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Background: The Orphan Regulation ((EC) No 141/2000) has successfully redirected private and public investment towards previously neglected areas through incentives, regulatory obligations and rewards. However, the growth in the number of licensed orphan medicinal products (OMPs) has led to concerns about increased costs. The aims were to investigate the trend in the costs of OMPs to the National Health Service in Wales, to attribute costs of medicines within and outside periods of marketing exclusivity, and estimate the contribution of individual medicines to the overall costs of OMPs. Methods: Expenditure on OMPs in Wales was analysed between the 2014/15 and 2019/20 financial years using data on prescriptions dispensed in primary care, secondary care, and specialised commissioned services. OMP spend was calculated as a proportion of total medicines expenditure, whether it was incurred during, or outside the marketing exclusivity period (MEP), and by therapeutic area and medicine. Results: Overall spend on OMPs and all medicines increased from £32 m to £82 m, and from £1,030 m to £1,198 m, respectively, with the proportion of spend on OMPs more than doubling from 3.1% to 6.9% per annum. Average year-on-year growth in the costs of OMPs was 21%, compared to 2% for other medicines. Costs following MEP expiry contributed significantly to overall OMP costs, increasing from £8 m to £30 m, corresponding to an increase from 24% to 37%. Treatments for 'malignant disease and immunosuppression', 'nutrition and blood' and the 'respiratory system' accounted for 90% of all OMP spend. Half of total OMP annual expenditure was on just 4 medicines in 2014/15, increasing to 8 in 2019/20. Conclusions: Both the number of OMPs and the amount spent on OMPs in Wales has increased over time, possibly as a consequence of favourable licensing conditions, permissive health technology assessment policies and dedicated funding. [ABSTRACT FROM AUTHOR]

Stigma may influence the use of HIV pre-exposure prophylaxis (PrEP). However, there is an absence of robust measures for PrEP-related stigma. We describe an adaptation of a HIV stigma scale for use in PrEP users and experiences of PrEP users in Wales (UK) with regards to PrEP-related stigma. A mixed methods study was conducted where PrEP users completed questionnaire items about PrEP-related stigma and a subset were interviewed about their experiences of taking PrEP. We adapted items from the HIV stigma scale and assessed construct validity and internal consistency. We analysed interview data using a framework approach, with themes focussing on enacted and anticipated stigma in order to identify areas for scale refinement. Our measure had good psychometric properties but additional items may be useful (e.g. specific instances of enacted stigma, concerns around homonegativity). Further work is needed to develop this scale and validate it in a larger sample. [ABSTRACT FROM AUTHOR]

We investigated the determinants of daily PrEP use and coverage of condomless anal sex (CAS) by PrEP among men who have sex with men in Wales, UK. We measured PrEP use by electronic monitors and CAS by secure online surveys. We defined PrEP use based on daily medication cap openings and coverage as CAS episodes preceded by ≥ 3 days of PrEP use and followed by ≥ 2 days of PrEP use. We included 57 participants (5463 observations). An STI diagnosis was associated with lower PrEP use but also lower PrEP coverage. Older adults had higher PrEP use. A belief that other PrEP users took PrEP as prescribed was associated with lower PrEP coverage. An STI diagnosis is an important cue for an intervention, reflecting episodes of high-risk sexual behaviour and low PrEP coverage. Other results provide a basis for the development of an evidence-informed intervention for promoting coverage of PrEP. [ABSTRACT FROM AUTHOR]

