The Difference Method Approach for Sampling Order Constrained Parameters: An Improved Implementation and Important Limitations.

A health economic model may include a set of related inputs whose true values are uncertain, but that can be assumed to follow a logical order. Various approaches are available for performing probabilistic sensitivity analysis while preserving the order constraint, one such approach is known as the difference method. The difference method approach appears to have many of the required properties, has been endorsed by good practice guidelines, and is likely to prove a popular approach. However, the proposed implementation of the difference method approach is cumbersome, requiring numerical estimation, which might present a barrier to its adoption. Furthermore, it is unclear whether the method can always be applied to three or more model inputs and whether it is unbiased across all possible input values. This study has investigated these three issues for ordered inputs bounded between 0 and 1. An analytic solution is given that allows for more straightforward and compact implementation. The difference method approach cannot always be applied to a set of three or more model inputs, and this depends on the relative size of the variances of the logit-transformed Beta distributions fitted to each variable. The approach can also produce samples with biased means and variances under certain combinations of input means and variances. It is recommended that the difference method approach be used where appropriate; however, an understanding of its limitations is necessary to identify such cases.

Choice of oral anticoagulant prescribed by general practices in Wales: Application of Dirichlet regression and linked data.

AIMS: There has been sustained growth in the prescribing of direct oral anticoagulants (OACs) in primary care in the UK. Given the different indications, properties and prices of OACs, variation between prescribers is expected; however, a high level of variation may be evidence of inappropriate or suboptimal prescribing. This study examined the variation in the relative use of OACs in primary care in Wales. METHODS: Data on total defined daily doses of all community-dispensed OACs in 2019 were linked at the GP practice level with disease registers, patient demographic data and GP and patient numbers. The relative use of each OAC, as a fraction of all OACs prescribed, was analysed using Dirichlet regression to quantify the association between prescribing patterns and practice and area-level characteristics. RESULTS: Across 417 GP practices, the mean (range) in the relative prescribing of warfarin was 37% (6%-64%), apixaban was 32% (2%-65%), rivaroxaban 23% (0%-66%), dabigatran 3% (0%-23%) and edoxaban 6% (0%-59%). Statistical modelling provided strong evidence that prescribing patterns are associated with a GP practice's health board and also their nearest major hospital. Compared to the null model, a model including health board resulted in a 15% fall in Akaike information criterion, increasing to 20% with the addition of nearest major hospital and 27% including further covariates. CONCLUSION: Systematic variation in OAC prescribing, by health board and based on nearest hospital, indicates that factors other than patient clinical characteristics and preferences may be influencing prescribing decisions.

Surgical microdiscectomy versus transforaminal epidural steroid injection in patients with sciatica secondary to herniated lumbar disc (NERVES): a phase 3, multicentre, open-label, randomised controlled trial and economic evaluation.

BACKGROUND: The optimal invasive treatment for sciatica secondary to herniated lumbar disc remains controversial, with a paucity of evidence for use of non-surgical treatments such as transforaminal epidural steroid injection (TFESI) over surgical microdiscectomy. We aimed to investigate the clinical and cost-effectiveness of these options for management of radicular pain secondary to herniated lumbar disc. METHODS: We did a pragmatic, multicentre, phase 3, open-label, randomised controlled trial at 11 spinal units across the UK. Eligible patients were aged 16-65 years, had MRI-confirmed non-emergency sciatica secondary to herniated lumbar disc with symptom duration between 6 weeks and 12 months, and had leg pain that was not responsive to non-invasive management. Participants were randomly assigned (1:1) to receive either TFESI or surgical microdiscectomy by an online randomisation system that was stratified by centre with random permuted blocks. The primary outcome was Oswestry Disability Questionnaire (ODQ) score at 18 weeks. All randomly assigned participants who completed a valid ODQ at baseline and at 18 weeks were included in the analysis. Safety analysis included all treated participants. Cost-effectiveness was estimated from the EuroQol-5D-5L, Hospital Episode Statistics, medication usage, and self-reported resource-use data. This trial was registered with ISRCTN, number ISRCTN04820368, and EudraCT, number 2014-002751-25. FINDINGS: Between March 6, 2015, and Dec 21, 2017, 163 (15%) of 1055 screened patients were enrolled, with 80 participants (49%) randomly assigned to the TFESI group and 83 participants (51%) to the surgery group. At week 18, ODQ scores were 30·02 (SD 24·38) for 63 assessed patients in the TFESI group and 22·30 (19·83) for 61 assessed patients in the surgery group. Mean improvement was 24·52 points (18·89) for the TFESI group and 26·74 points (21·35) for the surgery group, with an estimated treatment difference of -4·25 (95% CI -11·09 to 2·59; p=0·22). There were four serious adverse events in four participants associated with surgery, and none with TFESI. Compared with TFESI, surgery had an incremental cost-effectiveness ratio of £38 737 per quality-adjusted life-year gained, and a 0·17 probability of being cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year. INTERPRETATION: For patients with sciatica secondary to herniated lumbar disc, with symptom duration of up to 12 months, TFESI should be considered as a first invasive treatment option. Surgery is unlikely to be a cost-effective alternative to TFESI. FUNDING: Health Technology Assessment programme of the National Institute for Health Research (NIHR), UK.

