pandemic, and consider COVID-19 vaccination status (which will be an intercurrent event for those randomised pre-pandemic and a baseline covariate for those randomised post-pandemic), following emerging guidance on analytical approaches and estimand definitions. 52 …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial)

et al. 2023

View full text Add to dashboard Cite

IntroductionThe world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia.Methods and analysisWe will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models.Ethics and disseminationSTAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences.Trial registration numberNCT02099123.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial)

et al. 2023

View full text Add to dashboard Cite

show abstract

“…In the absence of missing data, the treatment policy, composite, and while-on-treatment/while-alive strategies can be estimated from a randomised trial with minimal assumptions. Conversely, estimation of hypothetical or principal stratum strategies requires stronger assumptions, which cannot be verified using the study data 4323335444548495051526061626364656667. This need for stronger assumptions is because the required data (such as the participant’s outcome in the hypothetical setting of interest or whether they belong to the principal stratum population) are unknown, and so assumptions about what these data might be are required.…”

Section: Aligning Study Methods With the Estimandmentioning

confidence: 99%

The estimands framework: a primer on the ICH E9(R1) addendum

Kahan,

Hindley,

Edwards

et al. 2024

BMJ

Self Cite

View full text Add to dashboard Cite

Estimands can be used in studies of healthcare interventions to clarify the interpretation of treatment effects. The addendum to the ICH E9 harmonised guideline on statistical principles for clinical trials (ICH E9(R1)) describes a framework for using estimands as part of a study. This paper provides an overview of the estimands framework, as outlined in the addendum, with the aim of explaining why estimands are beneficial; clarifying the terminology being used; and providing practical guidance on using estimands to decide the appropriate study design, data collection, and estimation methods. This article illustrates how to use the estimands framework by applying it to an ongoing trial in emergency bowel surgery. Estimands can be a useful way of clarifying the exact research question being evaluated in a study, both to avoid misinterpretation and to ensure that study methods are aligned to the overall study objectives.

show abstract

“…In this scenario, aligned with the estimand, a principled approach we explore to handle missing data is to use multiple imputation 7 to impute the missing data after the IE using the information observed up to the point of the IE. [8][9][10] As in superiority trials, the analysis of a non-inferiority trial may additionally be complicated by missing outcome data, for example due to missed patient visits. This is because any analysis will then involve untestable assumptions about the distribution of these data.…”

Section: Introductionmentioning

confidence: 99%

Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study

et al. 2023

Self Cite

View full text Add to dashboard Cite

Introduction The ICH E9 addendum outlining the estimand framework for clinical trials was published in 2019 but provides limited guidance around how to handle intercurrent events for non-inferiority studies. Once an estimand is defined, it is also unclear how to deal with missing values using principled analyses for non-inferiority studies. Methods Using a tuberculosis clinical trial as a case study, we propose a primary estimand, and an additional estimand suitable for non-inferiority studies. For estimation, multiple imputation methods that align with the estimands for both primary and sensitivity analysis are proposed. We demonstrate estimation methods using the twofold fully conditional specification multiple imputation algorithm and then extend and use reference-based multiple imputation for a binary outcome to target the relevant estimands, proposing sensitivity analyses under each. We compare the results from using these multiple imputation methods with those from the original study. Results Consistent with the ICH E9 addendum, estimands can be constructed for a non-inferiority trial which improves on the per-protocol/intention-to-treat-type analysis population previously advocated, involving respectively a hypothetical or treatment policy strategy to handle relevant intercurrent events. Results from using the ‘twofold’ multiple imputation approach to estimate the primary hypothetical estimand, and using reference-based methods for an additional treatment policy estimand, including sensitivity analyses to handle the missing data, were consistent with the original study’s reported per-protocol and intention-to-treat analysis in failing to demonstrate non-inferiority. Conclusions Using carefully constructed estimands and appropriate primary and sensitivity estimators, using all the information available, results in a more principled and statistically rigorous approach to analysis. Doing so provides an accurate interpretation of the estimand.

show abstract

Estimands and their Estimators for Clinical Trials Impacted by the COVID-19 Pandemic: A Report from the NISS Ingram Olkin Forum Series on Unplanned Clinical Trial Disruptions

Cited by 14 publications

References 41 publications

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial)

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial)

The estimands framework: a primer on the ICH E9(R1) addendum

Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study

Contact Info

Product

Resources

About