Introduction: HIV pre‐exposure prophylaxis (PrEP) involves the use of antiretroviral medication in HIV‐negative individuals considered to be at risk of acquiring HIV. It has been shown to prevent HIV and has been available in Wales since July 2017. Measuring and understanding adherence to PrEP is complex as it relies on the simultaneous understanding of both PrEP use and sexual activity. We aimed to understand the experiences of men who have sex with men (MSM) living in Wales initiating, implementing and persisting with HIV PrEP. Methods: We conducted semistructured interviews with MSM PrEP users in Wales who participated in a cohort study of PrEP use and sexual behaviour. Following completion of the cohort study, participants were invited to take part in a semistructured interview about their experiences of taking PrEP. We aimed to include both individuals who had persisted with and discontinued PrEP during the study. The interview topic guide was informed by the ABC taxonomy for medication adherence and the theory of planned behaviour. We analysed our data using reflexive thematic analysis. Results: Twenty‐one participants were interviewed, five having discontinued PrEP during the cohort study. The developed themes focused on triggers for initiating PrEP, habitual behaviour, drivers for discontinuation and engagement with sexual health services. Stigma surrounding both PrEP and HIV permeated most topics, acting as a driver for initiating PrEP, an opportunity to reduce discrimination against people living with HIV, but also a concern around the perception of PrEP users. Conclusion: This is the first study to investigate PrEP‐taking experiences incorporating established medication adherence taxonomy. We highlight key experiences regarding the initiation, implementation and persistence with PrEP and describe how taking PrEP may promote positive engagement with sexual health services. These findings may be useful for informing PrEP rollout programmes and need to be explored in other key populations. Patient and Public Contribution: PrEP users, in addition to PrEP providers and representatives of HIV advocacy and policy, were involved in developing the topic guide for this study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Advanced Therapy Medicinal Products (ATMPs), which include gene, somatic cell therapies and tissue‐engineered medicines, have the potential to transform current care pathways by offering durable and potentially curative outcomes. However, they are exceptionally expensive, with prices exceeding £1m per patient in some cases. With an expectation that a large number of ATMPs will soon gain marketing authorisation (global market is estimated to reach £9bn to £14bn by 2025), healthcare payers and providers face a number of challenges to facilitate patient access to this new category of medicines. This viewpoint reflects on the experience of introducing ATMPs into the National Health Service in Wales where £1 in every £200 spent on medicines (2019/2020) is expected to be on ATMPs for just 20 patients. Evidence to date makes it apparent that decisions regarding clinical and cost‐effectiveness and the scale of the budget impact of implementing ATMPs create both financial and health service risks. Consequently, there are significant policy implications. A critical examination is made of the approaches taken for the health technology assessment and appraisal of ATMPs, the methods of payment and service impacts of these medicines, and the approach taken to horizon scanning and subsequent modelling of the financial impact over the next 10 years. [ABSTRACT FROM AUTHOR]

Background: The All Wales Medicines Strategy Group (AWMSG) develops prescribing advice and is responsible for appraising new medicines for use in Wales. In this article, we examine the medicines appraisal process in Wales, its timeliness and its impact on medicines availability in Wales, and compare its processes and recommendations with the two other UK health technology appraisal bodies [the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC)].Methods: We reviewed the medicines appraisals conducted by AWMSG between October 2010 and September 2015. The duration of the process and the recommendations made by AWMSG were compared with those of NICE and SMC. Only publicly available data were considered in this review.Results: AWMSG conducted 171 single technology appraisals for 137 medicines during the study period (34 were for medicines previously appraised by AWMSG but these were for new indications). Of these, 152 appraisals were supported for use in NHS Wales (33 with restrictions) and 19 were not supported. Recommendations broadly concurred with SMC and NICE for the majority of appraisals. Compared with NICE recommendations, the median time advantage gained in Wales for those medicines that received a positive AWMSG recommendation and which were subsequently superseded by NICE advice was 10.6 months (range 3.5-48.3 months; n = 17).Conclusion: This review highlights the work carried out by AWMSG over a 5-year period, and provides evidence to support the effectiveness of the appraisal process in terms of patients in Wales gaining earlier access to medicines and efficiency through reduced duplication with NICE. [ABSTRACT FROM AUTHOR]

We have taken advantage of a natural experiment to measure the impact of the phased abolition of prescription co-payments in Wales. We investigated 3 study periods covering the phased abolition: from £6 to £4, £4 to £3, and £3 to £0. A difference-in-difference modelling was adopted and applied to monthly UK general practice level dispensing data on 14 selected medicines which had the highest percentage of items dispensed subject to a co-payment prior to abolition. Dispensing from a comparator region (North East of England) with similar health and socio-economic characteristics to Wales, and where prescription co-payments continued during the study periods, was used to isolate any non-price effects on dispensing in Wales. Results show a small increase in dispensing of 14 selected medicines versus the comparator. Compared with NE England, monthly average Welsh dispensing was increased by 11.93 items (7.67%; 95% CI [7.2%, 8.1%]), 6.37 items (3.38%; 95% CI [2.9%, 3.7%]) and 9.18 items (4.54%; 95% CI [4.2%, 4.9%]) per practice per 1,000 population during the periods when co-payment was reduced. Price elasticities of the selected medicines utilisation were -0.23, -0.13, and -0.04 in 3 analyses, suggesting the abolition of co-payment had small effect on Welsh dispensing. [ABSTRACT FROM AUTHOR]

