Variation of clinical outcomes used in glaucoma randomised controlled trials:a systematic review

Purpose: In randomised clinical trials (RCTs) the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. The purpose of this review is to identify different clinical outcomes reported in glaucoma trials.

Methods We conducted a systematic review of glaucoma RCTs. A sample or selection of glaucoma trials were included bounded by a time frame (between 2006 and March 2012). Only studies in English language were considered. All clinical measured and reported outcomes were included. The possible variations of clinical outcomes were defined prior to data analysis. Information on reported clinical outcomes was tabulated and analysed using descriptive statistics. Other data recorded included type of intervention and glaucoma, duration of the study, defined primary outcomes, and outcomes used for sample size calculation, if nominated.

Results The search strategy identified 4323 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Safety outcomes were commonly reported in 145 RCTs (62%) whereas visual field outcomes were used in 38 RCTs (16%).

Conclusions There is a large variation in the reporting of clinical outcomes in glaucoma RCTs. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

Offshoring Clinical Trials: The Mutable Ethics, Weak Protections and Vulnerable Subjects of EU Law

In this paper I engage with science and technology studies work on pharmaceuticalisation to explore how European Union (EU) law helps to produce and support the preference for pharmaceutical responses in public health governance, while authorising the production of vulnerable subjects through the growing off-shoring of clinical trials. Drawing on the analysis of legal and policy documents, I demonstrate how EU law allows and legitimates the use of data procured from vulnerable subjects abroad for market authorisation and corporate profitability at home. This is possible because the EU has (de)selected international ethical frameworks in order to support the continued and growing use of clinical trials data from abroad. This has helped to stimulate the revision of international ethical frameworks in light of market needs, inscribing EU public health law within specific politics (that often remained obscured by the joint workings of legal and technological discourses). I suggest that law operates as part of a broader ‘technology’ – encompassing ethics and human rights discourses – that functions to optimise life through resort to market reasoning. Law is thereby reoriented, instrumentalised and deployed as part of a broader project aimed at (re)defining and limiting the boundaries of the EU's responsibility for public health, including the broader social production of public health problems and the unequal global order that the EU represents and helps to depoliticise and perpetuate. Overall, this limits the EU's responsibility and accountability for these failures, as well as another: the weak and mutable protections and insecure legacies for vulnerable trial subjects abroad.

How Outcomes Are Defined in Clinical Trials of Mechanically Ventilated Adults and Children

Systematic reviews have considerable potential to provide evidence-based data to aid clinical decision-making. However, there is growing recognition that trials involving mechanical ventilation lack consistency in the definition and measurement of ventilation outcomes, creating difficulties in combining data for meta-analyses. To address the inconsistency in outcome definitions, international standards for trial registration and clinical trial protocols published recommendations, effectively setting the “gold standard” for reporting trial outcomes. In this Critical Care Perspective, we review the problems resulting from inconsistent outcome definitions and inconsistent reporting of outcomes (outcome sets). We present data highlighting the variability of the most commonly reported ventilation outcome definitions. Ventilation outcomes reported in trials over the last 6 years typically fall into four domains: measures of ventilator dependence; adverse outcomes; mortality; and resource use. We highlight the need, first, for agreement on outcome definitions and, second, for a minimum core outcome set for trials involving mechanical ventilation. A minimum core outcome set would not restrict trialists from measuring additional outcomes, but would overcome problems of variability in outcome selection, measurement, and reporting, thereby enhancing comparisons across trials.

Lung clearance index: Evidence for use in clinical trials in cystic fibrosis

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

A pilot study of a family focused, psychosocial intervention with war-exposed youth at risk of attack and abduction in north-eastern Democratic Republic of Congo

