Healthcare professional experiences and attitudes on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

Objectives: To investigate the knowledge and views of a range of healthcare professionals (consultant paediatricians, general practitioners (GPs), community pharmacists and paediatric nurses) regarding the use of unlicensed/off-label medicines in children and the participation of children in clinical trials.

Methods: A regional study in which a survey instrument with 39 items was issued to 500 randomly selected GPs, all community pharmacists (n?=?512), 50 hospital consultants and 150 paediatric nurses in Northern Ireland.

Results: Approximately half (46.5%) of the 1,212 healthcare professionals approached responded to the questionnaire. The majority of respondents indicated their familiarity with the term unlicensed (82.9%) or off-label (58.6%) prescribing with the most frequently quoted reason for such prescribing being younger age (33.6%). Apart from community pharmacists, most respondents reported having gained their knowledge through personal experience. Even though a large percentage of respondents expressed concerns about the safety (77.8%) or efficacy (87.9%) of unlicensed/off-label prescribing in children, only 30.7% reported informing parents/guardians of these concerns on the use of such medicines in children. In addition, only 56% of respondents believed that unlicensed/off-label medicines should undergo clinical trials in children. Overall, 28.4% of respondents (20.1% of GPs, 41.4% of community pharmacists, 27.7% of paediatric nurses and 94% of consultant paediatricians) indicated their willingness to be actively involved in, and recruit their patients for paediatric clinical research.

Conclusion: The use of unlicensed and off-label medicines remains a major issue in paediatric medicine. Until such times as more licensed medicines are available for children, clear guidance should be developed to allow consistency in practice across the spectrum of healthcare professionals who are involved with such medicines in their routine practice.

Children’s views on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

Objectives: To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. Methods: Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. Results: A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. Conclusions: This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. Practice implications Health care professionals should consider the views of children in decisions that affect their health.

Cognitive, global, and functional benefits of donepezil in Alzheimer's disease and vascular dementia:results from large-scale clinical trials

Alzheimer's disease (AD) and vascular dementia (VaD) are both associated with deficits in cholinergic neurotransmission that are amenable to therapeutic intervention. The cholinesterase inhibitor, donepezil, is clinically effective in both AD and VaD. Results from a 10-study metaanalysis of donepezil (5 or 10 mg/day) in AD and a two-study combined analysis of donepezil (5 or 10 mg/day) in VaD are presented to compare patient characteristics and donepezil treatment outcomes. The analyzed studies were randomized, placebo-controlled, and of up to 24 weeks duration. In both AD and VaD, donepezil provided significant benefits compared with placebo on measures of cognition and global function. Placebo-treated AD patients showed a decline in cognition and global function, whereas placebo-treated VaD patients remained stable, suggesting treatment effects of donepezil in VaD were driven by improvement rather than stabilization or reduced decline. More VaD patients than AD patients received concomitant medications. Cardiovascular adverse events were more common in VaD than AD patients but were not increased by donepezil. In conclusion, although there are differences between AD and VaD patients in comorbid conditions and concomitant medications, donepezil is effective and well tolerated in both types of dementia.

The geriatric minimum data set for clinical trials (GMDS)

To overcome the weak evidence base coming from often poor and insufficient clinical research in older people, a minimum data set to achieve harmonisation is highly advisable. This will lead to uniform nomenclature and to the standardisation of the assessment tools. Our primary objective was to develop a Geriatric Minimum Data Set (GMDS) for clinical research.

Clinical trials in cystic fibrosis

In patients with cystic fibrosis (CF), clinical trials are of paramount importance. Here, the current status of drug development in CF is discussed and future directions highlighted. Methods for pre-clinical testing of drugs with potential activity in CF patients including relevant animal models are described. Study design options for phase II and phase III studies involving CF patients are provided, including required patient numbers, safety issues and surrogate end point parameters for drugs, tested for different disease manifestations. Finally, regulatory issues for licensing new therapies for CF patients are discussed, including new directives of the European Union and the structure of a European clinical trial network for clinical studies involving CF patients is proposed.

Guideline on the design and conduct of cystic fibrosis clinical trials: The European Cystic Fibrosis Society–Clinical Trials Network (ECFS-CTN)

We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.

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.

Clinical Trials Abroad: The Marketable Ethics, Weak Protections and Vulnerable Subjects of EU Law

This chapter explores how the EU is a largely overlooked exporter of normative power through its facilitation and use of clinical trials data produced abroad for the marketing of safe pharmaceuticals at home; a move that helps to foster the growing resort to pharmaceuticals as a fix for public health problems. This is made possible by the EU’s (de)selection of international ethical frameworks in preference to the international technical standards it co-authors with other global regulators. Clinical trials abroad underscore how ethics are contingent and revisable in light of market needs, producing weak protections for the vulnerable subjects of EU law. I argue that these components and effects of the regime are ultimately about that which undergirds, shapes and directs regulatory design. That is, I point to the use, infiltration, perpetuation and extension of market-oriented ideas, values and rationalities into formally non-market domains like biomedical knowledge production and public health. I explain how these are central to efforts at producing and legitimating the EU, its related imagined socio-political order based on a more innovative, profitable and competitive pharmaceutical sector in order to foster economic growth, jobs and prosperity, and with them the project of European integration. ‘Bioethics as risk’ is highlighted as a way to reshape and redirect the regulatory regime in ways that are more consistent with the spirit and letter of the ethical standards (and through them the human rights) the EU claims to uphold.