Background: Prescribing policy recommendations aimed at moving immunosuppressant prescribing for renal transplant patients from primary to secondary care may result in benefits of increased safety and reduced cost. However, there is little evidence of patients' preferences for receiving their immunosuppressant therapy from hospitals compared to community dispensing. The aim of this study was to elicit patient preferences for different service configurations focusing in particular on home delivery versus collection of medication from hospital.Methods: A discrete choice experiment was administered to 265 renal transplant patients in North Wales. Respondents were presented 18 pairwise choices, labelled as either home delivery or hospital collection, and described by the attributes: frequency of supply, waiting time (for delivery or collection) and method of ordering (provider contact, patient contact via phone, patient contact electronically). Data were analysed using a random-effects logit model and marginal rates of substitution calculated based on the waiting time attribute.Results: A response rate of 63% was achieved, with 5332 usable observations from 150 respondents. Method of delivery (β coefficient 1.21; 95% confidence interval 1.05 to 1.38), frequency of supply (0.05; 0.03 to 0.08) waiting time (-0.00, -0.00 to -0.00), provider contact (desirable) (0.20; 0.12 to 0.27), patient contact by telephone (desirable) (0.09; 0.01 to 0.17) and patient contact electronically (undesirable) (-0.292; -0.37 to -0.21) were statistically significant (p < 0.05). Results indicate that patients are willing to increase waiting time by nearly 10 h to have a home delivery service.Conclusion: Patients indicate a clear preference for a home delivery service. They prefer providers to make contact when new immunosuppressant supplies are required and show preference against ordering medication electronically. A policy for secondary care prescribing and hospital collection of medicines does not align with this preference. [ABSTRACT FROM AUTHOR]

Background: All health care systems face the need to find the resources to meet new demands such as a new, cost-increasing health technology. In England and Wales, when a health technology is recommended by the National Institute for Health and Care Excellence (NICE), the National Health Service (NHS) is mandated to provide the funding to accommodate it within three months of publication of the recommendation. Identifying what, in practice, is foregone when new cost-increasing technologies are introduced is important for understanding the effects of health technology assessment (HTA) decisions on the NHS or any other health care system. Our objective was to investigate how in practice local NHS commissioners in Wales accommodated financial "shocks" arising from technology appraisals (TAs) issued by NICE and from other cost pressures.Methods: Semi-structured interviews were conducted with Finance Directors and Medical Directors from all seven Local Health Boards (LHBs) in NHS Wales. These interviews covered prioritisation processes, as well as methods of financing NICE TAs and other financial shocks at each LHB. We then undertook a systematic identification of themes and topics from the information recorded. The study relates to the period October 2010 to March 2013.Results: The financial impact of NICE TAs is generally anticipated and planned for in advance and the majority of LHBs have contingency funds available to cope with these and other financial shocks within-period. Efficiency savings (defined as reductions in costs with no assumed reductions in quality) were a source of funds for cost pressures of all kinds. Service displacements were not linkable to particular NICE TAs and there appears to be a general lack of explicit prioritisation activities. The Welsh Government has, on occasion, explicitly or implicitly acted as the funder of last resort.Conclusions: Services may be displaced as part of a response to the cumulative impact of all types of cost pressures, including cost-increasing health technologies recommended by NICE, but such displacements were not direct responses to the publication of individual NICE TAs. The additional cost pressure represented by a new NICE TA is likely to be accommodated at least partly by greater efficiency and increased expenditure rather than displacement of services. [ABSTRACT FROM AUTHOR]

