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Clinical Trials: Journal of the Society for Clinical Trials

David DeMets
With the initiation in the late 1960s of the data and safety monitoring board or equivalently the data monitoring committee in randomized clinical trials came the need for interim statistical reports for these committees to review for study conduct and early evidence of harm or overwhelming evidence of benefit, perhaps leading to early trial termination. Initially, the statistical team was part of the data coordinating center for the trial. Later, starting in the early 1990s in many industry-sponsored trials, this statistical unit was separated organizationally from the team that collected and managed the data...
May 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Vojtech Huser, Dikla Shmueli-Blumberg
Data sharing of de-identified individual participant data is being adopted by an increasing number of sponsors of human clinical trials. In addition to standardizing data syntax for shared trial data, semantic integration of various data elements is the focus of several initiatives that define research common data elements. This perspective article, in the first part, compares several data sharing platforms for de-identified clinical research data in terms of their size, policies and supported features. In the second part, we use a case study approach to describe in greater detail one data sharing platform (Data Share from National Institute of Drug Abuse)...
April 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Song Yang, Walter T Ambrosius, Lawrence J Fine, Adam P Bress, William C Cushman, Dominic S Raj, Shakaib Rehman, Leonardo Tamariz
Background/aims In clinical trials with time-to-event outcomes, usually the significance tests and confidence intervals are based on a proportional hazards model. Thus, the temporal pattern of the treatment effect is not directly considered. This could be problematic if the proportional hazards assumption is violated, as such violation could impact both interim and final estimates of the treatment effect. Methods We describe the application of inference procedures developed recently in the literature for time-to-event outcomes when the treatment effect may or may not be time-dependent...
April 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Lisa N Yelland, Brennan C Kahan, Elsa Dent, Katherine J Lee, Merryn Voysey, Andrew B Forbes, Jonathan A Cook
Background/aims In clinical trials, it is not unusual for errors to occur during the process of recruiting, randomising and providing treatment to participants. For example, an ineligible participant may inadvertently be randomised, a participant may be randomised in the incorrect stratum, a participant may be randomised multiple times when only a single randomisation is permitted or the incorrect treatment may inadvertently be issued to a participant at randomisation. Such errors have the potential to introduce bias into treatment effect estimates and affect the validity of the trial, yet there is little motivation for researchers to report these errors and it is unclear how often they occur...
April 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Thomas R Fleming, Susan S Ellenberg, David L DeMets
Maintaining confidentiality of emerging data and ensuring the independence of Data Monitoring Committees are best practices of considerable importance to the ability of these committees to achieve their mission of safeguarding the interests of study participants and enhancing the integrity and credibility of clinical trials. Even with the wide recognition of these principles, there are circumstances where confidentiality issues remain challenging, controversial or inconsistently addressed. First, consider settings where a clinical trial's interim data could provide the evidence regulatory authorities require for decisions about marketing approval, yet where such a trial would be continued post-approval to provide more definitive evidence about principal safety and/or efficacy outcomes...
April 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Schadrac C Agbla, Karla DiazOrdaz
BACKGROUND: Treatment non-adherence in randomised trials refers to situations where some participants do not receive their allocated treatment as intended. For cluster randomised trials, where the unit of randomisation is a group of participants, non-adherence may occur at the cluster or individual level. When non-adherence occurs, randomisation no longer guarantees that the relationship between treatment receipt and outcome is unconfounded, and the power to detect the treatment effects in intention-to-treat analysis may be reduced...
March 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Jonathan C Hibbard, Jonathan S Friedstat, Sonia M Thomas, Renee E Edkins, C Scott Hultman, Michael R Kosorok
BACKGROUND/AIMS: Laser treatment of burns scars is considered by some providers to be standard of care. However, there is little evidence-based research as to the true benefit. A number of factors hinder evaluation of the benefit of laser treatment. These include significant heterogeneity in patient response and possible delayed effects from the laser treatment. Moreover, laser treatments are often provided sequentially using different types of equipment and settings, so there are effectively a large number of overall treatment options that need to be compared...
March 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
James D Neaton, Birgit Grund, Deborah Wentworth
BACKGROUND: Data monitoring committees for randomized clinical trials have the responsibility of safeguarding interests of trial participants. To do so, the data monitoring committee must receive reports on safety and efficacy to assess risk/benefit and on trial conduct to ensure that the study can achieve its goals. This article outlines the key components of reports to the data monitoring committee and the important role of the unblinded statistician in preparing those reports. METHODS: Most data monitoring committee meetings include open and closed sessions...
March 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Sabine Landau, Richard Emsley, Graham Dunn
BACKGROUND: Random allocation avoids confounding bias when estimating the average treatment effect. For continuous outcomes measured at post-treatment as well as prior to randomisation (baseline), analyses based on (A) post-treatment outcome alone, (B) change scores over the treatment phase or (C) conditioning on baseline values (analysis of covariance) provide unbiased estimators of the average treatment effect. The decision to include baseline values of the clinical outcome in the analysis is based on precision arguments, with analysis of covariance known to be most precise...
