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.

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

Introduction The 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 analysis We 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 dissemination STAREE 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 number NCT02099123.

https://bmjopen.bmj.com/content/bmjopen/13/4/e069915.full.pdf

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)

Business judgment rule

Abstract Most reported treatment effects in medical research studies are ambiguously defined, which can lead to misinterpretation of study results. This is because most authors do not attempt to describe what the treatment effect represents, and instead require readers to deduce this based on the reported statistical methods. However, this approach is challenging, because many methods provide counterintuitive results. For example, some methods include data from all patients, yet the resulting treatment effect applies only to a subset of patients, whereas other methods will exclude certain patients while results will apply to everyone. Additionally, some analyses provide estimates pertaining to hypothetical settings in which patients never die or discontinue treatment. Herein we introduce estimands as a solution to the aforementioned problem. An estimand is a clear description of what the treatment effect represents, thus saving readers the necessity of trying to infer this from study methods and potentially getting it wrong. We provide examples of how estimands can remove ambiguity from reported treatment effects and describe their current use in practice. The crux of our argument is that readers should not have to infer what investigators are estimating; they should be told explicitly.

/pdf/eliminating-ambiguous-treatment-effects-using-estimands-3qipt07p.pdf

Eliminating Ambiguous Treatment Effects Using Estimands

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.

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

Abstract The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be revisited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions.

https://figshare.com/articles/journal_contribution/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/20163888/2/files/36056286.pdf

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

The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be re-visited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions.

Rejoinder: 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

When evaluating which G20 country to research we landed on Canada. It felt to us that on initial research there was enough evidence to support covering the similarities and differences between their governance practices compared to the US. We will cover some of the more exciting differences but throughout the theme you will notice is the similarity between their governance practices and the US. U.S. Executive Compensation We start by looking at the current structure in the United States. In the US the board of directors determines the pay of the CEO. The board is voted in to their appointment by shareholders, meaning shareholders indirectly affect executive compensation decisions in this way. Say on Pay legislation, as part of the Dodd Frank Act, gives shareholders a more direct way to influence pay. They can directly vote concerning executive pay as a result of that legislation. The board is required to list peer firms in reports provided to investors and regulators. By using these peer firms as a reference guide the board sets what they determine to be an appropriate pay level and composition of pay for the firm executives. Three mistakes that can be made in executive compensation determination revolve around paying too much, paying too little, or paying in the wrong way. These errors are usually not known until it is too late, meaning the CEO has left for a better paying job if they were undercompensated, the CEO is still there and was paid too generously compared to what their performance or firm performance warranted, or the CEO was enticed by the pay structure to make poor strategic decisions for the firm which only increased their pay. The interests of the principal and the agent should be aligned and the pay structure can promote this alignment. Shareholders want firm value to be increased or maintained and the CEO must be kept from trying to attain only what is in his own self-interest, as agency theory states. For example, stock options are given to CEO’s and the only way these compensation components increase in value for the CEO is if the firm stock increases in value. This would promote the same goal for both principal and agent. To counter this, long term equity incentives are given as an additional payment form to executives ensuring that the long term growth of the firm is not compromised by strategic decisions simply to raise stock price now to make the stock

Corporate Governance Practices in Canada and the United States

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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

Rejoinder: 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

Corporate Governance Practices in Canada and the United States