Background: Few studies to date have explored the stated preferences of national decision makers for health technology adoption criteria, and none of these have compared stated decision-making behaviours against actual behaviours. Assessment of the external validity of stated preference studies, such as discrete-choice experiments (DCEs), remains an under-researched area. Objectives: The primary aim was to explore the preferences of All Wales Medicines Strategy Group (AWMSG) appraisal committee and appraisal sub-committee (the New Medicines Group) members ('appraisal committees') for specific new medicines adoption criteria. Secondary aims were to explore the external validity of respondents' stated preferences and the impact of question choice options upon preference structures in DCEs. Methods: A DCE was conducted to estimate appraisal committees members' preferences for incremental cost effectiveness, quality-adjusted life-years (QALYs) gained, annual number of patients expected to be treated, the impact of the disease on patients before treatment, and the assessment of uncertainty in the economic evidence submitted for new medicines compared with current UK NHS treatment. Respondents evaluated 28 pairs of hypothetical new medicines, making a primary forced choice between each pair and a more flexible secondary choice, which permitted either, neither or both new medicines to be chosen. The performance of the resultant models was compared against previous AWMSG decisions. Results: Forty-one out of a total of 80 past and present members of AWMSG appraisal committees completed the DCE. The incremental cost effectiveness of new medicines, and the QALY gains they provide, significantly ( p < 0.0001) influence recommendations. Committee members were willing to accept higher incremental cost-effectiveness ratios and lower QALY gains for medicines that treat disease impacting primarily upon survival rather than quality of life, and where uncertainty in the cost-effectiveness estimates has been thoroughly explored. The number of patients to be treated by the new medicine did not exert a significant influence upon recommendations. The use of a flexible-choice question format revealed a different preference structure to the forced-choice format, but the performance of the two models was similar. Aggregate decisions of the AWMSG were well predicted by both models, but their sensitivity (64 %, 68 %) and specificity (55 %, 64 %) were limited. Conclusions: A willingness to trade the cost effectiveness and QALY gains against other factors indicates that economic efficiency and QALY maximisation are not the only considerations of committee members when making recommendations on the use of medicines in Wales. On average, appraisal committee members' stated preferences appear consistent with their actual decision-making behaviours, providing support for the external validity of our DCEs. However, as health technology assessment involves complex decision-making processes, and each individual recommendation may be influenced to varying degrees by a multitude of different considerations, the ability of our models to predict individual medicine recommendations is more limited. [ABSTRACT FROM AUTHOR]

Background: There have been several explorations of factors influencing the reimbursement decisions of the National Institute for Health and Clinical Excellence (NICE) but not of other UK-based health technology assessment (HTA) organizations. Objective: This study aimed to explore the factors influencing the recommendations of the All Wales Medicines Strategy Group (AWMSG) on the use of new medicines in Wales. Methods: Based on public data, logistic regression models were developed to evaluate the influence of cost effectiveness, the quality and quantity of clinical evidence, disease characteristics (including rarity), budget impact, and a range of other factors on the recommendations of AWMSG and its subcommittee, the New Medicines Group (NMG). Results: Multivariate analyses of 47 AWMSG appraisals between 2007-9 correctly predicted 87% of decisions. The results are suggestive of a positive influence on recommendations of the presence of probabilistic sensitivity analyses (PSAs) but, counter-intuitively, a statistically significant negative influence of evidence from high-quality randomized controlled trials (RCTs) [odds ratio 0.059; 95% CI 0.005, 0.699]. This latter observation may be attributed to our strict definition of high quality, which excluded the use of surrogate endpoints. Putative explanatory variables, including cost effectiveness, budget impact, underlying disease characteristics and 'ultra'-orphan drug status were not statistically significant predictors of final AWMSG decisions based on our dataset. Univariate analyses indicate that medicines with negative recommendations had significantly higher incremental costeffectiveness ratios than those with positive recommendations, consistent with the pursuit of economic efficiency. There is also evidence that AWMSG considers equity issues via an ultra-orphan drugs policy. Conclusions: Consideration of decision uncertainty via PSA appears to positively influence the reimbursement decisions of AWMSG. The significant negative impact of the presence of high-quality RCTs, and the lack of a significant positive impact of other expected factors, may reflect issues in the plausibility of supporting evidence for medicines that received negative recommendations. Furthermore, it serves to emphasize the difficulties in applying the usual hierarchies of evidence to the HTA process, and in particular to the appraisal of high-cost specialist medicines close to market launch. [ABSTRACT FROM AUTHOR]