Microdiscectomy compared with transforaminal epidural steroid injection for persistent radicular pain caused by prolapsed intervertebral disc: the NERVES RCT.

BACKGROUND: Sciatica is a common condition reported to affect > 3% of the UK population at any time and is most often caused by a prolapsed intervertebral disc. Currently, there is no uniformly adopted treatment strategy. Invasive treatments, such as surgery (i.e. microdiscectomy) and transforaminal epidural steroid injection, are often reserved for failed conservative treatment. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of microdiscectomy with transforaminal epidural steroid injection for the management of radicular pain secondary to lumbar prolapsed intervertebral disc for non-emergency presentation of sciatica of < 12 months' duration. INTERVENTIONS: Patients were randomised to either (1) microdiscectomy or (2) transforaminal epidural steroid injection. DESIGN: A pragmatic, multicentre, randomised prospective trial comparing microdiscectomy with transforaminal epidural steroid injection for sciatica due to prolapsed intervertebral disc with < 1 year symptom duration. SETTING: NHS services providing secondary spinal surgical care within the UK. PARTICIPANTS: A total of 163 participants (aged 16-65 years) were recruited from 11 UK NHS outpatient clinics. MAIN OUTCOME MEASURES: The primary outcome was participant-completed Oswestry Disability Questionnaire score at 18 weeks post randomisation. Secondary outcomes were visual analogue scores for leg pain and back pain; modified Roland-Morris score (for sciatica), Core Outcome Measures Index score and participant satisfaction at 12-weekly intervals. Cost-effectiveness and quality of life were assessed using the EuroQol-5 Dimensions, five-level version; Hospital Episode Statistics data; medication usage; and self-reported cost data at 12-weekly intervals. Adverse event data were collected. The economic outcome was incremental cost per quality-adjusted life-year gained from the perspective of the NHS in England. RESULTS: Eighty-three participants were allocated to transforaminal epidural steroid injection and 80 participants were allocated to microdiscectomy, using an online randomisation system. At week 18, Oswestry Disability Questionnaire scores had decreased, relative to baseline, by 26.7 points in the microdiscectomy group and by 24.5 points in the transforaminal epidural steroid injection. The difference between the treatments was not statistically significant (estimated treatment effect -4.25 points, 95% confidence interval -11.09 to 2.59 points). Nor were there significant differences between treatments in any of the secondary outcomes: Oswestry Disability Questionnaire scores, visual analogue scores for leg pain and back pain, modified Roland-Morris score and Core Outcome Measures Index score up to 54 weeks. There were four (3.8%) serious adverse events in the microdiscectomy group, including one nerve palsy (foot drop), and none in the transforaminal epidural steroid injection group. Compared with transforaminal epidural steroid injection, microdiscectomy had an incremental cost-effectiveness ratio of £38,737 per quality-adjusted life-year gained and a probability of 0.17 of being cost-effective at a willingness to pay threshold of £20,000 per quality-adjusted life-year. LIMITATIONS: Primary outcome data was invalid or incomplete for 24% of participants. Sensitivity analyses demonstrated robustness to assumptions made regarding missing data. Eighteen per cent of participants in the transforaminal epidural steroid injection group subsequently received microdiscectomy prior to their primary outcome assessment. CONCLUSIONS: To the best of our knowledge, the NErve Root Block VErsus Surgery trial is the first trial to evaluate the comparative clinical effectiveness and cost-effectiveness of microdiscectomy and transforaminal epidural steroid injection. No statistically significant difference was found between the two treatments for the primary outcome. It is unlikely that microdiscectomy is cost-effective compared with transforaminal epidural steroid injection at a threshold of £20,000 per quality-adjusted life-year for sciatica secondary to prolapsed intervertebral disc. FUTURE WORK: These results will lead to further studies in the streamlining and earlier management of discogenic sciatica. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04820368 and EudraCT 2014-002751-25. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 24. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Sciatica or pain related to nerve irritation travelling down the leg is common in young working adults and most likely to be caused by a 'slipped' (prolapsed) disc. Although the majority of cases get better on their own and within 4­6 weeks, a significant group of patients struggle with disabling symptoms sometimes beyond 1 year. Consequently, patients struggle to maintain their home and working lives. Many treatments are available for sciatica, but simpler treatments (e.g. pain tablets, physiotherapy and changing one's lifestyle) are often not very effective and patients have often tried all of them by the time they are seen in hospital to have tests, such as scans, done. Surgery to remove part of the disc is recommended in cases where the pain is accompanied by severe weakness in one or both legs, or where doctors think that nerves may be damaged because patients have bladder, bowel and sexual functioning difficulties (i.e. red flag symptoms). Surgery works well in alleviation of referred leg pain and also to relieve pressure on a physically compressed nerve that may be showing clinical sign of injury/weakness. An alternative to surgery is to inject a mixture of anaesthetic and steroid close to the site of the disc injury and nerve, but at the moment we do not know whether or not these injections work in the long term. They are cheaper and less invasive, with fewer risks than surgery, such as from anaesthetic or infection. WHAT DID OUR STUDY INVESTIGATE?: This study compared the usefulness of surgery with injections for patients who have had sciatica for < 1 year and who have tried simple remedies but are still in pain. Patients were allocated to have either surgery or the injection. Symptoms (e.g. pain) were assessed after 18 weeks. WHAT DID WE FIND?: We found that there was no significant difference between surgery and injection at the primary end point. Surgery was not significantly different from injection in terms of clinical outcome and was not cost-effective compared with injection. OUR CONCLUSION AND RECOMMENDATION: Given the cost of surgery and the risks to patients, we suggest that further studies should be carried out to explore whether or not all patients with sciatica due to a slipped disc should be considered suitable for an injection, unless there is a good reason not to.

