Association of the British Pharmaceutical Industry

Integrating nonclinical in vitro, in silico, and in vivo datasets holistically can improve hazard characterization and risk assessment. In pharmaceutical development, cardiovascular liabilities are a leading cause of compound attrition. Prior to clinical studies, functional cardiovascular data are generated in single-dose safety pharmacology telemetry studies, with structural pathology data obtained from repeat-dose toxicology studies with limited concurrent functional endpoints, eg, electrocardiogram via jacketed telemetry. Relationships between datasets remain largely undetermined. To address this gap, a cross-pharma collaboration collated functional and structural data from 135 compounds. Retrospective functional data were collected from good laboratory practice conscious dog safety pharmacology studies: effects defined as hemodynamic blood pressure or heart rate changes. Morphologic pathology findings (mainly degeneration, vacuolation, inflammation) from related toxicology studies in the dog (3-91 days repeat-dosing) were reviewed, harmonized, and location categorized: cardiac muscle (myocardium, epicardium, endocardium, unspecified), atrioventricular/aortic valves, blood vessels. The prevalence of cardiovascular histopathology changes was 11.1% of compounds, with 53% recording a functional blood pressure or heart rate change. Correlations were assessed using the Mantel-Haenszel Chi-square trend test, identifying statistically significant associations between cardiac muscle pathology and (1) decreased blood pressure, (2) increased heart rate, and between cardiovascular vessel pathology and increased heart rate. Negative predictive values were high, suggesting few compounds cause repeat-dose cardiovascular structural change in the absence of functional effects in single-dose safety pharmacology studies. Therefore, observed functional changes could prompt moving (sub)chronic toxicology studies forward, to identify cardiovascular liabilities earlier in development, and reduce late-stage attrition.

An analysis of the use ofin vitrotechniques in preclinical safety testing revealed a marked increase to >180 000 tests/year by 2012. Step changes in uptake were notable in the three main areas of ADME, safety pharmacology and genetic toxicology, correlated with relevant ICH guidelines.

In the UK the Coalition government has recently undertaken a far-reaching and very controversial reform of the National Health Service (NHS) health and social care services. This new Health and Social Care Act will facilitate the most radical restructuring of the health service in England since the creation of the NHS in 1948. Legistative approval has been obtained and from April 2013 general practitioners will control more than half of the annual budget of the health service. There are many provisions in the reform bill and these have yet to be implemented. The authors have therefore set out a chronological history of the NHS and its statutory structures so that there is to hand a concise and full reference to the development and management for the NHS as practised today. A comparision can be made in relation to the changes described in the provisions of the new but very disputed reform bill. A brief summary is given of the reform bill provisions.