Introduction The implantable cardioverter defibrillator (ICD) is a cardiac device recommended for use to prevent the occurrence of sudden cardiac death (SCD) in post-myocardial infarction (MI) patients with reduced left ventricular ejection fraction (LVEF). The evidence informing this guidance comes from landmark trials that are now more than 20 years old. The risk-benefit profile of ICD for the contemporary target population may have changed substantially since then, which raises the question of whether there is evidence for sparing patients a procedure associated with potentially severe complications and high healthcare costs. A main part of the PRevention Of sudden cardiac death aFter myocardial Infarction by Defibrillator implantation (PROFID) project is the PROFID EHRA trial, which is supported by the European Heart Rhythm Association. PROFID EHRA is a European Union-funded, prospective, randomised, multi-centre, non-inferiority study designed to compare optimal medical therapy (OMT) alone to ICD with OMT, for post-MI patients with reduced LVEF. The study also describes economic evaluation methods to quantify the cost and health implications of using OMT alone in place of ICD implantation plus OMT in this group of patients.Methods and analysis The economic evaluation has been designed to conduct a pre-trial cost-effectiveness analysis (CEA) prior to the availability of trial data, followed by a within-trial cost-consequences analysis (CCA) and a long-term post-trial CEA, conducted from the National Health Service and Personal Social Service perspective in England. The pre-trial CEA uses simulation modelling informed by available evidence to assess the lifetime costs and quality-adjusted life years of OMT alone and ICD+OMT in post-MI patients with reduced LVEF at risk of SCD, as defined in the PROFID EHRA trial. The within-trial CCA is intended to summarise the health-related quality of life (HRQoL), healthcare resource use and associated costs observed during the PROFID EHRA trial follow-up period. The post-trial CEA updates the pre-trial model by incorporating contemporary evidence about the HRQoL and costs observed during the trial and the occurrence of those events and outcomes accruing during the trial follow-up period and projecting them into the expected lifetime of the patients. Sensitivity analyses are performed to assess the robustness of the CEA results with respect to both model assumptions and uncertainty in the value of the model input parameters. Finally, a value of information analysis will identify the key drivers of uncertainty surrounding the model conclusions regarding the optimal treatment strategy, establishing if further research may be required.Ethics and dissemination The PROFID EHRA trial, under legal sponsorship of Charité—Universitätsmedizin Berlin, Germany, received its first ethics approval by the Medicine Research Ethics Committee of the La Paz University Hospital in Madrid, Spain (reference number LHS-2019-0209). Before including patients, for all participating study centres, the required local, central and/or national ethical approval has to be obtained. As of the date 13 November 2025, at least one participating study centre in the following countries has received ethical approvals from relevant ethics committees: Austria, Belgium, Czech Republic, Denmark, France, Germany, Great Britain, Hungary, Israel, the Netherlands, Poland and Spain. Results will be shared with the general public through various media channels and additionally with healthcare professionals and the scientific community through scientific meetings, conferences and publications.Trial registration number NCT05665608.

OBJECTIVES:Different pricing models have been proposed for multi-indication drugs. We compared the population health impact of 3 pricing policies: uniform pricing, indication-based pricing (IBP), and a hybrid policy of uniform pricing with IBP applied selectively. METHODS:We develop a policy model to compare how these pricing policies affect drug access, health benefits, innovation (numbers of new drugs and indications developed), and pharmaceutical costs over the product lifecycle. The framework is illustrated with numeric examples and case studies, using UK evidence. RESULTS:In the UK context, where the cost-effectiveness threshold (approval norm, £30 000/quality-adjusted life-year) is higher than both the evidence on and the government measure of opportunity cost (£15 000/quality-adjusted life-year), IBP is associated with lower overall population health than uniform pricing. The hybrid pricing policy results in lower population health than uniform pricing when innovation effects are not considered, but higher population health when these effects are considered. To improve health outcomes in the United Kingdom, where pricing decisions have limited impact on research and development owing to its small market size, IBP or hybrid policies would need to be implemented in conjunction with lower cost-effectiveness thresholds. Application of the framework to nivolumab and pembrolizumab found that IBP would approximately double expenditure for those products without improving access or health benefits. CONCLUSIONS:IBP and hybrid policies can improve access to new drugs but must be carefully designed to avoid cost increases that could harm overall population health. Lower approval norms are required for these policies to contribute positively to population health.