Objective: To assess effects of abolition of prescription copayments in Wales on rates of dispensing. Methods: General practice-level monthly dispensing data were compared before/after abolition between Wales and North East (NE) England where the charge was retained. Data for 14 medicines that had most items dispensed subject to charge before abolition were similarly compared with NE England. For those with over-the-counter substitutes, wholesale sales to pharmacies were examined. A survey examined local initiatives, which might differentially affect dispensing between the two areas. Results: Total dispensing rates (items/1000 patients) increased significantly in both areas but significantly less so in Wales (difference = −19.7, P = 0.024, 95% confidence interval [CI] = −36.7 to −2.6). For the 14 selected medicines, combined dispensing rates increased significantly in both areas but significantly more in Wales (difference = 27.51, P < 0.0001, 95% CI = 23.66–31.35). There was much variation for individual drugs, but categories tended to show this same trend except for antibiotics, where rates increased in Wales but decreased in NE England. The survey revealed few local initiatives that could explain these differences. Sales of over-the-counter substitutes did not explain the changes in dispensing. Conclusions: The Welsh policy was associated with a modest increase in dispensing rates relative to NE England for the 14 medicines with the highest number of items dispensed subject to charge before abolition. Although factors besides the copayment may have influenced these observations, the smaller relative increase in total dispensing rates in Wales suggests that the overall impact of abolition was minimal. [ABSTRACT FROM AUTHOR]

Objective: The aim of this economic evaluation was to assess whether home management could represent a cost-effective strategy in the patient pathway of type 1 diabetes (T1D). This is based on the Delivering Early Care In Diabetes Evaluation trial (ISRCTN78114042), which compared home versus hospital management from diagnosis in childhood diabetes and found no statistically significant difference in glycaemic control at 24 months., Design: Cost-effectiveness analysis alongside a randomised controlled trial., Setting: Eight paediatric diabetes centres in England, Wales and Northern Ireland., Participants: 203 clinically well children aged under 17 years, with newly diagnosed T1D and their carers., Outcome Measures: The base-case analysis adopted n National Health Service (NHS) perspective. A scenario analysis assessed costs from a broader societal perspective. The incremental cost-effectiveness ratio (ICER), expressed as cost per mmol/mol reduction in glycated haemoglobin (HbA1c), was based on the mean difference in costs between the home and hospital groups, divided by mean differences in effectiveness (HbA1c). Uncertainty was considered in terms of the probability of cost-effectiveness., Results: At 24 months postintervention, the base-case analysis showed a difference in costs between home and hospital, in favour of home management (mean difference -£2,217; 95% CI -£2825 to -£1,609; p<0.001). Home care dominated, with an ICER of £7434 (saved) per mmol/mol reduction of HbA1c. The results of the scenario analysis also favoured home management. The greatest driver of cost differences was hospitalisation during the initiation period., Conclusions: Home management from diagnosis of children with T1D who are medically stable represents a less costly approach for the NHS in the UK, without impacting clinical effectiveness., Trial Registration Number: ISRCTN78114042., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To describe the early impact of COVID-19 and associated control measures on the sexual behaviour of pre-exposure prophylaxis (PrEP) users in Wales., Methods: Data were obtained from an ecological momentary assessment study of PrEP use and sexual behaviour. Participants were individuals accessing PrEP through the National Health Service (NHS) sexual health clinics across four health boards in Wales. Weekly data documenting condomless sex in the preceding week were analysed between 03/02/2020 and 10/05/2020. The introduction of social distancing measures and changes to sexual health clinics in Wales occurred on the week starting 16/03/2020. Two-level logistic regression models were fitted to condomless sex (yes/no) over time, included an indicator for the week starting 16/03/2020, and were extended to explore differential associations by relationship status and sexual health clinic., Results: Data were available from 56 participants and included 697 person-weeks (89% of the maximum number that could have been obtained). On average, 42% of participants reported condomless sex in the period prior to the introduction of social distancing measures and 20% reported condomless sex after (OR=0.16, 95% CI 0.07 to 0.37, p<0.001). There was some evidence to suggest that this association was moderated by relationship status (OR for single participants=0.09, 95% CI 0.06 to 0.23; OR for not single participants=0.46, 95% CI 0.16 to 1.25)., Conclusions: The introduction of social distancing measures and changes to PrEP services across Wales was associated with a marked reduction in reported instances of condomless sexual intercourse among respondents, with a larger reduction in those who were single compared with those who were not. The long-term impact of COVID-19 and associated control measures on this population's physical and mental health and well-being requires close examination., Competing Interests: Competing interests: DG, KH and FW report receiving funding from Health and Care Research Wales during the conduct of this work. RM reports funding from National Institute for Health Research during the conduct of this study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Social distancing policies aimed to limit Covid-19 across the UK were gradually relaxed between May and August 2020, as peak incidences passed. Population density is an important driver of national incidence rates; however peak incidences in rural regions may lag national figures by several weeks. We aimed to forecast the timing of peak Covid-19 mortality rate in rural North Wales. Methods: Covid-19 related mortality data up to 7/5/2020 were obtained from Public Health Wales and the UK Government. Sigmoidal growth functions were fitted by non-linear least squares and model averaging used to extrapolate mortality to 24/8/2020. The dates of peak mortality incidences for North Wales, Wales and the UK; and the percentage of predicted mortality at 24/8/2020 were calculated. Results: The peak daily death rates in Wales and the UK were estimated to have occurred on the 14/04/2020 and 15/04/2020, respectively. For North Wales, this occurred on the 07/05/2020, corresponding to the date of analysis. The number of deaths reported in North Wales on 07/05/2020 represents 33% of the number predicted to occur by 24/08/2020, compared with 74 and 62% for Wales and the UK, respectively. Conclusion: Policies governing the movement of people in the gradual release from lockdown are likely to impact significantly on areas-principally rural in nature-where cases of Covid-19, deaths and immunity are likely to be much lower than in populated areas. This is particularly difficult to manage across jurisdictions, such as between England and Wales, and in popular holiday destinations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Hughes and Hughes.)

