How good are GPs at adhering to a pragmatic trial protocol in primary care? Results from the ADDITION-Cambridge cluster-randomized pragmatic trial

Objective: To assess the fidelity of general practitioners’ (GP) adherence to a long term pragmatic trial protocol. Design: Retrospective analyses of electronic primary care records of participants in the pragmatic cluster-randomised ADDITION (Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care)-Cambridge trial, comparing intensive multi-factorial treatment (IT) vs. routine care (RC). Data were collected from the date of diagnosis until December 2010. Setting: Primary care surgeries in the East of England Study sample/participants: A subsample (n=189, RC-arm: n=99, IT-arm: n=90) of patients from the ADDITION-Cambridge cohort (867 patients), consisting of 40-69 year old patients with screen detected diabetes mellitus. Interventions: In the RC-arm treatment was delivered according to concurrent treatment guidelines. Surgeries in the IT-arm received funding for additional contacts between GPs/nurses and patients, and GPs were advised to follow more intensive treatment algorithms for the management of glucose, lipids and blood pressure and aspirin therapy than in the RC-arm. Outcome measures: The number of annual contacts between patients and GPs/nurses, the proportion of patients receiving prescriptions for cardio-metabolic medication in years 1 to 5 after diabetes diagnosis, and the adherence to prescription algorithms. Results: The difference in the number of annual GP contacts (β=0.65) and nurse contacts (β=-0.15) between the study arms was small and insignificant. Patients in the IT-arm were more likely to receive glucose-lowering (OR=3.27), ACE-inhibiting (OR=2.03) and lipid-lowering drugs (OR=2.42, all p-values<0.01) than patients in the RC-arm. The prescription adherence varied between medication classes, but improved in both trial arms over the 5 year follow-up. Conclusions: The adherence of GPs to different aspects of the trial protocol was mixed. Background changes in health care policy need to be considered as they have the potential to dilute differences in treatment intensity and hence incremental effect. Clinical trial number: ISRCTN8676908

Association of psychological distress, quality of life and costs with carpal tunnel syndrome severity: a crosssectional analysis of the PALMS cohort

Objectives: The PALMS study is designed to identify prognostic factors for outcome from corticosteroid injection and surgical decompression for carpal tunnel syndrome (CTS) and predictors of cost over 2 years. The aim of this paper is to explore the cross-sectional association of baseline patient-reported and clinical severity with anxiety, depression, health-related quality of life and costs of CTS in patients referred to secondary care. Methods: Prospective, multi-centre cohort study initiated in 2013. We collected baseline data on patientreported symptom severity (CTS-6), psychological status (HADS), hand function (Michigan Hand Questionnaire) comorbidities, EQ5D-3L and sociodemographic variables. Nerve conduction tests classified patients into five severity grades (mild to very severe). Data were analysed using a general linear model. Results: 753 patients with CTS provided complete baseline data. Multivariable linear regression adjusting for age, sex, ethnicity, duration of CTS, smoking status, alcohol consumption, employment status, body mass index and comorbidities showed a highly statistically significant relationship between CTS-6 and anxiety, depression and the EQ-5D (p<0.0001 in each case). Likewise, a significant relationship was observed between electrodiagnostic severity and anxiety (p=0.027) but not with depression (p=0.986) or the EQ-5D (p=0.257). NHS and societal costs in the 3 months prior to enrolment were significantly associated with self-reported severity (p<0.0001) but not with electrodiagnostic severity. Conclusions: Patient-reported symptom severity in carpal tunnel syndrome is significantly and positively associated with anxiety, depression, health-related quality of life and NHS and societal costs even when adjusting for age, gender, body mass index, comorbidities, smoking, drinking and occupational status. In contrast there is little or no evidence of any relationship with objectively derived CTS severity. Future research is needed to understand the impact of approaches and treatments that address psychosocial stressors as well as biomedical factors on relief of symptoms from carpal tunnel syndrome.CJH was funded by the National Institute for Health Research (NIHR) through a NIHR Senior Research Fellowship. ECFW is funded by the NIHR Cambridge Biomedical Research Centre

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound

Background Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value. Objective To determine (1) whether current evidence suggests that screening is potentially cost effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps. Design, setting, and participants A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted. Intervention A single focused renal ultrasound scan compared with standard of care (no screening). Outcome measurements and statistical analysis Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum. Results and limitations Given a prevalence of RCC of 0.34% (0.18–0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08–0.25%), screening 60-yr-old women resulted in an ICER of £37 327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30 000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60 yr. Given the willingness to pay a threshold of £30 000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities. Conclusions Current evidence suggests that one-off screening of 60-yr-old men is potentially cost effective and that further research into this topic would be of value to society. Patient summary Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed

Computing the Expected Value of Sample Information Efficiently: Practical Guidance and Recommendations for Four Model-Based Methods