Linked Pharmacometric-Pharmacoeconomic Modeling and Simulation in Clinical Drug Development.

Market access and pricing of pharmaceuticals are increasingly contingent on the ability to demonstrate comparative effectiveness and cost-effectiveness. As such, it is widely recognized that predictions of the economic potential of drug candidates in development could inform decisions across the product life cycle. This may be challenging when safety and efficacy profiles in terms of the relevant clinical outcomes are unknown or highly uncertain early in product development. Linking pharmacometrics and pharmacoeconomics, such that outputs from pharmacometric models serve as inputs to pharmacoeconomic models, may provide a framework for extrapolating from early-phase studies to predict economic outcomes and characterize decision uncertainty. This article reviews the published studies that have implemented this methodology and used simulation to inform drug development decisions and/or to optimize the use of drug treatments. Some of the key practical issues involved in linking pharmacometrics and pharmacoeconomics, including the choice of final outcome measures, methods of incorporating evidence on comparator treatments, approaches to handling multiple intermediate end points, approaches to quantifying uncertainty, and issues of model validation are also discussed. Finally, we have considered the potential barriers that may have limited the adoption of this methodology and suggest that closer alignment between the disciplines of clinical pharmacology, pharmacometrics, and pharmacoeconomics, may help to realize the potential benefits associated with linked pharmacometric-pharmacoeconomic modeling and simulation.

Combining Model-Based Clinical Trial Simulation, Pharmacoeconomics, and Value of Information to Optimize Trial Design.

The Bayesian decision-analytic approach to trial design uses prior distributions for treatment effects, updated with likelihoods for proposed trial data. Prior distributions for treatment effects based on previous trial results risks sample selection bias and difficulties when a proposed trial differs in terms of patient characteristics, medication adherence, or treatment doses and regimens. The aim of this study was to demonstrate the utility of using pharmacometric-based clinical trial simulation (CTS) to generate prior distributions for use in Bayesian decision-theoretic trial design. The methods consisted of four principal stages: a CTS to predict the distribution of treatment response for a range of trial designs; Bayesian updating for a proposed sample size; a pharmacoeconomic model to represent the perspective of a reimbursement authority in which price is contingent on trial outcome; and a model of the pharmaceutical company return on investment linking drug prices to sales revenue. We used a case study of febuxostat versus allopurinol for the treatment of hyperuricemia in patients with gout. Trial design scenarios studied included alternative treatment doses, inclusion criteria, input uncertainty, and sample size. Optimal trial sample sizes varied depending on the uncertainty of model inputs, trial inclusion criteria, and treatment doses. This interdisciplinary framework for trial design and sample size calculation may have value in supporting decisions during later phases of drug development and in identifying costly sources of uncertainty, and thus inform future research and development strategies.