Abstract Background Statins and ezetimibe are the preferred lipid-lowering therapies (LLTs) for children with heterozygous familial hypercholesterolaemia (HeFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are newer add-on therapies for individuals not achieving low-density lipoprotein-cholesterol (LDL-C) targets. We evaluated the efficacy and safety of PCSK9i in children aged <18 years with HeFH. Methods Systematic review and pairwise meta-analyses of randomised-controlled trials (RCTs) of evolocumab, alirocumab and inclisiran. Comprehensive bibliographic searches were conducted in February 2026. Risk of bias was assessed with Cochrane RoB 2. Results Of 2798 unique records screened, three RCTs were included (n=451, mean age 13 years, follow-up 24 to 47 weeks). Each trial evaluated either evolocumab, alirocumab or inclisiran against placebo as add-on to baseline LLT. Participants had elevated LDL-C (>3.4 mmol/L [130 mg/dL]) despite stable LLT. Overall risk of bias was low. PCSK9i reduced LDL-C by an average of 35.44% (95% CI −41.74 to −29.14, I 2 =50.8%) and by 1.63 mmol/L [62.93 mg/dL] (95% CI −1.86 to −1.39, I 2 =18.6%) compared with placebo. There was no evidence of differences between PCSK9i and placebo in tolerability, growth and maturation, and overall incidence of adverse events. Conclusions PCSK9i add-on therapy leads to substantial reductions in LDL-C in paediatric patients with HeFH failing to achieve LDL-C targets with standard LLT. While the findings of this review support the use of PCSK9i in a subset of children and young people with HeFH, limited trial numbers and short follow-up periods underscore the need for future high-quality studies evaluating long-term safety, effectiveness and cost-effectiveness. Abstract Figure GRAPHICAL ABSTRACT PCSK9 inhibitors for children and adolescents with HeFH

Tighter price regulation would deliver fewer new drugs but improve global health. Tighter price regulation would deliver fewer new drugs but improve global health.

Background and aims Statins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons. Methods We conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage. Results Thirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I-2 = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI -11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo. Conclusions Statins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain.

Background Health systems experience difficult trade-offs when paying for new drugs. In England, funding recommendations by the National Institute for Health and Care Excellence (NICE) for new drugs might generate health gains, but inevitably result in forgone health as the funds cannot be used for alternative treatments and services. We aimed to evaluate the population-health impact of NICE recommendations for new drugs during 2000-20. Methods For this retrospective analysis, we identified technology appraisals for new drugs in England published in NICE's publicly available database of appraisals between 2000 and 2020. We excluded products with terminated appraisals, not recommended, or subsequently withdrawn from the market and excluded appraisals in programmes focusing on medical devices, diagnostics, or interventional procedures. We included drugs that underwent NICE appraisal within 5 years of initial regulatory approval. We collected data on drug name, appraised indication, and specific features of both the drug and its appraisal. We noted the value for money offered by new drugs, expressed as the incremental cost-effectiveness ratio (ICER), and data on health benefits, expressed as quality-adjusted life- years (QALYs). We estimated the number of patients receiving new drugs recommended by NICE using proprietary data on the total volumes of new drugs sold in England between Jan 1, 2000, and Dec 31, 2020. We calculated the net health effect of each appraisal using the difference between the incremental QALY gains from implementing the new drug within the National Health Service (NHS) and the estimated QALYs that could hypothetically be obtained by reallocating the same funds to other NHS services or treatments. We obtained forgone QALYs by dividing the incremental cost of the new drug by the health-opportunity cost of NHS expenditure. Findings NICE appraised 332 unique pharmaceuticals between 2000 and 2020; 276 (83%) had positive recommendations. Of these 276, 207 (75%) had a NICE appraisal within 5 years of regulatory approval. We included 183 (88%) of 207 drugs in this analysis, after excluding drugs that did not meet eligibility criteria. The median QALY gain across all 339 appraisals was 049 (IQR 015-113), equivalent to an additional half a year in full health. Median ICER for recommending new drugs increased from 21 pound 545 (IQR 14 175-26 173) per QALY gained for 14 appraisals published between 2000 and 2004 to 28 pound 555 (19 556-33 712) for 165 appraisals published between 2015 and 2020 (p=0014). Median ICER