Protecting patient privacy when sharing patient-level data from clinical trials

Abstract Background Greater transparency and, in particular, sharing of patient-level data for further scientific research is an increasingly important topic for the pharmaceutical industry and other organisations who sponsor and conduct clinical trials as well as generally in the interests of patients participating in studies. A concern remains, however, over how to appropriately prepare and share clinical trial data with third party researchers, whilst maintaining patient confidentiality. Clinical trial datasets contain very detailed information on each participant. Risk to patient privacy can be mitigated by data reduction techniques. However, retention of data utility is important in order to allow meaningful scientific research. In addition, for clinical trial data, an excessive application of such techniques may pose a public health risk if misleading results are produced. After considering existing guidance, this article makes recommendations with the aim of promoting an approach that balances data utility and privacy risk and is applicable across clinical trial data holders. Discussion Our key recommendations are as follows: 1. Data anonymisation/de-identification: Data holders are responsible for generating de-identified datasets which are intended to offer increased protection for patient privacy through masking or generalisation of direct and some indirect identifiers. 2. Controlled access to data, including use of a data sharing agreement: A legally binding data sharing agreement should be in place, including agreements not to download or further share data and not to attempt to seek to identify patients. Appropriate levels of security should be used for transferring data or providing access; one solution is use of a secure ‘locked box’ system which provides additional safeguards. Summary This article provides recommendations on best practices to de-identify/anonymise clinical trial data for sharing with third-party researchers, as well as controlled access to data and data sharing agreements. The recommendations are applicable to all clinical trial data holders. Further work will be needed to identify and evaluate competing possibilities as regulations, attitudes to risk and technologies evolve

Anodic stripping voltammetry with graphite felt electrodes for the trace analysis of silver

Graphite felt (GF) is a mass produced porous carbon electrode material commonly used in redox flow batteries. Previous studies have suggested GF may have valuable applications in electroanalysis as a low cost disposable carbon electrode material, although most GF sensors have used flow cell arrangements. In this work, an elegant wetting technique is employed that allows GF electrodes to be used in quiescent solution to detect trace levels of silver in water via anodic stripping voltammetry. GF electrodes display good repeatability and a limit of detection of 25 nM of Ag+ in 0.1 M HNO3, with a linear range spanning two orders of magnitude. This compares to a value of around 140 nM when using conventional carbon electrodes. Combined with their low cost and disposable nature, the results suggest GF electrodes can make a valuable contribution to electroanalysis

High locomotor reactivity to novelty is associated with an increased propensity to choose saccharin over cocaine: new insights into the vulnerability to addiction.

Drug addiction is associated with a relative devaluation of natural or socially-valued reinforcers that are unable to divert addicts from seeking and consuming the drug. Before protracted drug exposure, most rats prefer natural rewards, such as saccharin, over cocaine. However, a subpopulation of animals prefer cocaine over natural rewards and are thought to be vulnerable to addiction. Specific behavioral traits have been associated with different dimensions of drug addiction. For example, anxiety predicts loss of control over drug intake whereas sensation seeking and sign-tracking are markers of a greater sensitivity to the rewarding properties of the drug. However, how these behavioral traits predict the disinterest for natural reinforcers remains unknown. In a population of rats, we identified sensation seekers (HR) on the basis of elevated novelty-induced locomotor reactivity, high anxious rats (HA) based on the propensity to avoid open arms in an elevated-plus maze and sign-trackers (ST) that are prone to approach, and interaction with, reward-associated stimuli. Rats were then tested on their preference for saccharin over cocaine in a discrete-trial choice procedure. We show that HR rats display a greater preference for saccharin over cocaine compared with ST and HA whereas the motivation for the drug was comparable between the three groups. The present data suggest that high locomotor reactivity to novelty, or sensation seeking, by predisposing to an increased choice toward non-drug rewards at early stages of drug use history, may prevent the establishment of chronic cocaine use.This work was funded by an INSERM AVENIR and Agence Nationale de la Recherche (ANR) ANR12 SAMA00201 grant to DB, the région Poitou-Charentes, an AXA research fund fellowship to ABR, and a Ministère de la Recherche et de la Technologie grant to NV. AM was supported by the Behavioural and Clinical Neuroscience Institute of Cambridge.This is the accepted manuscript of a paper published in Neuropsychopharmacology (2015) 40, 577–589; doi:10.1038/npp.2014.204; published online 17 September 2014

The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking.

Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective μ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.The present study was funded by Medical Research Council Programme Grant (no. G1002231) and by GlaxoSmithKline (GSK), which has a commercial interest in GSK1521498. Charles R. Goodlett was funded by a grant from the IUPUI International Development Fund, which supported his sabbatical leave at the University of Cambridge. Maria Pilar Garcia-Pardo was funded by Val+id para investigadores en formación (Conselleria de educacion, Generalitat Valenciana), which also supported her stay at the University of Cambridge (January-April 2014) as a Visiting Student.This is the accepted manuscript. The final version is available from NPG at http://dx.doi.org/10.1038/npp.2015.15

The international dimensions of nationalism in Central Asia : can the relationship betweeninternational security, state sovereignty and emerging ethnonationalism be reconciled in Post-Soviet Central Asia?