Integration of Pharmacometrics and Pharmacoeconomics to Quantify the Value of Improved Forgiveness to Nonadherence: A Case Study of Novel Xanthine Oxidase Inhibitors for Gout.

Linked pharmacometric and pharmacoeconomic models provide a structured approach for assessing the value of candidate drugs in development. The aim of this study was to assess the utility of such an approach for identifying the properties of xanthine oxidase inhibitors (XOi) providing improved forgiveness to nonadherence and estimate the maximum reimbursement price. The pharmacometric and pharmacoeconomic models were used to simulate the time course of serum uric acid concentrations and estimate quality-adjusted life years and costs for the XOi febuxostat and a range of hypothetical analogues. Compounds with reduced clearance or increased potency were more forgiving to missed doses, however, even following relatively large changes in these properties the predicted maximum reimbursement prices represented an increase of only 19% above febuxostat 80 mg. Linked pharmacometric and pharmacoeconomic modeling methods have the potential to inform early drug development by providing an indication of pricing options that may permit reimbursement.

Modeling the Potential Impact of Changing Access Rates to Specialist Treatment for Alcohol Dependence for Local Authorities in England: The Specialist Treatment for Alcohol Model (STreAM).

OBJECTIVE: We modeled the impact of changing Specialist Treatment Access Rates to different treatment pathways on the future prevalence of alcohol dependence, treatment outcomes, service capacity, costs, and mortality. METHOD: Local Authority numbers and the prevalence of people "potentially in need of assessment for and treatment in specialist services for alcohol dependence" (PINASTFAD) are estimated by mild, moderate, severe, and complex needs. Administrative data were used to estimate the Specialist Treatment Access Rate per PINASTFAD person and classify 22 different treatment pathways. Other model inputs include natural remission, relapse after treatment, service costs, and mortality rates. "What-if" analyses assess changes to Specialist Treatment Access Rates and treatment pathways. Model outputs include the numbers and prevalence of people who are PINASTFAD, numbers treated by 22 pathways, outcomes (successful completion with abstinence, successfully moderated nonproblematic drinking, re-treatment within 6 months, dropout, transfer, custody), mortality rates, capacity requirements (numbers in contact with community services or staying in residential or inpatient places), total treatment costs, and general health care savings. Five scenarios illustrate functionality: (a) no change, (b) achieve access rates at the 70th percentile nationally, (c) increase access by 25%, (d) increase access to Scotland rate, and (e) reduce access by 25%. RESULTS: At baseline, 14,581 people are PINASTFAD (2.43% of adults) and the Specialist Treatment Access Rate is 10.84%. The 5-year impact of scenarios on PINASTFAD numbers (vs. no change) are (B) reduced by 191 (-1.3%), (C) reduced by 477 (-3.3%), (D) reduced by almost 2,800 (-19.2%), and (E) increased by 533 (+3.6%). The relative impact is similar for other outputs. CONCLUSIONS: Decision makers can estimate the potential impact of changing Specialist Treatment Access Rates for alcohol dependence.

Impact of Non-Adherence and Flare Resolution on the Cost-Effectiveness of Treatments for Gout: Application of a Linked Pharmacometric/Pharmacoeconomic Model.

