BackgroundCost-effectiveness analysis involves the comparison of the incremental cost-effectiveness ratio of a new technology, which is more costly than existing alternatives, with the cost-effectiveness threshold. This indicates whether or not the health expected to be gained from its use exceeds the health expected to be lost elsewhere as other health-care activities are displaced. The threshold therefore represents the additional cost that has to be imposed on the system to forgo 1 quality-adjusted life-year (QALY) of health through displacement. There are no empirical estimates of the cost-effectiveness threshold used by the National Institute for Health and Care Excellence.Objectives(1) To provide a conceptual framework to define the cost-effectiveness threshold and to provide the basis for its empirical estimation. (2) Using programme budgeting data for the English NHS, to estimate the relationship between changes in overall NHS expenditure and changes in mortality. (3) To extend this mortality measure of the health effects of a change in expenditure to life-years and to QALYs by estimating the quality-of-life (QoL) associated with effects on years of life and the additional direct impact on QoL itself. (4) To present the best estimate of the cost-effectiveness threshold for policy purposes.MethodsEarlier econometric analysis estimated the relationship between differences in primary care trust (PCT) spending, across programme budget categories (PBCs), and associated disease-specific mortality. This research is extended in several ways including estimating the impact of marginal increases or decreases in overall NHS expenditure on spending in each of the 23 PBCs. Further stages of work link the econometrics to broader health effects in terms of QALYs.ResultsThe most relevant ‘central’ threshold is estimated to be £12,936 per QALY (2008 expenditure, 2008–10 mortality). Uncertainty analysis indicates that the probability that the threshold is < £20,000 per QALY is 0.89 and the probability that it is < £30,000 per QALY is 0.97. Additional ‘structural’ uncertainty suggests, on balance, that the central or best estimate is, if anything, likely to be an overestimate. The health effects of changes in expenditure are greater when PCTs are under more financial pressure and are more likely to be disinvesting than investing. This indicates that the central estimate of the threshold is likely to be an overestimate for all technologies which impose net costs on the NHS and the appropriate threshold to apply should be lower for technologies which have a greater impact on NHS costs.LimitationsThe central estimate is based on identifying a preferred analysis at each stage based on the analysis that made the best use of available information, whether or not the assumptions required appeared more reasonable than the other alternatives available, and which provided a more complete picture of the likely health effects of a change in expenditure. However, the limitation of currently available data means that there is substantial uncertainty associated with the estimate of the overall threshold.ConclusionsThe methods go some way to providing an empirical estimate of the scale of opportunity costs the NHS faces when considering whether or not the health benefits associated with new technologies are greater than the health that is likely to be lost elsewhere in the NHS. Priorities for future research include estimating the threshold for subsequent waves of expenditure and outcome data, for example by utilising expenditure and outcomes available at the level of Clinical Commissioning Groups as well as additional data collected on QoL and updated estimates of incidence (by age and gender) and duration of disease. Nonetheless, the study also starts to make the other NHS patients, who ultimately bear the opportunity costs of such decisions, less abstract and more ‘known’ in social decisions.FundingThe National Institute for Health Research-Medical Research Council Methodology Research Programme.

BackgroundThe National Institute for Health and Care Excellence (NICE) commissioned a ‘mock technology appraisal’ to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal.MethodsOur research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia.ResultsAn assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately. Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision.ConclusionsIt is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further.FundingThe National Institute for Health Research Health Technology Assessment programme.

Literature reviews underpin the majority of research projects in the health sciences, and yet relatively little analysis has been published as to the most appropriate method to identify relevant literature, outside of specialist information journals. The method of applying keyword search queries to bibliographic databases using Boolean logic dominates literature reviews due to its easy application to the major online databases. However, it is recognised increasingly as being problematic where the research question cannot be clearly defined or requires an element of exploration, due to its reliance on author's use of titling and keywords and is unable to identify topics other than those defined in the search query. This paper discusses the relative merits of a systematic citation searching approach as both an alternative and a concurrent method to keyword searching. A method of citation searching, both forwards and backwards, which is iterated to form a closed loop solution, is discussed. An illustrative example is presented of both methods, applying them to the topic of the UK National Institute for Health and Care Excellence (NICE) cost-effectiveness threshold. The case study finds the citation searching approach dominates the traditional keyword searching approach, finding 76 papers of relevance, including all 15 found by the alternative approach. Conceptually, and in the example presented, it is demonstrated that the proposed method can represent a dominant strategy to the more traditional approach in some situations, highlighting that, wherever possible, it is preferential to employ multiple methods of searching. However, it is clear that a better understanding is required as to how we can most efficiently search the ever-growing sea of literature.

BackgroundScaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. Immediate surgical fixation of this fracture has increased, in spite of insufficient evidence of improved outcomes over non-surgical management. We compared the clinical effectiveness of surgical fixation with cast immobilization and early fixation of those that fail to unite, for ≤2 mm displaced scaphoid waist fractures in adults. MethodsThis pragmatic, multicentre, open-label, parallel-group, two-arm randomised clinical trial included adults who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear, bicortical fracture of the scaphoid waist on radiographs. Participants were randomly assigned to early surgical fixation or below-elbow cast immobilization followed by immediate fixation of confirmed non-union. The primary outcome was the Patient Rated Wrist Evaluation (PRWE) total score at 52 weeks post-randomisation. Registration ISRCTN67901257. FindingsOf 439 randomised patients (mean age 33 years, 363 [83%] men), 408 (93%) were included in the primary analyses. There was no difference in PRWE score at 52 weeks (adjusted mean difference -2•1 points, 95% CI -5•8 to 1•6, p=0•27). There were no differences at 52 weeks for the PRWE pain or function subscales. More participants in the surgery group experienced a surgery-related potentially serious complication than in the cast group (n=31, 14% vs n=3, 1%), but fewer had cast-related complications (n=5, 2% vs n=40, 18%). The number experiencing a medical complication (n=4, 2% vs n=5, 2%) was similar in the two groups." InterpretationAdult patients with ≤2 mm displaced scaphoid waist fracture should have initial cast immobilization and suspected non-unions confirmed and immediately fixed. This will help avoid risks of surgery and mostly limit its use to fixing non-union.

IntroductionLung cancer is the world’s leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation.Methods and analysisUsing a single-consent Zelen’s design, ever-smokers aged 55–80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCOM2012 (threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies.Ethics and disseminationThe study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website.Trial registration numbersISRCTN42704678 and NCT03750110.