Value of information (VOI) analyses can help policy makers make informed decisions about whether to conduct and how to design future studies. Historically a computationally expensive method to compute the expected value of sample information (EVSI) restricted the use of VOI to simple decision models and study designs. Recently, 4 EVSI approximation methods have made such analyses more feasible and accessible. Members of the Collaborative Network for Value of Information (ConVOI) compared the inputs, the analyst's expertise and skills, and the software required for the 4 recently developed EVSI approximation methods. Our report provides practical guidance and recommendations to help inform the choice between the 4 efficient EVSI estimation methods. More specifically, this report provides: (1) a step-by-step guide to the methods' use, (2) the expertise and skills required to implement the methods, and (3) method recommendations based on the features of decision-analytic problems

Ozanimod for treating moderately to severely active ulcerative colitis [ID3841] A Single Technology Appraisal

This report was commissioned by the NIHR Systematic Reviews Programme as project number 13/54/43Executive Summary: This summary provides a brief overview of the key issues identified by the evidence review group (ERG) as being potentially important for decision-making. It also includes the ERG’s preferred assumptions and the resulting incremental cost-effectiveness ratios (ICERs). • Section 1.1 provides an overview of the key issues and the differences in the assumptions of the company and the ERG in economic analysis. • Section 1.2 provides an overview of key model outcomes and the modelling assumptions that have the greatest effect on the ICER. • Sections 1.3 to 1.5 explain the key issues in more detail. Background information on the condition, technology and evidence and information on non-key issues are in the main ERG report. • Sections 1.6 and 1.7 provide an overview of the ERG’s preferred base case and sensitivity analyses undertaken by the ERG. All issues identified represent the ERG’s view, not the opinion of the National Institute for Health and Care Excellence (NICE)

Meta-analysis of the prevalence of renal cancer detected by abdominal ultrasonography

$\textbf{BACKGROUND}$: The potential for an ultrasound-based screening programme for renal cell carcinoma (RCC) to improve survival through early detection has been the subject of much debate. The prevalence of ultrasound-detected asymptomatic RCC is an important first step to establishing whether a screening programme may be feasible. $\textbf{METHODS}$: A systematic search of MEDLINE and Embase was performed up to March 2016 to identify studies reporting the prevalence of renal masses and RCC. Two populations of patients were chosen: asymptomatic individuals undergoing screening ultrasonography and patients undergoing ultrasonography for abdominal symptoms not related to RCC. A random-effects meta-analysis was performed. Study quality was evaluated using a validated eight-point checklist. $\textbf{RESULTS}$: Sixteen studies (413 551 patients) were included in the final analysis. The pooled prevalence of renal mass was 0·36 (95 per cent c.i. 0·23 to 0·52) per cent and the prevalence of histologically proven RCC was 0·10 (0·06 to 0·15) per cent. The prevalence of RCC was more than double in studies from Europe and North America than in those from Asia: 0·17 (0·09 to 0·27) versus 0·06 (0·03 to 0·09) per cent respectively. Data on 205 screen-detected RCCs showed that 84·4 per cent of tumours were stage T1-T2 N0, 13·7 per cent were T3-T4 N0, and only 2·0 per cent had positive nodes or metastases at diagnosis. $\textbf{CONCLUSION}$: At least one RCC would be detected per 1000 individuals screened. The majority of tumours identified are early stage (T1-T2).E.C.F.W. and G.D.S. are joint senior authors of this article. The authors thank J. J. Earnshaw, D. Hanbury and C. Watson for their advice and contribution to the design of the study. The authors acknowledge the Urology Foundation, which provided a travel grant for S.H.R. covering the cost of a course on performing meta-analyses, and the Renal Cancer Research Fund for providing a grant for S.H.R. to attend a health economics course. E.C.F.W. is funded by the NIHR Cambridge Biomedical Research Centre and S.H.R. is funded by an NIHR Academic Clinical Fellowship. There are no other sources of funding

The HTA risk analysis chart: visualising the need for and potential value of managed entry agreements in health technology assessment

Background Recent changes to the regulatory landscape of pharmaceuticals may sometimes require reimbursement authorities to issue guidance on technologies that have a less mature evidence base. Decision makers need to be aware of risks associated with such health technology assessment (HTA) decisions and the potential to manage this risk through managed entry agreements (MEAs). Objective This work develops methods for quantifying risk associated with specific MEAs and for clearly communicating this to decision makers. Methods We develop the ‘HTA risk analysis chart’, in which we present the payer strategy and uncertainty burden (P-SUB) as a measure of overall risk. The P-SUB consists of the payer uncertainty burden (PUB), the risk stemming from decision uncertainty as to which is the truly optimal technology from the relevant set of technologies, and the payer strategy burden (PSB), the additional risk of approving a technology that is not expected to be optimal. We demonstrate the approach using three recent technology appraisals from the UK National Institute for Health and Clinical Excellence (NICE), each of which considered a price-based MEA. Results The HTA risk analysis chart was calculated using results from standard probabilistic sensitivity analyses. In all three HTAs, the new interventions were associated with substantial risk as measured by the P-SUB. For one of these technologies, the P-SUB was reduced to zero with the proposed price reduction, making this intervention cost effective with near complete certainty. For the other two, the risk reduced substantially with a much reduced PSB and a slightly increased PUB. Conclusions The HTA risk analysis chart shows the risk that the healthcare payer incurs under unresolved decision uncertainty and when considering recommending a technology that is not expected to be optimal given current evidence. This allows the simultaneous consideration of financial and data-collection MEA schemes in an easily understood format. The use of HTA risk analysis charts will help to ensure that MEAs are considered within a standard utility-maximising health economic decision-making framework