BACKGROUND: Dual urate-lowering therapy (ULT) with lesinurad in combination with either allopurinol or febuxostat is an option for patients with gout unsuccessfully treated on either monotherapy. Treatment failure is often a result of poor medication adherence. Imperfect adherence in clinical trials may lead to biased estimates of treatment effect and confound the results of cost-effectiveness analyses. OBJECTIVES: To estimate the impact of varying medication adherence on the cost effectiveness of lesinurad dual therapy and estimate the value-based price of lesinurad at which the incremental cost-effectiveness ratio is equal to £20,000 per quality-adjusted life-year (QALY). METHODS: Treatment effect was simulated using published pharmacokinetic-pharmacodynamic models and scenarios representing adherence in clinical trials, routine practice, and perfect use. The subsequent cost and health impacts, over the lifetime of a patient cohort, were estimated using a bespoke pharmacoeconomic model. RESULTS: The base-case incremental cost-effectiveness ratios comparing lesinurad dual ULT with monotherapy ranged from £39,184 to £78,350/QALY gained using allopurinol and £31,901 to £124,212/QALY gained using febuxostat, depending on the assumed medication adherence. Results assuming perfect medication adherence imply a per-quarter value-based price of lesinurad of £45.14 when used in dual ULT compared with allopurinol alone and £57.75 compared with febuxostat alone, falling to £25.41 and £3.49, respectively, in simulations of worsening medication adherence. CONCLUSIONS: The estimated value-based prices of lesinurad only exceeded that which has been proposed in the United Kingdom when assuming both perfect drug adherence and the eradication of gout flares in sustained treatment responders.

Impact of non-adherence on the safety and efficacy of uric acid-lowering therapies in the treatment of gout.

AIMS: Dual-urate-lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs. METHODS: The impact of poor medication adherence was studied using two-compartment pharmacokinetic (PK) models based on published evidence, and a semi-mechanistic four-compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual-ULT in gout patients with either under-excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random. RESULTS: Simulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under-excreters taking a 20-day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria. CONCLUSIONS: Suboptimal medication adherence may compromise the safety and efficacy of mono- and dual-ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate.

The Type and Impact of Evidence Review Group Exploratory Analyses in the NICE Single Technology Appraisal Process.

BACKGROUND: As part of the UK National Institute for Health and Care Excellence (NICE) single technology appraisal process, independent evidence review groups (ERGs) critically appraise a company's submission relating to a specific technology and indication. OBJECTIVES: To explore the type of additional exploratory analyses conducted by ERGs and their impact on the recommendations made by NICE. METHODS: The 100 most recently completed single technology appraisals with published guidance were selected for inclusion. A content analysis of relevant documents was undertaken to identify and extract relevant data, and narrative synthesis was used to rationalize and present these data. RESULTS: The types of exploratory analysis conducted in relation to companies' models were fixing errors, addressing violations, addressing matters of judgment, and the provision of a new, ERG-preferred base case. Ninety-three of the 100 ERG reports contained at least one of these analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category "Matters of judgment," which was reported in 83 reports (89%). At least one of the exploratory analyses conducted and reported by an ERG is mentioned in 97% of NICE appraisal consultation documents and 94% of NICE final appraisal determinations, and had a clear influence on recommendations in 72% of appraisal consultation documents and 47% of final appraisal determinations. CONCLUSIONS: These results suggest that the additional analyses undertaken by ERGs in the appraisal of company submissions are highly influential in the policy-making and decision-making process.

Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process.

BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre-defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost-effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship.

The use of exploratory analyses within the National Institute for Health and Care Excellence single technology appraisal process: an evaluation and qualitative analysis.

BACKGROUND: As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process, independent Evidence Review Groups (ERGs) critically appraise the company submission. During the critical appraisal process the ERG may undertake analyses to explore uncertainties around the company's model and their implications for decision-making. The ERG reports are a central component of the evidence considered by the NICE Technology Appraisal Committees (ACs) in their deliberations. OBJECTIVE: The aim of this research was to develop an understanding of the number and type of exploratory analyses undertaken by the ERGs within the STA process and to understand how these analyses are used by the NICE ACs in their decision-making. METHODS: The 100 most recently completed STAs with published guidance were selected for inclusion in the analysis. The documents considered were ERG reports, clarification letters, the first appraisal consultation document and the final appraisal determination. Over 400 documents were assessed in this study. The categories of types of exploratory analyses included fixing errors, fixing violations, addressing matters of judgement and the ERG-preferred base case. A content analysis of documents (documentary analysis) was undertaken to identify and extract relevant data, and narrative synthesis was then used to rationalise and present these data. RESULTS: The level and type of detail in ERG reports and clarification letters varied considerably. The vast majority (93%) of ERG reports reported one or more exploratory analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category 'matters of judgement', which was reported in 83 (89%) reports. The category 'ERG base-case/preferred analysis' was reported in 45 (48%) reports, the category 'fixing errors' was reported in 33 (35%) reports and the category 'fixing violations' was reported in 17 (18%) reports. The exploratory analyses performed were the result of issues raised by an ERG in its critique of the submitted economic evidence. These analyses had more influence on recommendations earlier in the STA process than later on in the process. LIMITATIONS: The descriptions of analyses undertaken were often highly specific to a particular STA and could be inconsistent across ERG reports and thus difficult to interpret. CONCLUSIONS: Evidence Review Groups frequently conduct exploratory analyses to test or improve the economic evaluations submitted by companies as part of the STA process. ERG exploratory analyses often have an influence on the recommendations produced by the ACs. FUTURE WORK: More in-depth analysis is needed to understand how ERGs make decisions regarding which exploratory analyses should be undertaken. More research is also needed to fully understand which types of exploratory analyses are most useful to ACs in their decision-making. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Potential benefits of minimum unit pricing for alcohol versus a ban on below cost selling in England 2014: modelling study.

