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An adaptive trial design to optimize dose-schedule regimes with delayed outcomes
This paper proposes a two-stage phase I-II clinical trial design to optimize doseschedule regimes of an experimental agent within ordered disease subgroups in terms of the toxicity-efficacy trade-off. The design is motivated by settings where prior biological information indicates it is certain that efficacy will improve with ordinal subgroup level. We formulate a flexible Bayesian hierarchical model to account for associations among subgroups and regimes, and to characterize ordered subgroup effects. Sequentially adaptive decisionmaking is complicated by the problem, arising from the motivating application, that efficacy is scored on day 90 and toxicity is evaluated within 30 days from the start of therapy, while the patient accrual rate is fast relative to these outcome evaluation intervals. To deal with this in a practical manner, we take a likelihood-based approach that treats unobserved toxicity and efficacy outcomes as missing values, and use elicited utilities that quantify the efficacy-toxicity trade-off as a decision criterion. Adaptive randomization is used to assign patients to regimes while accounting for subgroups, with randomization probabilities depending on the posterior predictive distributions of utilities. A simulation study is presented to evaluate the design’s performance under a variety of scenarios, and to assess its sensitivity to the amount of missing data, the prior, and model misspecification.
Journal Article
Registry-Based Pragmatic Trials in Heart Failure: Current Experience and Future Directions
Purpose of Review
Randomized controlled trials (RCTs) in heart failure (HF) are becoming increasingly complex and expensive to conduct and if positive deliver expensive therapy tested only in selected populations.
Recent Findings
Electronic health records and clinical cardiovascular quality registries are providing opportunities for pragmatic and registry-based prospective randomized clinical trials (RRCTs). Simplified regulatory, ethics, and consent procedures; recruitment integrated into real-world care; and simplified or automated baseline and outcome collection allow assessment of study power and feasibility, fast and efficient recruitment, delivery of generalizable findings at low cost, and potentially evidence-based and novel use of generic drugs with low costs to society.
Summary
There have been no RRCTs in HF to date. Major challenges include generating funding, international collaboration, and the monitoring of safety and adherence for chronic HF treatments. Here, we use the Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF), to be conducted in the Swedish Heart Failure Registry, to exemplify the advantages and challenges of HF RRCTs.
Journal Article
The Nuremberg military tribunals and the origins of international criminal law
This book provides a comprehensive legal analysis of the twelve war crimes trials held in the American zone of occupation between 1946 and 1949, collectively known as the Nuremberg Military Tribunals (NMTs). The judgments the NMTs produced have played a critical role in the development of international criminal law, particularly in terms of how courts currently understand war crimes, crimes against humanity, and the crime of aggression. The trials are also of tremendous historical importance, because they provide a far more comprehensive picture of Nazi atrocities than their more famous predecessor, the International Military Tribunal at Nuremberg (IMT). The IMT focused exclusively on the ‘major war criminals’ — the Goerings, the Hesses, the Speers. The NMTs, by contrast, prosecuted doctors, lawyers, judges, industrialists, bankers — the private citizens and lower-level functionaries whose willingness to take part in the destruction of millions of innocents manifested what Hannah Arendt famously called ‘the banality of evil’. The book is divided into five sections. The first section traces the evolution of the twelve NMT trials. The second section discusses the law, procedure, and rules of evidence applied by the tribunals, with a focus on the important differences between Law No. 10 and the Nuremberg Charter. The third section, the heart of the book, provides a systematic analysis of the tribunals' jurisprudence. It covers Law No. 10's core crimes — crimes against peace, war crimes, and crimes against humanity — as well as the crimes of conspiracy and membership in a criminal organization. The fourth section then examines the modes of participation and defences that the tribunals recognized. The final section deals with sentencing, the aftermath of the trials, and their historical legacy.
eBook
Three randomized controlled trials evaluating the impact of “spin” in health news stories reporting studies of pharmacologic treatments on patients’/caregivers’ interpretation of treatment benefit
Background
News stories represent an important source of information. We aimed to evaluate the impact of “spin” (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients’/caregivers’ interpretation of treatment benefit.
Methods
We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants’ interpretation assessed by one specific question “What do you think is the probability that ‘treatment X’ would be beneficial to patients?” (scale, 0 [very unlikely] to 10 [very likely]).
Results
For each RCT, 300 participants were randomly assigned to assess a news story with spin (
n
= 150) or without spin (
n
= 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0–2.3],
p
< 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0–2.5],
p
< 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4–3.2],
p
< 0.001).
Conclusions
Spin in health news stories reporting studies of pharmacologic treatments affects patients’/caregivers’ interpretation.
Trial registration
ClinicalTrials.gov,
NCT03094078
,
NCT03094104
,
NCT03095586
Journal Article
What does a juror do?
The Constitution of the United States lists many rights for citizens. A fair trial by jury is one of those rights. A jury is made up of people from the place where the crime happened. These jurors are picked from a pool of citizens. Jurors hear evidence and receive directions from the judge for the case. After hearing the case, jurors decide if a person is guilty or innocent. In some cases, jurors also decide the punishment. This book will explore what it means to be a juror through an inquiry-based approach aligned with C3 standards. --Amazon
Book
Common Sense Oncology principles for the design, analysis, and reporting of phase 3 randomised clinical trials
Common Sense Oncology (CSO) prioritises treatments providing meaningful benefits for people with cancer. Here, we describe CSO principles aimed at improving the design, analysis, and reporting of randomised, controlled, phase 3 clinical trials evaluating cancer treatments. These principles include: (1) control treatment should be the best current standard of care; (2) the preferred primary endpoint is overall survival or a validated surrogate; (3) an absolute measure of benefit should be provided, such as the difference between groups in median overall survival times or the proportion of surviving patients at a prespecified time; (4) health-related quality of life should be at least a secondary endpoint; (5) toxicity should be described objectively without subjective language diminishing its importance; (6) trials should be designed to show or rule out clinically meaningful differences in outcomes, rather than a statistically significant difference alone; (7) censoring should be detailed, and sensitivity analyses done to determine its possible effects; (8) experimental treatments known to improve overall survival at later disease stages should be offered and funded for patients progressing in the control group; and (9) reports of trials should include a lay-language summary. We include checklists to guide compliance with these principles. By encouraging adherence, CSO aims to ensure that clinical trials yield results that are scientifically robust and meaningful to patients.
Journal Article