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Estimands aim to incorporate intercurrent events in design, data collection and estimation of treatment effects in clinical trials. Our aim was to understand what estimands may correspond to efficacy analyses commonly employed in clinical trials conducted before publication of ICH E9(R1). We re‐analysed six clinical trials evaluating a new anti‐depression treatment. We selected the following analysis methods—ANCOVA on complete cases, following last observation carried forward (LOCF) imputation and following multiple imputation; mixed‐models for repeated measurements without imputation (MMRM), MMRM following LOCF imputation and following jump‐to‐reference imputation; and pattern‐mixture mixed models. We included a principal stratum analysis based on the predicted subset of the study population who would not discontinue due to adverse events or lack of efficacy. We translated each analysis into the implicitly targeted estimand, and formulated corresponding clinical questions. We could map six estimands to analysis methods. The same analysis method could be mapped to more than one estimand. The major difference between estimands was the strategy for intercurrent events, with other attributes mostly the same across mapped estimands. The quantitative differences in MADRS10 population‐level summaries between the estimands were 4–8 points. Not all six estimands had a clinically meaningful interpretation. Only a few analyses would target the same estimand, hence only few could be used as sensitivity analyses. The fact that an analysis could estimate different estimands emphasises the importance of prospectively defining the estimands targeting the primary objective of a trial. The fact that an estimand can be targeted by different analyses emphasises the importance of prespecifying precisely the estimator for the targeted estimand. [ABSTRACT FROM AUTHOR]

Abstract–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. [ABSTRACT FROM AUTHOR]

Real‐world data and patient‐level data from completed randomized controlled trials are becoming available for secondary analysis on an unprecedented scale. A range of novel methodologies and study designs have been proposed for their analysis or combination. However, to make novel analytical methods acceptable for regulators and other decision makers will require their testing and validation in broadly the same way one would evaluate a new drug: prospectively, well‐controlled, and according to a pre‐agreed plan. From a European regulators' perspective, the established methods qualification advice procedure with active participation of patient groups and other decision makers is an efficient and transparent platform for the development and validation of novel study designs. [ABSTRACT FROM AUTHOR]

Data Monitoring Committees (DMCs) are an integral part of clinical drug development. Their use has evolved along with changing study designs and regulatory expectations, which has associated statistical and ethical implications. Although there is guidance from the different regulatory agencies, there are opportunities to bring more consistency to address practical issues of establishing and operating a DMC. Challenging issues include defining the scope of DMC decisions, the regulatory requirements and expectations, the perceived independence of DMCs, the specific focus primarily on safety, etc. Wider use of adaptive clinical trial designs in recent years introduce additional challenges in terms of trial governance and the complexity of DMC activities. A panel comprised of clinical and statistical experts from across academia, industry, and regulatory agencies shared their experience and thoughts on the importance of these aspects and offered perspectives on the future of the DMCs. This paper documents the thinking from the panel session at the CEN‐ISBS conference held in Vienna, Austria, 2017. [ABSTRACT FROM AUTHOR]

The article focuses on global standardization of clinical research data in the U.S. It mentions that standards specific to therapeutic areas have been developed collaboratively through Coalition for Accelerating Standards and Therapies that has included Critical Path Institute and U.S. Food & Drug Administration. It mentions that governmental authorities and professional medical societies have charged with recommending ways to improve efficacy and safety of medicines and health technologies.

AbstractWe aim to explore data-generating models to jointly simulate outcomes and intercurrent events for randomized clinical trials to enable the investigation of estimands. We develop four possible data-generating models for the joint distribution of longitudinal continuous clinical outcomes and intercurrent events under the scenario where they are observable: a selection model, a pattern-mixture mixed model, a shared-parameter model, and a joint model of longitudinally observed outcomes and a survival model for intercurrent events. We present a case study in a short-term depression trial with repeated measurements of continuous outcomes and two types of intercurrent events, and evaluate the potential and challenges of such data-generating models. Simulating randomized trials with outcomes and intercurrent events is a complex undertaking. We found that the four possible data-generating models can simulate different types of intercurrent events and associated longitudinal outcomes. They can be used to emulate envisaged patterns of intercurrent events and outcomes informed by prior available trial data or expectations. Model and parameter choice for a given application require further development. The four possible data-generating models could be used to investigate different estimands and their properties in-depth in the design stage. Thereby they are useful tools for the selection of estimands a priori. [ABSTRACT FROM AUTHOR]

The article focuses on the benefits of the European regulatory rule for the research on pathophysiology of central nervous system (CNS) disease in European countries. Topics discussed include the development of drug treatment for psychiatry and neurology disease, medical therapy for Alzheimer's disease and development of biomarkers. It also suggests pharmaceutical industries to consider seeking scientific advices from its drug development studies.

Background and Aim of the Study: Cardiac valve calcification (CVC) and coronary artery calcification (CAC) appear to be linked pathogenetically, and both are associated with a poor prognosis among patients with chronic kidney disease on dialysis (CKD-5D). Little is known, however, about factors that affect the progression of CVC and CAC., Methods: A post-hoc analysis was performed of the ADVANCE study to assess whether patients with CVC are more prone to CAC progression, and whether CVC predicts the response to different treatments for secondary hyperparathyroidism., Results: Subjects were randomized to treatment with either cinacalcet and low doses of vitamin D analogs or larger, varying doses of vitamin D. Among 235 subjects, aortic valve or mitral valve calcification was detected in 108 (46%) and 118 (50%), respectively; 69 subjects (29%) had calcification of both valves. CVC was associated both with baseline CAC and CAC progression (p < 0.05). Subjects with aortic valve calcification who were treated with cinacalcet and low doses of vitamin D experienced less progression of CAC than subjects given larger, varying doses of vitamin D (adjusted OR: 0.26; 95% CI: 0.10, 0.64). This effect was greater in subjects with larger CAC burden at baseline., Conclusion: The study findings suggest that CVC is a predictor of CAC progression and, potentially, of greater cardiovascular vulnerability. Treatment with cinacalcet combined with low doses of vitamin D slowed the progression of CAC compared to therapy using larger, varying doses of vitamin D.

Objectives: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA)., Methods: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area., Results: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003)., Conclusions: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.