Patient-reported outcomes in clinical trials of inhaled asthma medications: systematic review and research needs

Numerous validated PRO instruments are available but it is unclear why few are used in asthma clinical trials. Problems include poor reporting, and uncritical analysis and interpretation of PRO scores. Research needs include identifying and recommending a set of PROs for use in asthma clinical research and providing guidance for researchers on the application, analysis and interpretation of PRO measures in clinical trials

Placental growth factor (alone or in combination with soluble fms-like tyrosine kinase 1) as an aid to the assessment of women with suspected pre-eclampsia: systematic review and economic analysis

Background: Pre-eclampsia (PE) prediction based on blood pressure, presence of protein in the urine, symptoms and laboratory test abnormalities can result in false-positive diagnoses. This may lead to unnecessary antenatal admissions and preterm delivery. Blood tests that measure placental growth factor (PlGF) or the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to PlGF could aid prediction of PE if either were added to routine clinical assessment or used as a replacement for proteinuria testing.Objectives: To evaluate the diagnostic accuracy and cost-effectiveness of PlGF-based tests for patients referred to secondary care with suspected PE in weeks 20–37 of pregnancy.Design: Systematic reviews and an economic analysis.Data sources: Bibliographic databases including MEDLINE, EMBASE, Web of Science and The Cochrane Library and Database of Abstracts of Reviews of Effects were searched up to July 2015 for English-language references. Conferences, websites, systematic reviews and confidential company submissions were also accessed.Review methods: Systematic reviews of test accuracy and economic studies were conducted to inform an economic analysis. Test accuracy studies were required to include women with suspected PE and report quantitatively the accuracy of PlGF-based tests; their risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. The economic studies review had broad eligibility criteria to capture any types of economic analysis; critical appraisal employed standard checklists consistent with National Institute for Health and Care Excellence criteria. Study selection, critical appraisal and data extraction in both reviews were performed by two reviewers.Economic analysis: An independent economic analysis was conducted based on a decision tree model, using the best evidence available. The model evaluates costs (2014, GBP) from a NHS and Personal Social Services perspective. Given the short analysis time horizon, no discounting was undertaken.Results: Four studies were included in the systematic review of test accuracy: two on Alere’s Triage® PlGF test (Alere, Inc., San Diego, CA, USA) for predicting PE requiring delivery within a specified time and two on Roche Diagnostics’ Elecsys® sFlt-1 to PlGF ratio test (Roche Diagnostics GmbH, Mannheim, Germany) for predicting PE within a specified time. Three studies were included in the systematic review of economic studies, and two confidential company economic analyses were assessed separately. Study heterogeneity precluded meta-analyses of test accuracy or cost-analysis outcomes, so narrative syntheses were conductedto inform the independent economic model. The model predicts that, when supplementing routine clinical assessment for rule-out and rule-in of PE, the two tests would be cost-saving in weeks 20–35 of gestation, and marginally cost-saving in weeks 35–37, but with minuscule impact on quality of life. Length of neonatal intensive care unit stay was the most influential parameter in sensitivity analyses. All othersensitivity analyses had negligible effects on results.Limitations: No head-to-head comparisons of the tests were identified. No studies investigated accuracy of PlGF-based tests when used as a replacement for proteinuria testing. Test accuracy studies were found to be at high risk of clinical review bias.Conclusions: The Triage and Elecsys tests would save money if added to routine clinical assessment for PE. The magnitude of savings is uncertain, but the tests remain cost-saving under worst-case assumptions. Further research is required to clarify how the test results would be interpreted and applied in clinical practice.Study registration: This study is registered as PROSPERO CRD42015017670.Funding: The National Institute for Health Research Health Technology Assessment programme

The clinical effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C in children and young people:a systematic review and economic evaluation