varied by therapeutic area, ranging from 6478 pound (3526-12 912) for 12 appraisals of anti- infective drugs to 30 pound 000 (22 395-45 870) for 144 appraisals of oncology drugs (p<00001). New drugs generated an estimated 375 million additional QALYs across 1982 million patients who received new drugs recommended by NICE. The use of new drugs resulted in an estimated additional cost to the NHS of 75 pound1 billion. If the resources allocated to new drugs had been spent on existing services in the NHS, an estimated 500 million additional QALYs could have been generated during 2000-20. Overall, the cumulative population-health impact of drugs recommended by NICE was negative, with a net loss of approximately 125 million QALYs. Interpretation During 2000-20, NHS coverage of new drugs displaced more population health than it generated. Our results highlight the inherent trade-offs between individuals who directly benefit from new drugs and those who forgo health due to the reallocation of resources towards new drugs. Funding The Commonwealth Fund. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Background Transitions from hospital to home are a risky time for older people (aged 75 years and older). Unplanned and often avoidable hospital re-admissions are therefore high in this group. This research aimed to understand if increased involvement of older people in their care in hospital would improve the safety and experience of care transitions. Objectives In six work packages we set out to: understand patient and carer involvement in and experience of care transitions explore staff experiences of delivering good transitional care develop and validate a new measure (the Partners at Care Transitions Measure) to assess patient experience and safety during care transitions create a theory and logic model to inform the co-designed transitions intervention followed by a formative evaluation test the feasibility of delivering a trial to evaluate the intervention evaluate the clinical- and cost-effectiveness of the transitions intervention with a parallel process evaluation. Design Qualitative methods (1 and 2), literature reviewing, Delphi techniques and validation testing (3), co-design (4), cluster feasibility trial (5) and cluster randomised controlled trial (6). Settings National Health Service acute hospital trusts, general practices, patients and carer homes across the north of England, United Kingdom. Participants Patients aged 75 years and older and their caregivers. National Health Service staff working in acute National Health Service trusts on wards delivering the intervention. Intervention ‘Your Care Needs You’ intervention to support patient and carer involvement in hospital care in preparation for returning home. This comprised fixed components: a booklet, an advice sheet for managing at home and a film; and flexible components: ongoing staff involvement of patients through multiple approaches. Implementation included a nominated lead, staff training and posters. Main outcome measures Primary outcome was unplanned 30-day hospital re-admissions. Secondary outcomes included: unplanned 60- and 90-day hospital re-admissions; quality of transition; health-related quality of life (EuroQol-5 Dimensions, five-level version); and self-reported healthcare resource use. Data sources National Health Service Secondary Use Services data and Hospital Episodes data for work package 2 and routinely recorded National Health Service acute trust hospital data on re-admissions for work packages 5 and 6. Review methods Systematic narrative review for preparatory work on patient involvement; narrative meta review of transitions interventions; scoping review of transitions measures. Results Work package 1: Six themes relating to patient experience of care transitions. Patient involvement in hospital care found to be challenging ‘work’ that was often invisible to staff. Work package 2: National Health Service staff reported that high-quality care transitions were facilitated primarily through trust and strong relationships. Work package 3: A measure of quality and safety of care transitions (Partners at Care Transitions Measure) developed and validated with good internal reliability and internal consistency. Work package 4: An intervention called ‘Your Care Needs You’ that required revisions to support implementation. Work package 5: Primary outcome data were collected for 90% of participants. Follow-up questionnaire response rates were lower than anticipated (75% vs. 85%). Information on the acceptability, usability and implementation of the intervention informed iterations to the intervention and implementation package. Work package 6: 4947 participants from 39 hospital wards took part in the main trial. Six hundred and thirteen participants from 35 wards took part in the nested cohort. No differences were observed in the primary outcome of unplanned re-admission (Y/N) at 30 days post discharge [17% experienced re-admission