National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme research funding and UK burden of disease.

BACKGROUND: HTA Programme funding is governed by the need for evidence and scientific quality, reflecting funding of the National Institute for Health Research (NIHR) by the NHS. The need criterion incorporates covering the spectrum of diseases, but also taking account of research supported by other funders. This study compared the NIHR HTA Programme portfolio of research with the UK burden of disease as measured by Disability-adjusted Life Years (DALYs). METHODS: A retrospective cross-sectional study using a cohort of all funded primary research and evidence syntheses projects received by the HTA Programme from April 2011 to March 2016 (n = 363); to determine the proportion of spend by disease compared with burden of disease in the UK calculated using 2015 UK DALY data. RESULTS: The programme costing just under £44 million broadly reflected UK DALY burden by disease. Spend was lower than disease burden for cancer, cardiovascular and musculoskeletal diseases, which may reflect the importance of other funders, notably medical charities, which concentrate on these diseases. CONCLUSION: The HTA Programme spend, adjusted for other relevant funders, broadly matches disease burden in the UK; no diseases are being neglected.

The completeness of intervention descriptions in published National Institute of Health Research HTA-funded trials: a cross-sectional study.

OBJECTIVES: The objective of this study was to assess whether National Institute of Health Research (NIHR) Health Technology Assessment (HTA)-funded randomised controlled trials (RCTs) published in the HTA journal were described in sufficient detail to replicate in practice. SETTING: RCTs published in the HTA journal. PARTICIPANTS: 98 RCTs published in the HTA journal up to March 2011. Completeness of the intervention description was assessed independently by two researchers using a checklist, which included assessments of participants, intensity, schedule, materials and settings. Disagreements in scoring were discussed in the team; differences were then explored and resolved. PRIMARY AND SECONDARY OUTCOME MEASURES: Proportion of trials rated as having a complete description of the intervention (primary outcome measure). The proportion of drug trials versus psychological and non-drug trials rated as having a complete description of the intervention (secondary outcome measures). RESULTS: Components of the intervention description were missing in 68/98 (69.4%) reports. Baseline characteristics and descriptions of settings had the highest levels of completeness with over 90% of reports complete. Reports were less complete on patient information with 58.2% of the journals having an adequate description. When looking at individual intervention types, drug intervention descriptions were more complete than non-drug interventions with 33.3% and 30.6% levels of completeness, respectively, although this was not significant statistically. Only 27.3% of RCTs with psychological interventions were deemed to be complete, although again these differences were not significant statistically. CONCLUSIONS: Ensuring the replicability of study interventions is an essential part of adding value in research. All those publishing clinical trial data need to ensure transparency and completeness in the reporting of interventions to ensure that study interventions can be replicated.

Registration of noncommercial randomised clinical trials: the feasibility of using trial registries to monitor the number of trials.

BACKGROUND: A 2003 survey suggested the number of noncommercial trials in the UK was declining. Formation of the NIHR in 2006 and increased research spending by the Department of Health may have increased the number of noncommercial trials but no data are available. METHODS: Available data on UK noncommercial trials (were obtained from the two relevant registries: ISRCTN register for the UK, and US ClinicalTrials.gov. Data on each trial were sorted by start year, and compared with the: 2003 survey, and UKCRN portfolio database from 2007. RESULTS: The number of UK noncommercial trials registered rose from 25 in 1990 to 188 in 1999, peaked at 533 in 2003, and fell back to 334 in 2009. Total trials registered was similar to but slightly above those in the 2003 survey up to 1998, then rose sharply to 2002 before falling to 2007. From 2007 to 2009 the number registered to start each year was similar to but slightly above the UKCRN database. Less than 10% of UK noncommercial trials registered with ClinGov for most years before 2005, but this rose to 35% by 2009. CONCLUSIONS: For the periods of overlap, trial registration data provide fairly similar totals to other sources on the number of noncommercial trials starting each year. The rise and fall in the number of trials registered between 1999 and 2007 was due to those registered in the ISRCTN database as funded by NHS Trusts. After 2007, the number of trials registered as funded by NHS Trusts has fallen in the ISRCTN register but these trials may have migrated to the US ClinGov register. The total number of noncommercial trial starts, excluding those funded by NHS Trusts, has been upward since around 2002. By 2009 the two main funders were NIHR and charities. Feasibility of using registration data to monitor the number of noncommercial trials has been demonstrated but is complicated by the use of two registers and difficulties in accessing the data. We recommend an annual report on the number of noncommercial trials registering each year.

An exploratory investigation of the influence of publication on translational medicine research.

BACKGROUND: Changes in clinical practice are brought about by the weight of clinical evidence for and against an intervention. Clinical evidence of efficacy relies on the dissemination of research results, usually by publication in medical journals which is often seen as a pre-requisite for progression of an intervention through further clinical trials or implementation studies. HOW FAR HAS RESEARCH PROGRESSED ALONG THE TRANSLATIONAL PATHWAY?: We undertook an exploratory exercise to determine where basic and translational medical research is currently published. Original research articles (329 in total) published in high impact general and specialist medical journals were classified into different stages of research within the translational medicine pathway. WHERE IS TRANSLATIONAL RESEARCH PUBLISHED?: The general medical journals had the broadest spread of published research over the translational pathway. The specialist journals tended to be positioned to disseminate the research findings of early stage translational research from basic science results through to early stages of clinical testing. CONCLUSION: It is not possible for one journal to satisfy all the needs of the reader and the author along the translational medicine pathway. For an intervention to progress along the translational pathway background information should be readily accessible in the article. This pathway is currently being actively managed by the funding agencies but the next challenge is to ensure the pathway operates efficiently and does not allow promising innovations to languish and to provide a smoother transition for interventions to reach the clinic in a quicker timescale. It is clear that the dissemination of results in the right place at the right time is crucial to the transition of an intervention from the laboratory to clinical practice.

Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein.

There is increasing evidence that modified phospholipid products of low density lipoprotein (LDL) oxidation mediate inflammatory processes within vulnerable atherosclerotic lesions. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is present in vulnerable plaque regions where it acts on phospholipid oxidation products to generate the pro-inflammatory lysophsopholipids and oxidized non-esterified fatty acids. This association together with identification of circulating Lp-PLA(2) levels as an independent predictor of cardiovascular disease provides a rationale for development of Lp-PLA(2) inhibitors as therapy for atherosclerosis. Here we report a systematic analysis of the effects of in vitro oxidation in the absence and presence of an Lp-PLA(2) inhibitor on the phosphatidylcholine (PC) composition of human LDL. Mass spectrometry identifies three classes of PC whose concentration is significantly enhanced during LDL oxidation. Of these, a series of molecules, represented by peaks in the m/z range 594-666 and identified as truncated PC oxidation products by accurate mass measurements using an LTQ Orbitrap mass spectrometer, are the predominant substrates for Lp-PLA(2). A second series of oxidation products, represented by peaks in the m/z range 746-830 and identified by LTQ Orbitrap analysis as non-truncated oxidized PCs, are quantitatively more abundant but are less efficient Lp-PLA(2) substrates. The major PC products of Lp-PLA(2), saturated and mono-unsaturated lyso-PC, constitute the third class. Mass spectrometric analysis confirms the presence of many of these PCs within human atherosclerotic lesions, suggesting that they could potentially be used as in vivo markers of atherosclerotic disease progression and response to Lp-PLA(2) inhibitor therapy.