The thesis tracks the emergence of western forms of nationalism in republics of Post-Soviet Central Asia, and assesses the likelihood of ethnic conflict in the region, and itsprobably consequences. It also considers the means by which the heterogenouspopulations in Central Asia may be more effectively accommodated within theindividual republics.The thesis is conceived in three sections. The first section examines the causes andconsequences of ethnic conflict, and discusses the implications of ethnic conflict inCentral Asia from the perspective of state sovereignty and international security. Thesecond section assesses the evolution of ethnicity and identity in Central Asia, theimpact of Soviet nationalities policies and the impact of newly enforceable territorialsovereignty on the interconnected populations of the region. The third, and concluding,section considers the impact of state actors and regional and international institutions onthe Central Asian republics, and considers strategies that may mitigate the potential forethnic conflict in the region.The thesis concludes that emerging ethnonationalism in Post-Soviet Central Asia posesa real threat to regional and international security. The individual republics are pursuingpolicies which discriminate against large proportions of their populations. The CentralAsian republics are also struggling with their newly found sovereignty, especially inrespect to their asymmetrical relationships with states such as Russia, China and theU.S.A. The republics should consider alternative forms of governance, such as nationalcultural autonomy or consociation, which may contribute to a lessening of the tensionsbetween ethnic or identity groups. The international community, in the form of theUnited Nations or other appropriate organisations, should recognise the potential forethnic conflict in the region, and should actively encourage the states to adoptinnovative forms of government that accommodate the diverse needs of theirheterogenous populations

Factors influencing treatment escalation from long-acting muscarinic antagonist monotherapy to triple therapy in patients with COPD: a retrospective THIN-database analysis

John R Hurst,1 Maria Dilleen,2 Kevin Morris,3 Siân Hills,3 Birol Emir,4 Rupert Jones5 1UCL Respiratory, University College London, London, UK; 2Statistics, Global Product Development, Pfizer, Tadworth, UK; 3Medical Affairs, Pfizer, Tadworth, UK; 4Biostatistics, Global Product Development, Pfizer, New York, NY, USA; 5Clinical Trials & Health Research, Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK Purpose: Inappropriate use of an inhaled corticosteroid (ICS) for COPD has clinical and economic disadvantages. This retrospective analysis of The UK Health Improvement Network (THIN) database identified factors influencing treatment escalation (step-up) from a long-acting muscarinic antagonist (LAMA) to triple therapy (LAMA + long-acting β-agonist-ICS). Secondary objectives included time to step up from first LAMA prescription, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grouping (2011/2013, 2017), and Medical Research Council (MRC) grade prior to treatment escalation. Materials and methods: Data were included from 14,866 people ≥35 years old with a COPD diagnosis (June 1, 2010–May 10, 2015) and initiated on LAMA monotherapy. The most commonly used LAMA at baseline was tiotropium (92%). Results: Multivariate analysis (10,492 patients) revealed that COPD exacerbations, lower forced expiratory volume in 1 second (FEV1), “asthma”, MRC grade, proactive and reactive COPD primary care, elective secondary-care contact, cough, and number of short-acting bronchodilator prescriptions were positively associated with treatment escalation (P<0.05). Being older, a current/ex-smoker, or having increased sputum symptom codes were negatively associated with treatment escalation (P<0.05). Median MRC score was 2 at baseline and 3 prior to treatment escalation. Using the last MRC reading and exacerbation history in the year prior to escalation, GOLD 2017 groupings were A 27.4%, B 37.3%, C 15.3%, and D 20%. In patients with available FEV1 measures, exacerbations, and MRC code (n=1,064), GOLD 2011/2013 groupings were A 20.4%, B 19.2%, C 24.8%, and D 35.6%. Conclusion: While the presence of COPD exacerbations seems to be the main driver for treatment escalation, according to the 2017 GOLD strategy many patients appear to be overtreated, as they would not be recommended for treatment escalation. Reviewing patients’ treatment in the light of the new GOLD strategy has the potential to reduce inappropriate use of triple therapy. Keywords: inhaled corticosteroid, treatment step-up, GOLD 2017 grouping, patient overtreatmen

Factors influencing treatment escalation from long-acting muscarinic antagonist monotherapy to triple therapy in patients with COPD: a retrospective THIN-database analysis.

Purpose: Inappropriate use of an inhaled corticosteroid (ICS) for COPD has clinical and economic disadvantages. This retrospective analysis of The UK Health Improvement Network (THIN) database identified factors influencing treatment escalation (step-up) from a long-acting muscarinic antagonist (LAMA) to triple therapy (LAMA + long-acting β-agonist-ICS). Secondary objectives included time to step up from first LAMA prescription, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grouping (2011/2013, 2017), and Medical Research Council (MRC) grade prior to treatment escalation. Materials and methods: Data were included from 14,866 people ≥35 years old with a COPD diagnosis (June 1, 2010-May 10, 2015) and initiated on LAMA monotherapy. The most commonly used LAMA at baseline was tiotropium (92%). Results: Multivariate analysis (10,492 patients) revealed that COPD exacerbations, lower forced expiratory volume in 1 second (FEV1), "asthma", MRC grade, proactive and reactive COPD primary care, elective secondary-care contact, cough, and number of short-acting bronchodilator prescriptions were positively associated with treatment escalation (P<0.05). Being older, a current/ex-smoker, or having increased sputum symptom codes were negatively associated with treatment escalation (P<0.05). Median MRC score was 2 at baseline and 3 prior to treatment escalation. Using the last MRC reading and exacerbation history in the year prior to escalation, GOLD 2017 groupings were A 27.4%, B 37.3%, C 15.3%, and D 20%. In patients with available FEV1 measures, exacerbations, and MRC code (n=1,064), GOLD 2011/2013 groupings were A 20.4%, B 19.2%, C 24.8%, and D 35.6%. Conclusion: While the presence of COPD exacerbations seems to be the main driver for treatment escalation, according to the 2017 GOLD strategy many patients appear to be overtreated, as they would not be recommended for treatment escalation. Reviewing patients' treatment in the light of the new GOLD strategy has the potential to reduce inappropriate use of triple therapy