within 30 days in the ‘Your Care Needs You’ group, 18% in care-as-usual, odds ratio: (0.93; 95% confidence interval, 0.78 to 1.10; p = 0.372)], and also at 60 and 90 days post discharge but all results were in favour of the intervention with a reduction in total re-admissions of 13% over 90 days [incidence rate ratio: 0.87 (0.76 to 0.99), p = 0.039]. There was a statistically significant reduction in Partners at Care Transitions Measure safety concerns at 30 days post discharge. The intervention is likely to be cost-effective. Limitations The main trial was conducted during the COVID-19 pandemic which exacerbated staffing challenges and limited opportunities to enhance and support implementation of the intervention. Participant recruitment to the nested study was challenging, resulting in fewer patients than planned and a less diverse sample than that included in the primary cohort. Therefore, while our primary cohort is representative of the patients in the hospital during the trial period, the nested cohort may suffer from some bias. Conclusions The ‘Your Care Needs You’ intervention offers a way to support staff and patients/families to facilitate greater involvement in care. This research demonstrates that increased involvement in hospital care has the potential to improve safety at transitions. Finding ways to support staff to encourage better patient involvement could lead to even more benefits being realised. Future work Hospitals could consider involving volunteers in supporting greater patient and family involvement. There was some indication that the component of the intervention most favoured was the patient advice for discharge. Trial registration This trial is registered as Current Controlled Trials ISRCTN51154948 (WP5) and ISRCTN17062524 (WP6). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20017) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Moving from hospital to home (the ‘transition’) is a risky time for older patients (75+ years). Around 18% of patients end up back in hospital as an emergency. Most of the time, these re-admissions cannot be avoided, but oftentimes they can. In this research, we wanted to understand and improve the experience and safety of care for older people as they move from hospital to home to reduce unnecessary hospital re-admissions. To do this, we conducted six pieces of research (called work packages). First, we tried to understand from patients, families and staff how they experienced care transitions. Next, we developed a tool to measure these experiences. We then worked with staff and patients and members of the public to develop an approach (called ‘Your Care Needs You’), to help involve and prepare older people for going home after a hospital stay. ‘Your Care Needs You’ included a booklet, an advice sheet for managing at home, and a film, for patients. We then ran a trial to find out if people who received ‘Your Care Needs You’ were less likely to go back into hospital. For this, we put ‘Your Care Needs You’ into 18 wards and compared hospital re-admissions there with 21 wards which delivered care as usual. We found that the rate at which patients were re-admitted to hospital was better in the ‘Your Care Needs You’ wards but this was not significantly better. Three months after discharge, the number of people being re-admitted to the hospital was 13% less in the ‘Your Care Needs You’ wards. The approach also reduced the problems that people experienced (such as falls) around 1 month after discharge. We found that many of the wards did not deliver the approach as planned, so not all patients got ‘Your Care Needs You’. This was mainly because of staffing pressures after the COVID-19 pandemic. While some patients found the approach useful, others thought it was not for them. The approach is cheap to deliver and, on balance, is worth the cost. Scientific summary Background For older people and those with complex needs, the transition from hospital to home is risky. Approximately one in five patients experience an adverse event; two-thirds of which could be prevented or ameliorated. Rates of unplanned hospital re-admissions have increased over the last 10 years, particularly for older people. Systematic reviews of transition interventions reveal that most include multiple elements, with strategies prior to and following discharge and variable success. Knowing which of these elements represent the active ingredients is important for the management of scarce resources. There is some suggestion that interventions that seek to involve patients are most effective, but no definitive evidence. Here we address this gap in understanding. Aim To investigate whether greater involvement of patients and their families can improve patient experience and safety at transitions. Objectives Work package 1 To capture the experiences of older patients (75 years +) and their families during the transition from hospital to home. To identify opportunities for greater