OBJECTIVE: To evaluate the potential impact of two alcohol control policies under consideration in England: banning below cost selling of alcohol and minimum unit pricing. DESIGN: Modelling study using the Sheffield Alcohol Policy Model version 2.5. SETTING: England 2014-15. POPULATION: Adults and young people aged 16 or more, including subgroups of moderate, hazardous, and harmful drinkers. INTERVENTIONS: Policy to ban below cost selling, which means that the selling price to consumers could not be lower than tax payable on the product, compared with policies of minimum unit pricing at £0.40 (€0.57; $0.75), 45 p, and 50 p per unit (7.9 g/10 mL) of pure alcohol. MAIN OUTCOME MEASURES: Changes in mean consumption in terms of units of alcohol, drinkers' expenditure, and reductions in deaths, illnesses, admissions to hospital, and quality adjusted life years. RESULTS: The proportion of the market affected is a key driver of impact, with just 0.7% of all units estimated to be sold below the duty plus value added tax threshold implied by a ban on below cost selling, compared with 23.2% of units for a 45 p minimum unit price. Below cost selling is estimated to reduce harmful drinkers' mean annual consumption by just 0.08%, around 3 units per year, compared with 3.7% or 137 units per year for a 45 p minimum unit price (an approximately 45 times greater effect). The ban on below cost selling has a small effect on population health-saving an estimated 14 deaths and 500 admissions to hospital per annum. In contrast, a 45 p minimum unit price is estimated to save 624 deaths and 23,700 hospital admissions. Most of the harm reductions (for example, 89% of estimated deaths saved per annum) are estimated to occur in the 5.3% of people who are harmful drinkers. CONCLUSIONS: The ban on below cost selling, implemented in the England in May 2014, is estimated to have small effects on consumption and health harm. The previously announced policy of a minimum unit price, if set at expected levels between 40 p and 50 p per unit, is estimated to have an approximately 40-50 times greater effect.

Alcohol tax pass-through across the product and price range: do retailers treat cheap alcohol differently?

BACKGROUND AND AIMS: Effective use of alcohol duty to reduce consumption and harm depends partly on retailers passing duty increases on to consumers via price increases, also known as 'pass-through'. The aim of this analysis is to provide evidence of UK excise duty and sales tax (VAT) pass-through rates for alcohol products at different price points. SETTING: March 2008 to August 2011, United Kingdom. DESIGN AND MEASUREMENTS: Panel data quantile regression estimating the effects of three duty changes, two VAT changes and one combined duty and VAT change on UK alcohol prices, using product-level supermarket price data for 254 alcohol products available weekly. Products were analysed in four categories: beers, ciders/ready to drink (RTDs), spirits and wines. FINDINGS: Within all four categories there exists considerable heterogeneity in the level of duty pass-through for cheaper versus expensive products. Price increases for the cheapest 15% of products fall below duty rises (undershifting), while products sold above the median price are overshifted (price increases are higher than duty increases). The level of undershifting is greatest for beer [0.85 (0.79, 0.92)] and spirits [0.86 (0.83, 0.89)]. Undershifting affects approximately 67% of total beer sales and 38% of total spirits sales. CONCLUSIONS: Alcohol retailers in the United Kingdom appear to respond to increases in alcohol tax by undershifting their cheaper products (raising prices below the level of the tax increase) and overshifting their more expensive products (raising prices beyond the level of the tax increase). This is likely to impact negatively on tax policy effectiveness, because high-risk groups favour cheaper alcohol and undershifting is likely to produce smaller consumption reductions.