Rural communities in the Haut-Uele Province of northern Democratic Republic of Congo live in constant danger of attack and/or abduction by units of the Lord's Resistance Army operating in the region. This pilot study sought to develop and evaluate a community-participative psychosocial intervention involving life skills and relaxation training and Mobile Cinema screenings with this war-affected population living under current threat. 159 war-affected children and young people (aged 7-18) from the villages of Kiliwa and Li-May in north-eastern DR Congo took part in this study. In total, 22% of participants had been abduction previously while 73% had a family member abducted. Symptoms of post-traumatic stress reactions, internalising problems, conduct problems and pro-social behaviour were assessed by blinded interviewers at pre- and post-intervention and at 3-month follow-up. Participants were randomised (with an accompanying caregiver) to 8 sessions of a group-based, community-participative, psychosocial intervention (n=79) carried out by supervised local, lay facilitators or a wait-list control group (n=80). Average seminar attendance rates were high: 88% for participants and 84% for caregivers. Drop-out was low: 97% of participants were assessed at post-intervention and 88% at 3 month follow-up. At post-test, participants reported significantly fewer symptoms of post-traumatic stress reactions compared to controls (Cohen's d=0.40). At 3 month follow up, large improvements in internalising symptoms and moderate improvements in pro-social scores were reported, with caregivers noting a moderate to large decline in conduct problems among the young people. Trial Registration clinicalTrials.gov, Identifier: NCT01542398.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

The Role of Victims in the International Criminal Tribunals of the Second World War

This article analyses the role of victims within the founding international criminal tribunals of the Second World War, drawing from historical research of the practice and judgements of the Nuremberg and Tokyo tribunals. While some commentators have decried the absence of victims at Nuremberg and Tokyo, numerous victim-witnesses testified before these tribunals. However, the outcome of these tribunals has been disappointing to victims who still seek justice over sixty-five years later. This article considers the implications of the Nuremberg and Tokyo tribunals not providing justice to victims and how this has impacted on their legacy. Although these tribunals are neglected in contemporary discussions of victim provisions, they can still provide some important lessons for modern international criminal justice mechanisms, such as the International Criminal Court, to learn from.

An overview of waste crime, its characteristics, and the vulnerability of the EU waste sector

While waste is increasingly viewed as a resource to be globally traded, increased regulatory control on waste across Europe has created the conditions where waste crime now operates alongside a legitimate waste sector. Waste crime,is an environmental crime and a form of white-collar crime, which exploits the physical characteristics of waste, the complexity of the collection and downstream infrastructure, and the market opportunities for profit. This paper highlights some of the factors which make the waste sector vulnerable to waste crime. These factors include new legislation and its weak regulatory enforcement, the economics of waste treatment, where legal and safe treatment of waste can be more expensive than illegal operations, the complexity of the waste sector and the different actors who can have some involvement, directly or indirectly, in the movement of illegal wastes, and finally that waste can be hidden or disguised and creates an opportunity for illegal businesses to operate alongside legitimate waste operators. The study also considers waste crime from the perspective of particular waste streams that are often associated with illegal shipment or through illegal treatment and disposal. For each, the nature of the crime which occurs is shown to differ, but for each, vulnerabilities to waste crime are evident. The paper also describes some approaches which can be adopted by regulators and those involved in developing new legislation for identifying where opportunities for waste crime occurs and how to prevent it.

Comparing a trauma focused and non trauma focused intervention with war affected Congolese youth: a preliminary randomised trial

While there is broad consensus about the need for interventions to help psychologically distressed, war affected youth, there is also limited research and even less agreement on which interventions work best. Therefore, this paper presents a randomised trial of trauma focused, and non trauma focused, interventions with war affected Congolese youth. Fifty war affected Congolese youth, who had been exposed to multiple adverse life events, were randomly assigned to either a Trauma Focused Cognitive Behavioural Therapy group or a non trauma based psychosocial intervention (Child Friendly Spaces). Non clinically trained, Congolese facilitators ran both groups. A convenience sample, waiting list group was also formed. Using blind assessors, participants were individually interviewed at pre intervention, post intervention and a 6-month follow-up using self-report posttraumatic stress and internalising symptoms, conduct problems and pro social behaviour. Both treatment groups made statistically significant improvements, compared to the control group. Large, within subject, effect sizes were reported at both post intervention and follow-up. At the 6-month follow-up, only the Child Friendly Spaces group showed a significant decrease in pro social behaviour. The paper concludes that both trauma focused and non trauma focused interventions led to reductions in psychological distress in war affected youth.