patient involvement in care. Work package 2 To explore how high-performing teams successfully deliver safe care to older people during transitions. Work package 3 To develop a measure of the quality-of-care transitions. Work package 4 To develop and test the acceptability of the transition intervention. Work package 5 To assess the feasibility of the ‘Your Care Needs You’ (YCNY) intervention and trial processes. Work package 6 To determine the clinical effectiveness of YCNY in a full cluster randomised controlled trial (cRCT). To determine the cost-effectiveness of YCNY compared to care as usual. Methods Work package 1: Qualitative study of patient and family experience of care transitions A longitudinal ethnographic study in two NHS Trusts exploring the involvement and experience of 32 community-dwelling older patients (75 years +) and 18 family members during their transitions from hospital to home. Semistructured interviews at up to five points from hospital admission to 3 months post discharge, supplemented with non-participant observations and go-along interviews. Data were analysed using thematic analysis. Work package 2: Qualitative study exploring how high-performing teams support care transitions A positive deviance approach to identify four wards and six general practices showing exceptionally low or reducing rates of hospital re-admissions compared to similar services. Semistructured interviews and focus groups with 157 multidisciplinary staff and observation of 9 discharge meetings. Interviews and focus groups were recorded and transcribed verbatim and data analysed using a pen-portrait approach. Work package 3: Development and testing of a care transitions measure Measure development and pilot testing A conceptual model of the transitional period developed based on findings from literature reviews and WP1 findings. A pool of items tapping into the constructs of this model was refined and simplified resulting in a two-part measure: Partners at Care Transitions Measure 1 (PACT-M1) and Partners at Care Transitions Measure 2 (PACT-M2). PACT-M1 underwent pilot testing with 15 older patients. Descriptive statistics and frequencies were calculated for each questionnaire item. Measure validation A validation study measuring internal reliability and internal consistency in the PACT-M1 and PACT-M2 within one NHS hospital trust. Eligible patients were administered the questionnaire by telephone and post. Reliability was assessed using Cronbach’s alpha and exploratory factor analysis used to evaluate dimensionality. Response rates and missing data were scrutinised and subscales refined. Work package 4: Development and refinement of a care transitions intervention Intervention development Functional resonance analysis method was used to model the transition process. This revealed the informal handover of four functional care activities to patients and families at discharge: management of medications; daily activities; health conditions; and escalation processes. The programme theory proposed that for patients to manage these activities they would need to practise them in hospital. A scoping review and stakeholder workshops supported the development of the Partners at Care Transitions (PACT) intervention. Formative evaluation and intervention refinement A formative evaluation to explore the acceptability and usability of the prototype intervention and identified implementation strategies. On 3 wards in 1 NHS trust, we recruited 25 older patients and interviewed 15 staff and 6 informal carers. Data collection using semistructured interviews and observations of intervention use. Analysis was iterative, using template analysis and group discussions leading to intervention refinement and the YCNY intervention. Work package 5: Trial feasibility study of Your Care Needs You A cRCT was conducted to test the feasibility of the YCNY intervention and trial methodology. Wards caring for older people were recruited and randomised on a 3 : 2 basis. The feasibility of accessing hospital re-admission data for our primary outcome together with other trial critical data capture was assessed. We also tested the process of data collection for our secondary outcomes, patient experience (measured by PACT-M) at 5, 30 and 90 days post discharge. We aimed to recruit 20 older patients per ward, over a 4- to 5-month period. The feasibility of conducting a full cost-effectiveness analysis was evaluated. Acceptability, usefulness and feasibility of the intervention and implementation package were assessed by observations and interviews. Work package 6: Cluster randomised controlled trial assessing the clinical effectiveness, cost-effectiveness and fidelity of Your Care Needs You with parallel process evaluation Clinical effectiveness trial data collection A cRCT of YCNY. Forty wards, covering a range of specialties and routinely caring for older people, from 11 NHS Trusts were randomly allocated equally to 1 of 2 arms: intervention or