Estimation of own and cross price elasticities of alcohol demand in the UK--A pseudo-panel approach using the Living Costs and Food Survey 2001-2009.

The estimation of price elasticities of alcohol demand is valuable for the appraisal of price-based policy interventions such as minimum unit pricing and taxation. This study applies a pseudo-panel approach to the cross-sectional Living Cost and Food Survey 2001/2-2009 to estimate the own- and cross-price elasticities of off- and on-trade beer, cider, wine, spirits and ready-to-drinks in the UK. A pseudo-panel with 72 subgroups defined by birth year, gender and socioeconomic status is constructed. Estimated own-price elasticities from the base case fixed effect models are all negative and mostly statically significant (p<0.05). Off-trade cider and beer are most elastic (-1.27 and -0.98) and off-trade spirits and on-trade ready-to-drinks are least elastic (-0.08 and -0.19). Estimated cross-price elasticities are smaller in magnitude with a mix of positive and negative signs. The results appear plausible and robust and could be used for appraising the estimated impact of price-based interventions in the UK.

Effects of minimum unit pricing for alcohol on different income and socioeconomic groups: a modelling study.

BACKGROUND: Several countries are considering a minimum price policy for alcohol, but concerns exist about the potential effects on drinkers with low incomes. We aimed to assess the effect of a £0·45 minimum unit price (1 unit is 8 g/10 mL ethanol) in England across the income and socioeconomic distributions. METHODS: We used the Sheffield Alcohol Policy Model (SAPM) version 2.6, a causal, deterministic, epidemiological model, to assess effects of a minimum unit price policy. SAPM accounts for alcohol purchasing and consumption preferences for population subgroups including income and socioeconomic groups. Purchasing preferences are regarded as the types and volumes of alcohol beverages, prices paid, and the balance between on-trade (eg, bars) and off-trade (eg, shops). We estimated price elasticities from 9 years of survey data and did sensitivity analyses with alternative elasticities. We assessed effects of the policy on moderate, hazardous, and harmful drinkers, split into three socioeconomic groups (living in routine or manual households, intermediate households, and managerial or professional households). We examined policy effects on alcohol consumption, spending, rates of alcohol-related health harm, and opportunity costs associated with that harm. Rates of harm and costs were estimated for a 10 year period after policy implementation. We adjusted baseline rates of mortality and morbidity to account for differential risk between socioeconomic groups. FINDINGS: Overall, a minimum unit price of £0.45 led to an immediate reduction in consumption of 1.6% (-11.7 units per drinker per year) in our model. Moderate drinkers were least affected in terms of consumption (-3.8 units per drinker per year for the lowest income quintile vs 0.8 units increase for the highest income quintile) and spending (increase in spending of £0.04 vs £1.86 per year). The greatest behavioural changes occurred in harmful drinkers (change in consumption of -3.7% or -138.2 units per drinker per year, with a decrease in spending of £4.01), especially in the lowest income quintile (-7.6% or -299.8 units per drinker per year, with a decrease in spending of £34.63) compared with the highest income quintile (-1.0% or -34.3 units, with an increase in spending of £16.35). Estimated health benefits from the policy were also unequally distributed. Individuals in the lowest socioeconomic group (living in routine or manual worker households and comprising 41.7% of the sample population) would accrue 81.8% of reductions in premature deaths and 87.1% of gains in terms of quality-adjusted life-years. INTERPRETATION: Irrespective of income, moderate drinkers were little affected by a minimum unit price of £0.45 in our model, with the greatest effects noted for harmful drinkers. Because harmful drinkers on low incomes purchase more alcohol at less than the minimum unit price threshold compared with other groups, they would be affected most by this policy. Large reductions in consumption in this group would however coincide with substantial health gains in terms of morbidity and mortality related to reduced alcohol consumption. FUNDING: UK Medical Research Council and Economic and Social Research Council (grant G1000043).

Estimation of usual occasion-based individual drinking patterns using diary survey data.