Measuring Health Utilities in Children and Adolescents: A Systematic Review of the Literature.

BACKGROUND: The objective of this review was to evaluate the use of all direct and indirect methods used to estimate health utilities in both children and adolescents. Utilities measured pre- and post-intervention are combined with the time over which health states are experienced to calculate quality-adjusted life years (QALYs). Cost-utility analyses (CUAs) estimate the cost-effectiveness of health technologies based on their costs and benefits using QALYs as a measure of benefit. The accurate measurement of QALYs is dependent on using appropriate methods to elicit health utilities. OBJECTIVE: We sought studies that measured health utilities directly from patients or their proxies. We did not exclude those studies that also included adults in the analysis, but excluded those studies focused only on adults. METHODS AND FINDINGS: We evaluated 90 studies from a total of 1,780 selected from the databases. 47 (52%) studies were CUAs incorporated into randomised clinical trials; 23 (26%) were health-state utility assessments; 8 (9%) validated methods and 12 (13%) compared existing or new methods. 22 unique direct or indirect calculation methods were used a total of 137 times. Direct calculation through standard gamble, time trade-off and visual analogue scale was used 32 times. The EuroQol EQ-5D was the most frequently-used single method, selected for 41 studies. 15 of the methods used were generic methods and the remaining 7 were disease-specific. 48 of the 90 studies (53%) used some form of proxy, with 26 (29%) using proxies exclusively to estimate health utilities. CONCLUSIONS: Several child- and adolescent-specific methods are still being developed and validated, leaving many studies using methods that have not been designed or validated for use in children or adolescents. Several studies failed to justify using proxy respondents rather than administering the methods directly to the patients. Only two studies examined missing responses to the methods administered with respect to the patients' ages

First, do no harm: time for a systems approach to address the problem of health-care-derived pharmaceutical pollution

This is the final version. Available on open access from Elsevier via the DOI in this recor

A Modeling Study of the Cost Effectiveness of a Risk-Stratified Surveillance Program for Melanoma in the United Kingdom

Background: Population-wide screening for melanoma is unlikely to be cost-effective. Nevertheless, targeted surveillance of high-risk individuals may be. Objectives: To estimate the cost effectiveness of various surveillance strategies in the UK population, stratified by risk using a simple self-assessment tool scoring between 0 and 67. Methods: A decision model comparing alternative surveillance policies from the perspective of the UK National Health Service over 30 years was developed. The strategy with the highest expected net benefit for each risk score was identified, resulting in a compound risk-stratified policy describing the most cost-effective population-wide strategy. The overall expected cost and quality-adjusted life-years (QALYs), the incremental cost-effectiveness ratio, and associated uncertainty were reported. Results: The most cost-effective strategy is for those with a Williams score of 15 to 21 (relative risk [RR] of 0.79–1.60 vs. a mean score of 17 in the United Kingdom) to be offered a one-off full-body skin examination, and for those with a score of 22 or more (RR 1.79+) to be enrolled into a quinquennial monitoring program, rising to annual recall for those with a risk score greater than 43 (RR 20.95+). Expected incremental cost would be £164 million per annum (~0.1% of the National Health Service budget), gaining 15,947 additional QALYs and yielding an incremental cost-effectiveness ratio of £10,199/QALY gained (51.3% probability <£30,000). Conclusions: The risk-stratified policy would be expensive to implement but cost-effective compared with typical UK thresholds (£20,000–£30,000/QALY gained), although decision uncertainty is high. Phased implementation enrolling only higher risk individuals would be substantially less expensive, but with consequent foregone health gain.This study was supported in part by F. M. Walter’s Clinician Scientist Award from the National Institute for Health Research (NIHR) (grant no. RG 68235). E. C. F. Wilson is funded by the NIHR Cambridge Biomedical Research Centre. J. Usher-Smith was funded by an NIHR Clinical Lectureship. J. Emery is funded by an National Health and Medical Research Council (NHMRC) Practitioner Fellowship. The analysis was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/), provided by Dell, Inc., using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and funding from the Science and Technology Facilities Council