Background: Optimal therapy for children with chronic hepatitis C is unclear. Two treatment regimens are currently licensed in children. Objectives: To assess the clinical effectiveness and cost-effectiveness of peginterferon alfa-2a (Pegasys®, Roche) and peginterferon alfa-2b [ViraferonPeg®, Merck Sharp & Dohme (MSD)] in combination with ribavirin (RBV), within their licensed indications, for the treatment of chronic hepatitis C virus (HCV) in children and young people aged 3–17 years. Data sources: Twelve electronic bibliographic databases, including The Cochrane Library, MEDLINE and EMBASE, were searched from inception to November 2012. Bibliographies of retrieved papers, key hepatitis C websites and symposia and manufacturers’ submissions to the National Institute for Health and Care Excellence were also searched, and clinical experts were contacted. Review methods: Systematic reviews of clinical effectiveness and cost-effectiveness were conducted, including studies of health-related quality of life (HRQoL), following standard guidelines to ensure methodological rigour. Clinical effectiveness studies were included if they were in children and young people aged 3–17 years with chronic compensated HCV of any severity, including those with human immunodeficiency virus co-infection and those who were treatment naive or had been previously treated. Eligible interventions were peginterferon alfa-2a or peginterferon alfa-2b, each in combination with RBV, compared against best supportive care (BSC) or against each other, and study designs were randomised controlled trials (RCTs) or non-RCTs, or uncontrolled cohort studies. Outcomes included sustained virological response (SVR) and adverse events. Previously published Markov state-transition economic models of chronic HCV in adults were adapted to estimate the cost-effectiveness of peginterferon alfa-2a and -2b (in combination with RBV), compared with BSC and with one another in children. The model extrapolated the impact of SVR on life expectancy, quality-adjusted life expectancy and lifetime costs. Uncertainty was explored through probabilistic and deterministic sensitivity analyses. Results: Seven studies [two peginterferon alfa-2a and RBV (Copegus®, Roche), and five peginterferon alfa-2b and RBV (Rebetol®, MSD)] were included in the review of clinical effectiveness. Six were single-arm cohort studies and one was a RCT for which only those data for a single arm met the inclusion criteria. Overall, the studies were relatively small and of generally poor quality. SVR rates ranged from 53% to 66% (peginterferon alfa-2a) and 29% to 75% (peginterferon alfa-2b) (49% to 65% if excluding two studies with very small sample sizes). Rates of non-response and relapse were variable and adverse events were generally mild. No studies of cost-effectiveness or HRQoL in children and young people met the inclusion criteria. HRQoL, utilities and costs of treatment were therefore taken from studies of adults with chronic HCV. From this model, peginterferon alfa (-2a or -2b) in combination with RBV was more effective and had lower lifetime costs than BSC. Peginterferon alfa-2a had slightly lower lifetime costs and higher quality-adjusted life-years than peginterferon alfa-2b; therefore, peginterferon alfa-2b was dominated by peginterferon alfa-2a. Results were robust to changes in the sensitivity analyses. Limitations: There were few good quality studies and parameter data had to be taken from adult studies, which is a limitation of the work. Conclusions: Treatment of children and young people with peginterferon (alfa-2a or -2b) and RBV may be an effective therapy. Results from the independent Markov model suggest that peginterferon (alfa-2a or -2b) in combination with RBV is cost-effective compared with BSC. However, the available evidence is of poor quality. Future research into the impact of these treatments on growth and quality of life in children and young people is recommended. Study registration: This study is registered as PROSPERO CRD42012002743. Funding: The National Institute for Health Research Health Technology Assessment programme

Accuracy of fundus autofluorescence imaging for the diagnosis and monitoring of retinal conditions: a systematic review

BackgroundNatural fluorescence in the eye may be increased or decreased by diseases that affect theretina. Imaging methods based on confocal scanning laser ophthalmoscopy (cSLO) can detect this ‘fundusautofluorescence’ (FAF) by illuminating the retina using a specific light ‘excitation wavelength’. FAFimaging could assist the diagnosis or monitoring of retinal conditions. However, the accuracy of themethod for diagnosis or monitoring is unclear.ObjectiveTo conduct a systematic review to determine the accuracy of FAF imaging using cSLO for thediagnosis or monitoring of retinal conditions, including monitoring of response to therapy.Data sourcesElectronic bibliographic databases; scrutiny of reference lists of included studies andrelevant systematic reviews; and searches of internet pages of relevant organisations, meetings and trialregistries. Databases included MEDLINE, EMBASE, The Cochrane Library, Web of Science and the Mediondatabase of diagnostic accuracy studies. Searches covered 1990 to November 2014 and were limited tothe English language.Review methodsReferences were screened for relevance using prespecified inclusion criteria to capturea broad range of retinal conditions. Two reviewers assessed titles and abstracts independently. Full-textversions of relevant records were retrieved and screened by one reviewer and checked by a second. Datawere extracted and critically appraised using the Quality Assessment of Diagnostic Accuracy Studies criteria(QUADAS) for assessing risk of bias in test accuracy studies by one reviewer and checked by a second.At all stages any reviewer disagreement was resolved through discussion or arbitration by a third reviewer.ResultsEight primary research studies have investigated the diagnostic accuracy of FAF imaging in retinalconditions: choroidal neovascularisation (one study), reticular pseudodrusen (three studies), cystoid macularoedema (two studies) and diabetic macular oedema (two studies). Sensitivity of FAF imaging using anexcitation wavelength of 488 nm was generally high (range 81–100%), but was lower (55% and 32%) intwo studies using longer excitation wavelengths (514 nm and 790 nm, respectively). Specificity rangedfrom 34% to 100%. However, owing to limitations of the data, none of the studies provide conclusiveevidence of the diagnostic accuracy of FAF imaging.LimitationsNo studies on the accuracy of FAF imaging for monitoring the progression of retinalconditions or response to therapy were identified. Owing to study heterogeneity, pooling of diagnosticoutcomes in meta-analysis was not conducted. All included studies had high risk of bias. In most studiesthe patient spectrum was not reflective of those who would present in clinical practice and no studiesadequately reported how FAF images were interpreted.ConclusionsAlthough already in use in clinical practice, it is unclear whether or not FAF imaging isaccurate, and whether or not it is applied and interpreted consistently for the diagnosis and/or monitoringof retinal conditions. Well-designed prospective primary research studies, which conform to the paradigmof diagnostic test accuracy assessment, are required to investigate the accuracy of FAF imaging in diagnosisand monitoring of inherited retinal dystrophies, early age-related macular degeneration, geographicatrophy and central serous chorioretinopathy.Study registrationThis study is registered as PROSPERO CRD42014014997.FundingThe National Institute for Health Research Health Technology Assessment programme