BACKGROUND: In order to successfully address excessive alcohol consumption it is essential to have a means of measuring the drinking patterns of a nation. Owing to the multi-dimensional nature of drinking patterns, usual survey methods have their limitations. The aim of this study was to make use of extremely detailed diary survey data to demonstrate a method of combining different survey measures of drinking in order to reduce these limitations. METHODS: Data for 1724 respondents of the 2000/01 National Diet and Nutrition Survey was used to obtain a drinking occasion dataset, by plotting the respondent's blood alcohol content over time. Drinking frequency, level and variation measures were chosen to characterise drinking behaviour and usual behaviour was estimated via statistical methods. RESULTS: Complex patterns in drinking behaviour were observed amongst population subgroups using the chosen consumption measures. The predicted drinking distribution combines diary data equivalent coverage with a more accurate proportion of non-drinkers. CONCLUSIONS: This statistical analysis provides a means of obtaining average consumption measures from diary data and thus reducing the main limitation of this type of data for many applications. We hope that this will facilitate the use of such data in a wide range of applications such as risk modelling, especially for acute harms, and burden of disease studies.

Trend analysis and modelling of gender-specific age, period and birth cohort effects on alcohol abstention and consumption level for drinkers in Great Britain using the General Lifestyle Survey 1984-2009.

BACKGROUND AND AIMS: British alcohol consumption and abstinence rates have increased substantially in the last 3 decades. This study aims to disentangle age, period and birth cohort effects to improve our understanding of these trends and suggest groups for targeted interventions to reduce resultant harms. DESIGN: Age, period, cohort analysis of repeated cross-sectional surveys using separate logistic and negative binomial models for each gender. SETTING: Great Britain 1984-2009. PARTICIPANTS: Annual nationally representative samples of approximately 20 000 adults (16+) within 13 000 households. MEASUREMENTS: Age (eight groups: 16-17 to 75+ years), period (six groups: 1980-84 to 2005-09) and birth cohorts (19 groups: 1900-04 to 1990-94). Outcome measures were abstinence and average weekly alcohol consumption. Controls were income, education, ethnicity and country. FINDINGS: After accounting for period and cohort trends, 18-24-year-olds have the highest consumption levels (incident rate ratio = 1.18-1.15) and lower abstention rates (odds ratio = 0.67-0.87). Consumption generally decreases and abstention rates increase in later life. Until recently, successive birth cohorts' consumption levels were also increasing. However, for those born post-1985, abstention rates are increasing and male consumption is falling relative to preceding cohorts. In contrast, female drinking behaviours have polarized over the study period, with increasing abstention rates accompanying increases in drinkers' consumption levels. CONCLUSIONS: Rising female consumption of alcohol and progression of higher-consuming birth cohorts through the life course are key drivers of increased per capita alcohol consumption in the United Kingdom. Recent declines in alcohol consumption appear to be attributable to reduced consumption and increased abstinence rates among the most recent birth cohorts, especially males, and general increased rates of abstention across the study period.

Adjusting for unrecorded consumption in survey and per capita sales data: quantification of impact on gender- and age-specific alcohol-attributable fractions for oral and pharyngeal cancers in Great Britain.

AIMS: Large discrepancies are typically found between per capita alcohol consumption estimated via survey data compared with sales, excise or production figures. This may lead to significant inaccuracies when calculating levels of alcohol-attributable harms. Using British data, we demonstrate an approach to adjusting survey data to give more accurate estimates of per capita alcohol consumption. METHODS: First, sales and survey data are adjusted to account for potential biases (e.g. self-pouring, under-sampled populations) using evidence from external data sources. Secondly, survey and sales data are aligned using different implementations of Rehm et al.'s method [in (2010) Statistical modeling of volume of alcohol exposure for epidemiological studies of population health: the US example. Pop Health Metrics 8, 1-12]. Thirdly, the impact of our approaches is tested by using our revised survey dataset to calculate alcohol-attributable fractions (AAFs) for oral and pharyngeal cancers. RESULTS: British sales data under-estimate per capita consumption by 8%, primarily due to illicit alcohol. Adjustments to survey data increase per capita consumption estimates by 35%, primarily due to under-sampling of dependent drinkers and under-estimation of home-poured spirits volumes. Before aligning sales and survey data, the revised survey estimate remains 22% lower than the revised sales estimate. Revised AAFs for oral and pharyngeal cancers are substantially larger with our preferred method for aligning data sources, yielding increases in an AAF from the original survey dataset of 0.47-0.60 (males) and 0.28-0.35 (females). CONCLUSION: It is possible to use external data sources to adjust survey data to reduce the under-estimation of alcohol consumption and then account for residual under-estimation using a statistical calibration technique. These revisions lead to markedly higher estimated levels of alcohol-attributable harm.