care-as-usual (control). Wards were stratified by specialty, the percentage of patients over 75 years, and NHS trust. Our primary outcome measure of 30-day unplanned hospital re-admission rates (routine data) required a sample size of 5440 based on a 10% attrition rate to detect a 4.5% difference in re-admissions with 80% power. We used a nested cohort to assess the quality of transitions (PACT-M and the validated Care Transition Measure-3) as secondary outcomes. Allowing for clustering and attrition, this required a sample size of 1000 for 80% power. Clinical effectiveness analysis Analysis for the primary outcome (30-day unplanned hospital re-admissions) included treatment allocation, ward type, baseline ward re-admission rate, percentage of patients 75 + and gender as fixed effects and trust and ward as random effects to account for clustering. Two sensitivity analyses were conducted as well as a secondary complier-average causal effect analysis to assess the impact of fidelity on outcomes. The same model specifications were used for the 60- and 90-day re-admission data. A mixed-effects linear regression approach was used to analyse patient experience measures [PACT-M and Coleman’s Transition Measure-3 (CTM-3)] data and similar sensitivity analysis to those for the primary outcome were applied. All other data were summarised descriptively. Fidelity data collection and analysis We used the modified Conceptual Framework for Implementation to underpin frame fidelity assessment. Data were gathered from all intervention wards using a 26-item measure covering intervention delivery, receipt, engagement with and usefulness. An overall score from 0 to 3 was calculated, with three representing high fidelity. Health economics analysis Short-term cost-effectiveness (during the first 90 days post discharge) was calculated from the mean costs of intervention delivery (intervention group) and service utilisation (both groups) and quality-adjusted life-years (QALYs) for each group generated within the trial. Long-term (over a lifetime) cost-effectiveness was calculated using a de novo hybrid model comprising a decision-tree model and a partitioned survival model. Process evaluation data collection and analysis A process evaluation on eight intervention wards (across four trusts) to understand how the intervention was delivered, received and used by staff and patients and how this was shaped by context. We interviewed 23 staff and 19 patients (pre and post discharge) and conducted 94 hours of ward observations. Interview data in the form of recordings and detailed notes were analysed using constant comparison to identify themes/subthemes. Results Work package 1: Qualitative study of patient and family involvement and experience of care transitions We identified six themes relating to: a disappointing discharge; delivery and receipt of community care; involvement (in care), choice and decision-making; information provision; physical and social environment; and medicines. While people mostly felt safe and cared for in hospital, many ‘handed over’ their care and so were unprepared for picking this back up when they returned home. Work package 2: Qualitative study exploring how teams support care transitions Three themes were identified that demonstrate how high-performing teams support safe care transitions: building relationships with patients based on a holistic understanding of their needs; having relationships with other staff (within and across teams) based on valuing and trusting one another; and bridging gaps in care by enhanced communication, adjusting patient expectations and adapting to competing priorities. Despite being identified as high-performing, staff in these teams described that delivering exceptionally safe care was very challenging and only possible for the most complex patients. Work package 3: Development and testing of a measure of care transitions Development and pilot testing Through modelling of transitions and item generation and refinement a measure comprising two parts: PACT-M1 administered to patients shortly after discharge with eight items measuring experiences of preparedness for managing at home and seven safety items measuring post-discharge adverse events; and the PACT-M2, administered 1 month post discharge with eight items measuring the patient experience of managing care at home and the same adverse event items. Participants reported that items were easy to understand and complete. Measure validation One hundred and eighty-five patients were recruited. Response rates were 75% (n = 138) at time point 1, 59% (n = 110) at time point 2 and 50% (n = 92) at time point 3. Reliability analyses of the PACT-M1 and PACT-M2 were good (α = 0.84 and 0.92, respectively). The factor analysis revealed a single-factor solution explaining 44% of the variance for PACT-M1 and 60% for PACT-M2. All items were retained. Work package 4: Development and refinement of a transitions intervention Intervention