Improving public health by improving clinical trial guidelines and their application.

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.

Pharmaceutical companies' policies on access to trial data, results, and methods: audit study.

Objectives To identify the policies of major pharmaceutical companies on transparency of trials, to extract structured data detailing each companies' commitments, and to assess concordance with ethical and professional guidance.Design Structured audit.Setting Pharmaceutical companies, worldwide.Participants 42 pharmaceutical companies.Main outcome measures Companies' commitments on sharing summary results, clinical study reports (CSRs), individual patient data (IPD), and trial registration, for prospective and retrospective trials.Results Policies were highly variable. Of 23 companies eligible from the top 25 companies by revenue, 21 (91%) committed to register all trials and 22 (96%) committed to share summary results; however, policies commonly lacked timelines for disclosure, and trials on unlicensed medicines and off-label uses were only included in six (26%). 17 companies (74%) committed to share the summary results of past trials. The median start date for this commitment was 2005. 22 companies (96%) had a policy on sharing CSRs, mostly on request: two committed to share only synopses and only two policies included unlicensed treatments. 22 companies (96%) had a policy to share IPD; 14 included phase IV trials (one included trials on unlicensed medicines and off-label uses). Policies in the exploratory group of smaller companies made fewer transparency commitments. Two companies fell short of industry body commitments on registration, three on summary results. Examples of contradictory and ambiguous language were documented and summarised by theme. 23/42 companies (55%) responded to feedback; 7/1806 scored policy elements were revised in light of feedback from companies (0.4%). Several companies committed to changing policy; some made changes immediately.Conclusions The commitments made by companies to transparency of trials were highly variable. Other than journal submission for all trials within 12 months, all elements of best practice were met by at least one company, showing that these commitments are realistic targets.

Embryonic stem cells as a source of pulmonary epithelium in vitro and in vivo.

Embryonic stem cells (ESCs) derived from the preimplantation blastocyst are pluripotent and capable of indefinite expansion in vitro. As such, they present a cell source to derive a potentially inexhaustible supply of pulmonary cells and tissue. ESC-derived pulmonary epithelium could be used for in vitro cell or tissue models or, in the future, implanted into the damaged or diseased lung to effect repair. Efforts to date have largely focused on obtaining distal lung epithelial phenotypes from ESCs, notably alveolar epithelium. Several disparate methods have been developed to enhance differentiation of ESCs into pulmonary epithelial lineages; these are broadly based on recapitulating developmental signaling events, mimicking the physical environment, or forcibly reprogramming the ESC nucleus. Early findings of our preclinical experiments implanting differentiated ESCs into the injured lung are also described here. Future efforts will focus on maximizing ESC differentiation efficiency and yield of the target phenotype, as well as characterizing the function of derived cells in vivo and in vitro.

Stem cells in lung repair and regeneration.

Repair or regeneration of defective lung tissue would be of great clinical use. Potential cellular sources for the regeneration of lung tissue in vivo or lung tissue engineering in vitro include endogenous pulmonary stem cells, extrapulmonary circulating stem cells and embryonic stem cells. This review summarizes the recent research on each of these stem cell types and their potential for use in the treatment of lung injury and disease.

The developing cervical spinal ventral commissure of the rat: a highly controlled axon-glial system.

The floor plate of the neural tube is of major importance in determining axonal behaviour, such that, having crossed, decussating axons do not cross back again. The ventral commissure (VC) of the spinal cord forms immediately ventral to the floor plate shortly after neural tube closure. It is the principal location in which decussating axons cross the midline. It is probably also of major importance in neural tube development, but has received relatively little attention. This study analyses the growth and development of the rat VC and also axon-glial relationships within it throughout the crucial prenatal period of extensive transmedian axon growth, when key biochemical interactions between the two tissues are taking place. The morphometric, stereological and immunohistochemical methods used show that the axonal and glial populations remain in a finely balanced equilibrium throughout a period of almost a hundred-fold growth of both elements. At all stages axons are highly segregated into small bundles of constant size by glial processes, to which they are closely apposed. Thus, glial-axon contact is remarkably precocious, uniquely intimate and persists throughout VC development. This suggests that the relationship between the two tissues is highly controlled through interactions between them. The VC is likely to be the physical basis of a second set of glial-axonal interactions, namely, those which are well known to influence axon crossing behaviour. In mediating these, the extensive axon-glial contact is an ideal arrangement for molecular transfer between them, and is probably the substrate for altering axon responsiveness and ensuring reliable transmedian decussation. The VC is therefore a segregating matrix temporally and spatially specialised for a range of key developmental axon-glial interactions.