Background: The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS., Objectives: (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients., Design: A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre., Setting: Fifteen diabetes clinics in hospitals in England and Wales., Participants: Patients aged 7 months to 15 years., Interventions: Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D., Data Sources: Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data., Outcomes: The primary outcome was glycosylated haemoglobin (HbA 1c ) concentration at 12 months. The secondary outcomes were (1) HbA 1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained., Results: A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n  = 149; MDI, n  = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n  = 143; MDI, n  = 142). At 12 months, age-adjusted least mean squares HbA 1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA 1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p  = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs)., Limitations: Generalisability beyond 12 months is uncertain., Conclusions: No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population., Future Work: Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered., Trial Registration: Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25., 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. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs., Competing Interests: Joanne Blair undertakes paid advisory work for, and has received funding for research, to attend academic meetings and to support a nursing salary from, Novo Nordisk Ltd (Gatwick, UK), a pharmaceutical company that manufactures some of the insulins used in the SubCutaneous Insulin: Pumps or Injections? (SCIPI) study. The work undertaken by Joanne Blair for Novo Nordisk Ltd relates to growth hormone therapy and not diabetes. Mohammed Didi has received payment for advisory work and funding to attend academic meetings and to support a nursing salary from Novo Nordisk Ltd. The work undertaken by Mohammed Didi for Novo Nordisk Ltd relates to growth hormone therapy and not diabetes. Mohammed Didi has received expenses from Merck Serono Ltd (Feltham, UK) to attend educational meetings. Carrol Gamble is a member of the Efficacy and Mechanism Evaluation Programme Board of the National Institute for Health Research. Dyfrig Hughes is a member of the Health Technology Assessment (HTA) Clinical Trials Board (2010–16), the HTA Funding Teleconference (2015–16) and the Pharmaceuticals Panel (2008–12). John W Gregory reports grants from Cardiff University during the conduct of the study, and membership of the HTA Commissioning Board (2010–14). John W Gregory received speaker fees from Pfizer Inc. and Eli Lilly and Company (Basingstoke, UK), fees for attending an advisory board for Eli Lilly and Company and financial assistance to attend annual meetings of the European Society for Paediatric Endocrinology from Sanofi Genzyme (Guildford, UK), Merck Serono Ltd, Ipsen and Novo Nordisk Ltd.

Background: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak., Objectives: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism., Design: FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453., Settings: Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool., Participants: Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research., Interventions: Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners., Main Outcome Measures: Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use., Results: Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%)., Conclusions: The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM., Trial Registration: Current Controlled Trials ISRCTN37558856., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.

Objectives: patient co-payments for prescription medicines in Wales were abolished in April 2007 and there has been much speculation on the possible effects. We analysed patient-reported use of medicines before and after abolition of the prescription charge, noting changes in the number of items prescribed, number of non-prescription medicines purchased and participants not collecting all prescribed items (primary non-adherence)., Methods: a sample of community pharmacists across Wales (n = 249) issued questionnaires to customers at the point of dispensing who were not exempt from the prescription charge. A second questionnaire was delivered by post to those who returned the first questionnaire (n = 1027) and expressed a willingness to participate further. Paired t-tests were applied to responses from those completing both questionnaires (n = 593). Further analyses were carried out according to gender, age and reported levels of household income., Key Findings: there was a statistically significant (P = 0.03) rise in the number of items prescribed, and a statistically significant fall (P = 0.02) in the number of non-prescription medicines purchased. Primary non-adherence was also found to fall between pre- and post-abolition periods. Those most affected in terms of increase in number of prescribed items prescribed were the older age group (45-59 years), and those with household income of between £15600 and £36400. The most affected in the fall in number of medicines purchased were males, those in the lower age group (25-34 years) and those with a higher household income (>£36400)., Conclusions:  although the rise in number of items prescribed and fall in number of medicines purchased was generally anticipated, there appeared to be little or no effect for those on the lowest incomes.

