Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice

The National Research Council (NRC) Expert Panel Report on Prevention and Treatment of Missing Data in Clinical Trials highlighted the need for clearly defining objectives and estimands. That report sparked considerable discussion and literature on estimands and how to choose them. Importantly, consideration moved beyond missing data to include all postrandomization events that have implications for estimating quantities of interest (intercurrent events, aka ICEs). The ICH E9(R1) draft addendum builds on that research to outline key principles in choosing estimands for clinical trials, primarily with focus on confirmatory trials. This paper provides additional insights, perspectives, details, and examples to help put ICH E9(R1) into practice. Specific areas of focus include how the perspectives of different stakeholders influence the choice of estimands; the role of randomization and the intention-to-treat principle; defining the causal effects of a clearly defined treatment regimen, along with the implications this has for trial design and the generalizability of conclusions; detailed discussion of strategies for handling ICEs along with their implications and assumptions; estimands for safety objectives, time-to-event endpoints, early-phase and one-arm trials, and quality of life endpoints; and realistic examples of the thought process involved in defining estimands in specific clinical contexts.</p

Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinsons disease: an open-label study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Achieving optimal symptom control with minimal side effects is a major goal in clinical practice. Dual-agent dopamine receptor agonist (DA) therapy in Parkinsons disease (PD) may represent a promising approach to treatment, as the combination of different pharmacokinetic/pharmacological profiles may result in a lesser need for high dosages and, accordingly, may be well tolerated. The objective of the current study was to investigate safety and efficacy of rotigotine transdermal system as add-on to oral DA in patients with advanced PD inadequately controlled with levodopa and low-dose oral DA. Methods PD0015 was an open-label, multinational study in patients with advanced-PD and sleep disturbance or early-morning motor impairment. Patients were titrated to optimal dose rotigotine (≤8 mg/24 h) over 1–4 weeks and maintained for 4–7 weeks (8-week treatment). Dosage of levodopa and oral DA (pramipexole ≤1.5 mg/day, ropinirole ≤6.0 mg/day) was stable. Primary variable was Clinical Global Impressions (CGI) item 4: side effects, assessing safety. Other variables included adverse events (AEs), Patient Global Impressions of Change (PGIC), Unified Parkinsons Disease Rating Scale (UPDRS) II and III, Parkinsons Disease Sleep Scale (PDSS-2), Pittsburgh Sleep Quality Index (PSQI), and off time. Results Of 90 patients who received rotigotine, 79 (88%) completed the study; 5 (6%) withdrew due to AEs. Most (83/89; 93%) had a CGI-4 score <3 indicating that rotigotine add-on therapy did not interfere with functioning; 6 (7%) experienced drug-related AEs that interfered with functioning (score ≥3). AEs occurring in ≥5% were application site pruritus (13%), dizziness (10%), orthostatic hypotension (10%), nausea (8%), dyskinesia (8%), and nasopharyngitis (6%). Numerical improvements in motor function (UPDRS III), activities of daily living (UPDRS II), sleep disturbances (PDSS-2, PSQI), and reduction in off time were observed. The majority (71/88; 81%) improved on PGIC. Conclusions Addition of rotigotine transdermal system to low-dose oral DA in patients with advanced-PD was feasible and may be associated with clinical benefit. Trial registration ClinicalTrials.gov identifier NCT01723904 . Trial registration date: November 6, 2012

Defining Efficacy Estimands in Clinical Trials: Examples Illustrating ICH E9(R1) Guidelines

This paper provides examples of defining estimands in real-world scenarios following ICH E9(R1) guidelines. Detailed discussions on choosing the estimands and estimators can be found in our companion papers. Three scenarios of increasing complexity are illustrated. The first example is a proof-of-concept trial in major depressive disorder where the estimand is chosen to support the sponsor decision on whether to continue development. The second and third examples are confirmatory trials in severe asthma and rheumatoid arthritis respectively. We discuss the intercurrent events expected during each trial and how they can be handled so as to be consistent with the study objectives. The estimands discussed in these examples are not the only acceptable choices for their respective scenarios. The intent is to illustrate the key concepts rather than focus on specific choices. Emphasis is placed on following a study development process where estimands link the study objectives with data collection and analysis in a coherent manner, thereby avoiding disconnect between objectives, estimands, and analyses.</p