SOSA MORALES, MANUEL Y NOVIA [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

The CEEDER database of evidence reviews: An open-access evidence service for researchers and decision-makers

Evidence-informed decision-making aims to deliver effective actions informed by the best available evidence. Given the large quantity of primary literature, and time constraints faced by policy-makers and practitioners, well-conducted evidence reviews can provide a valuable resource to support decision-making. However, previous research suggests that some evidence reviews may not be sufficiently reliable to inform decisions in the environmental sector due to low standards of conduct and reporting. While some evidence reviews are of high reliability, there is currently no way for policy-makers and practitioners to quickly and easily find them among the many lower reliability ones. Alongside this lack of transparency, there is little incentive or support for review authors, editors and peer-reviewers to improve reliability. To address these issues, we introduce a new online, freely available and first-of-its-kind evidence service: the Collaboration for Environmental Evidence Database of Evidence Reviews (CEEDER: www.environmentalevidence.org/ceeder). CEEDER aims to transform communication of evidence review reliability to researchers, policy-makers and practitioners through independent assessment of key aspects of the conduct, reporting and data limitations of available evidence reviews claiming to assess environmental impacts or the effectiveness of interventions relevant to policy and practice. At the same time, CEEDER will provide support to improve the standards of future evidence reviews and support evidence translation and knowledge mobilisation to help inform environmental decision-making

An economic model of school-based behavioral interventions to prevent sexually transmitted infections

Objectives: Reducing sexually transmitted infections (STI) and teenage pregnancy through effective health education is a high priority for health policy. Behavioral interventions which teach skills to practice safer sex may reduce the incidence of STIs. We evaluated the cost-effectiveness of school-based behavioral interventions in young people. Methods: We developed an economic model to estimate the total number of STI cases averted, consequent gain in health related quality of life (HRQoL) and savings in medical costs, based on changes in sexual behavior. The parameters for the model were derived from a systematic literature search on the intervention effectiveness, epidemiology of STIs, sexual behavior and lifestyles, HRQoL and health service costs. Results: The costs of providing teacher-led and peer-led behavioral interventions were €5.16 and €18 per pupil, respectively. For a cohort of 1000 boys and 1000 girls aged 15 years, the model estimated that the behavioral interventions would avert two STI cases and save 0.35 Quality Adjusted Life Years (QALYs). Compared to standard education, the incremental cost-effectiveness of the teacher-led and peer-led interventions was €24,268 and €96,938 per QALY gained, respectively. Conclusions: School-based behavioral interventions which provide information and teach young people sexual health skills can bring about improvements in knowledge and increased self-efficacy, though these may be limited in terms of impact on sexual behavior. There was uncertainty around the results due to the limited effect of the intervention on behavioral outcomes and paucity of data for other input parameters

Standards of conduct and reporting in evidence syntheses that could inform environmental policy and management decisions

Accurate, unbiased and concise synthesis of available evidence following clear methodology and transparent report‑ ing is necessary to support effective environmental policy and management decisions. Without this, less reliable and/ or less objective reviews of evidence could inform decision making, leading to ineffective, resource wasteful inter‑ ventions with potential for unintended consequences. We evaluated the reliability of over 1000 evidence syntheses (reviews and overviews) published between 2018 and 2020 that provide evidence on the impacts of human activities or effectiveness of interventions relevant to environmental management. The syntheses are drawn from the Col‑ laboration for Environmental Evidence Database of Evidence Reviews (CEEDER), an online, freely available evidence service for evidence users that assesses the reliability of evidence syntheses using a series of published criteria. We found that the majority of syntheses have problems with transparency, replicability and potential for bias. Overall, our results suggest that most recently published evidence syntheses are of low reliability to inform decision making. Reviews that followed guidance and reporting standards for evidence synthesis had improved assessment ratings, but there remains substantial variation in the standard of reviews amongst even these. Furthermore, the term ‘system‑ atic review’, which implies conformity with a methodological standard, was frequently misused. A major objective of the CEEDER project is to improve the reliability of the global body of environmental evidence reviews. To this end we outline freely available online resources to help improve review conduct and reporting. We call on authors, editors and peer reviewers to use these resources to ensure more reliable syntheses in the future