In 2005 the National Institute for Health and Clinical Excellence Guidance on Cancer Services: Improving Outcomes in Children and Young People with Cancer, identified the need to quantify the substantial contribution made by charities to NHS provision to this group of patients. This article quantifies the contribution in England and Wales. It identifies 51 charities established specifically to assist this patient group, estimates that 340 charities made some financial contribution and 28 organizations administered charitable funds for hospices. The financial contribution to services by charities was estimated to be between pound25 million and pound38 million in 2003, representing between one-third and a half of the total resources directed to the treatment and support of children and young people with cancer in specialist centres across England and Wales. Reliance on the substantial charitable funding of health care in England and Wales raises concerns over government responsibility, and the potential misalignment between NHS priorities and those of the charities.

The feasibility, reliability and validity of a Welsh version of the EQ-5D health-related quality of life questionnaire were evaluated by means of a postal questionnaire administered on two occasions to a sample of adults across Welsh-speaking areas of Wales. The absolute response rate was 126 (out of 1,000), though after considering language and expected response to Welsh language questionnaires, the adjusted response rate was 50%. Respondents' mean age was 56.8 +/- 18 years and 38.7% reported having chronic illness. The number of missing items from the descriptive EQ-5D (aggregated for both administrations) was 4, representing 0.33% of all responses. Five EQ-VAS responses were returned incomplete. 97 (85.8%) respondents reported no change in health in the fortnight between the first and second administration. The Spearman rank coefficients for these respondents were 0.828 for EQ-5D scores, and 0.815 for EQ-VAS, respectively (both P < 0.000). Construct validity was confirmed by the power of the EQ-5D to discriminate between those expected to be healthy or otherwise, as assessed by self-reported health, presence of chronic illness, receipt of treatment, and age (all P < 0.0001). It is concluded that the Welsh version of the EQ-5D is both valid and reliable for measuring health status in subjects across Wales.

Objective: To investigate the cost effectiveness of a parenting programme., Design: An incremental cost effectiveness analysis alongside a pragmatic randomised controlled trial of the effectiveness of a group parenting programme delivered through Sure Start in the community., Setting: Sure Start areas in north and mid Wales., Participants: Parents of 116 children aged 36-59 months (87% of the clinical sample) at risk of developing conduct disorders defined by scoring over the clinical cut off on the Eyberg child behaviour inventory). Children were identified by health visitors and recruited by the research team., Intervention: The Webster-Stratton Incredible Years basic parenting programme or a six month waiting list control., Main Outcome Measure: Incremental cost per unit of improvement on the intensity score of the Eyberg child behaviour inventory., Results: The bootstrapped incremental cost effectiveness ratio point estimate was 73 pounds sterling (109 euros, $142) per one point improvement on the intensity score (95% confidence interval 42 pounds sterling to 140 pounds sterling ). It would cost 5486 (8190 euros, $10,666) to bring the child with the highest intensity score to below the clinical cut-off point and 1344 (2006 euros, $2618) to bring the average child in the intervention group within the non-clinical limits on the intensity score (below 127). For a ceiling ratio of 100 pounds sterling (149 euros, $194) per point increase in intensity score, there is an 83.9% chance of the intervention being cost effective. The mean cost per child attending the parenting group was 1934 pounds sterling (2887 euros, $3760) for eight children and 1289 pounds sterling (1924 euros, $2506) for 12 children, including initial costs and materials for training group leaders. When we categorised the sample into relatively mild, moderate, and severe behaviour groups based on intensity scores at baseline the intervention seemed more cost effective in those with the highest risk of developing conduct disorder., Conclusion: This parenting programme improves child behaviour as measured by the intensity score of the Eyberg child behaviour inventory at a relatively low cost and was cost effective compared with the waiting list control. This parenting programme involves modest costs and demonstrates strong clinical effect, suggesting it would represent good value for money for public spending.