Design and Execution of Sustainable Decentralized Clinical Trials

The decentralized clinical trial (DCT) approach is increasingly recognized as a means to accelerate the development of potential therapeutic interventions. DCTs have a crucial advantage over traditional clinical trials: patients are monitored in their environment using technology (e.g., wearables), that capture data as they continue in daily life. This narrative review outlines a gap analysis focused on the frameworks and guidance from expert working groups and regulatory agencies for the design and execution of DCTs. Eight DCT elements guided the analysis and summarized the frameworks and guidance: (1) suitability, (2) protocol, (3) investigational medicinal product (IMP) supply, (4) investigators and health care providers, (5) safety, (6) regulatory and ethics, (7) data and technology, and (8) engagement, communication, and advocacy. Based on the gap analysis, two key takeaways were identified: (1) a need for a comprehensive sustainability assessment of each DCT element; and (2) current frameworks and guidance provide recommendations on social sustainability and some on economic sustainability. DCTs are an essential evolution in healthcare research; however, more guidance related to a comprehensive assessment of designing and executing sustainable DCTs is needed. This is especially the case for environmental sustainability, including, for example, carbon footprint and disposal of IMPs and sensors.ISSN:0009-9236ISSN:1532-653

Choosing Estimands in Clinical Trials: Putting the ICH E9(R1) Into Practice

The National Research Council (NRC) Expert Panel Report on Prevention and Treatment of Missing Data in Clinical Trials highlighted the need for clearly defining objectives and estimands. That report sparked considerable discussion and literature on estimands and how to choose them. Importantly, consideration moved beyond missing data to include all postrandomization events that have implications for estimating quantities of interest (intercurrent events, aka ICEs). The ICH E9(R1) draft addendum builds on that research to outline key principles in choosing estimands for clinical trials, primarily with focus on confirmatory trials. This paper provides additional insights, perspectives, details, and examples to help put ICH E9(R1) into practice. Specific areas of focus include how the perspectives of different stakeholders influence the choice of estimands; the role of randomization and the intention-to-treat principle; defining the causal effects of a clearly defined treatment regimen, along with the implications this has for trial design and the generalizability of conclusions; detailed discussion of strategies for handling ICEs along with their implications and assumptions; estimands for safety objectives, time-to-event endpoints, early-phase and one-arm trials, and quality of life endpoints; and realistic examples of the thought process involved in defining estimands in specific clinical contexts.status: publishe

Assessment of potential confounding bias in historical new users of ace inhibitors (ACEIS)

Background: As a FDA post-marketing requirement, a cohort study is needed to assess the incidence of angioedema in Black heart failure (HF) patients treated with sacubitril/valsartan using an active control group (defined as naïve to ACEI). A sufficiently large contemporaneous cohort that is naïve to ACEI may be difficult to accrue as many HF patients are treated with an ACEI prior to their HF diagnosis due to other comorbidities. Using historical ACEI control patients, prior to market approval of sacubitril/valsartan, is one solution. Objectives: To evaluate the potential for bias introduced by historical controls. Methods: A cohort study was conducted in adult HF patients from 5 sites within the Cardiovascular Research Network. Patients were naïve to ACEI in the year preceding their first diagnosis of HF in the database, but subsequently were dispensed an ACEI. We defined 9 yearly cohorts based on patients\u27 first ACEI dispensing (index date). The first cohort covered Jul 2006 to Jun 2007, the last Jul 2014 to Jun 2015. Standardized differences ([SDif] mean difference/standard deviation) assessed bias in patient characteristics for each cohort as compared to the year preceding sacubitril/valsartan launch (July 2015) with SDif \u3e0.2 indicative of imbalance. Characteristics assessed included the following key factors determined a priori for their relationship with angioedema: age, sex, smoking status, HF severity, diabetes, and allergic reactions, and several non-key factors. Results: Of the 360,000 HF patients, 37,102 met the inclusion criteria for the yearly cohorts, with 5,909 being Black. None of the key factors showed imbalance at SDif \u3e0.2. For example, among Black patients in the first compared to last cohort, SDif were: 0.04 (age), -0.06 (sex), -0.14 (smoking status), -0.07 (HF severity), -0.03 (diabetes), and 0.05 (allergic reactions). Non-key factors suggested a similar trend with 2 (of 35) characteristics reporting an SDif \u3e0.2 (largest was 0.26). Conclusions: Results suggest key factors of Black HF patients newly initiating ACEI are balanced over time and indicate historical controls have low potential to bias results of the planned study for measured predictors of angioedema