March 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Peter A Nigrovic, Timothy Beukelman, George Tomlinson, Brian M Feldman, Laura E Schanberg, Yukiko Kimura
BACKGROUND: Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely...
March 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Theodore Karrison, Masha Kocherginsky
BACKGROUND: Restricted mean survival time is a measure of average survival time up to a specified time point. There has been an increased interest in using restricted mean survival time to compare treatment arms in randomized clinical trials because such comparisons do not rely on proportional hazards or other assumptions about the nature of the relationship between survival curves. METHODS: This article addresses the question of whether covariate adjustment in randomized clinical trials that compare restricted mean survival times improves precision of the estimated treatment effect (difference in restricted mean survival times between treatment arms)...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Yiyi Chu, Ying Yuan
BACKGROUND: The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical modeling has been proposed to adaptively borrow information across cancer types to improve the statistical power of basket trials. Although conceptually attractive, research has shown that Bayesian hierarchical models cannot appropriately determine the degree of information borrowing and may lead to substantially inflated type I error rates...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Alexandra Wright-Hughes, Elizabeth Graham, David Cottrell, Amanda Farrin
BACKGROUND: Use of routine data sources within clinical research is increasing and is endorsed by the National Institute for Health Research to increase trial efficiencies; however there is limited evidence for its use in clinical trials, especially in relation to self-harm. One source of routine data, Hospital Episode Statistics, is collated and distributed by NHS Digital and contains details of admissions, outpatient, and Accident and Emergency attendances provided periodically by English National Health Service hospitals...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Holly L Peay, Barbara B Biesecker, Benjamin S Wilfond, Jill Jarecki, Kendall L Umstead, Diana M Escolar, Aad Tibben
BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Yu Lan, Daniel F Heitjan
BACKGROUND: In event-based clinical trials, it is common to conduct interim analyses at planned landmark event counts. Accurate prediction of the timing of these events can support logistical planning and the efficient allocation of resources. As the trial progresses, one may wish to use the accumulating data to refine predictions. PURPOSE: Available methods to predict event times include parametric cure and non-cure models and a nonparametric approach involving Bayesian bootstrap simulation...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Rebecca Kahn, Matt Hitchings, Steven Bellan, Marc Lipsitch
Background/aims Network structure and individuals' level of exposure to a pathogen can impact results from efficacy evaluation studies of interventions against infectious diseases. Heterogeneity in infection risk can cause randomized groups to increasingly differ as a trial progresses and as more high-risk individuals become infected (described in prior work as the "frailty" phenomenon). Here, we show the impact this phenomenon can have on an individually randomized trial of a leaky vaccine in which all participants are exchangeable a priori...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Tiago Rua, Sanjay Vijayanathan, David Parkin, Vicky Goh, Paul McCrone, Sam Gidwani
Background Wrist injury is a common presentation to the Emergency Department in the United Kingdom. Among these injuries, the scaphoid is the most common fractured carpal bone. However, given the limited ability of conventional radiography to accurately diagnose a suspected scaphoid fracture on presentation, its diagnosis and management remain challenging. Despite the vast clinical evidence supporting the superior accuracy of magnetic resonance imaging, there is little to no evidence around the real-world clinical and economic impact of immediate magnetic resonance imaging in the management of suspected scaphoid fractures...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Stephen P Juraschek, Timothy B Plante, Jeanne Charleston, Edgar R Miller, Hsin-Chieh Yeh, Lawrence J Appel, Gerald J Jerome, Debra Gayles, Nowella Durkin, Karen White, Arlene Dalcin, Manuel Hermosilla
BACKGROUND/AIMS: Despite widespread Internet adoption, online advertising remains an underutilized tool to recruit participants into clinical trials. Whether online advertising is a cost-effective method to enroll participants compared to other traditional forms of recruitment is not known. METHODS: Recruitment for the Survivorship Promotion In Reducing IGF-1 Trial, a community-based study of cancer survivors, was conducted from June 2015 through December 2016 via in-person community fairs, advertisements in periodicals, and direct postal mailings...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Cindy L Cooper, Amy Whitehead, Edward Pottrill, Steven A Julious, Stephen J Walters
BACKGROUND/AIMS: External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually predicts randomisation and attrition rates in the main trial. To assess the use of external pilot trials in trial design, we compared randomisation and attrition rates in publicly funded randomised controlled trials with rates in their pilots. METHODS: Randomised controlled trials for which there was an external pilot trial were identified from reports published between 2004 and 2013 in the Health Technology Assessment Journal...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Mirjam Moerbeek
Background This article studies the design of trials that compare three treatment conditions that are delivered by two types of health professionals. The one type of health professional delivers one treatment, and the other type delivers two treatments, hence, this design is a combination of a nested and crossed design. As each health professional treats multiple patients, the data have a nested structure. This nested structure has thus far been ignored in the design of such trials, which may result in an underestimate of the required sample size...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
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