development Guided by stakeholder workshops with patients and staff we co-designed a prototype intervention to support management of the four key functions (see above): knowing more, moving more, managing medicines and escalation. A scoping review and activities to consolidate all available evidence-supported intervention development. Formative evaluation and intervention refinement Staff and patients saw the value in, and need for, the intervention, but several challenges with the acceptability and usability of the prototype were identified. Examples include the messages within the booklet not being strong enough and the lack of time to complete the discharge template (by staff). We identified implementation strategies and key changes to the intervention. Work package 5: Trial feasibility study of the Partners at Care Transitions intervention We randomised 10 wards (6 to intervention and 4 to control) across 3 NHS Trusts. Subsequently, due to extreme staff shortages, five wards could not participate but were retained and treated according to their randomised allocation. Of 721 patients screened, 161 were recruited (95 intervention, 66 control). Routine primary outcome data were gathered for 90% of participants. Item completion within questionnaires was high. The COVID-19 pandemic meant follow-up data collection ceased early. Patient attrition rate (17.4%; n = 28) was higher than expected (10%). Data on usability, acceptability and implementation were gathered from 10 patients and 17 staff alongside 91 ward-level observations. Staff reported the need for, and value of, the intervention and patients varied in their views about its value and manner in how they engaged with it. Full implementation of the intervention was challenging because of staff shortages, lack of information technology embedding/integration (film and discharge summary), lack of buy-in from the wider ward team and organisational impediments. We responded to these challenges by modifying the intervention and enhancing the implementation strategy. Work package 6: Cluster randomised controlled trial of the Partners at Care Transitions intervention A total of 4947 patients from 39 wards were included in the primary analysis cohort. For the nested cohort, 613 participants from 35 wards were recruited. Clinical effectiveness There was no significant difference in the primary outcome of unplanned 30-day re-admissions or 60 or 90 days (as odds ratios) between intervention and control. However, at all time points, the rate was lower in the intervention group. Total number of re-admissions was also lower in the intervention group at all time points and this reached statistical significance across 90 days post discharge with 13% fewer re-admissions. At 30 days post discharge, significant differences were observed in PACT-M adverse event items and in the CTM-3 in favour of the intervention but not at other times. Fidelity Twenty-three per cent of patients reported receiving booklets and 77% found them useful or very useful. Further, 29% of patients reported receiving the advice sheet for managing at home and 86% found them useful or very useful. Overall fidelity to the intervention was moderate for majority of wards (n = 11, 68.75%) and low for the remaining five (31.25%). Fidelity to the intervention had no impact on re-admissions at 30 days. Cost-effectiveness In the short term, differences in costs and QALYs were in favour of the intervention, suggesting that the intervention could be cost-effective. Similarly in the longer term (over a lifetime), the intervention is likely to be cost-effective. Process evaluation While the core values of the intervention appeared to be understood and valued by the staff, translating this into practice was oftentimes challenging and the patients interviewed felt they already had the knowledge in the booklet. Conclusion We developed a novel intervention called YCNY to support safety and experience for older people leaving hospital and going home. We also developed and validated (PACT-M) to measure patient experience and safety during care transitions. A randomised controlled trial of YCNY found some evidence of clinical benefit with the majority of results in favour of YCNY, although only secondary outcomes were statistically significant (total number of unplanned re-admissions after 3 months and the number of patient-reported adverse events after 30 days). YCNY is likely to be cost-effective in both the short term and long term. Staff valued YCNY intervention, but they struggled to fully implement it in the challenging post-COVID era. Implications for health care There is some promise for promoting safety at transitions from hospital to home through greater involvement of patients and their relatives in their care. To optimise the potential gains, staff need to engage differently with patients, and this was not always possible in the current depleted healthcare system. The intervention is freely available to all NHS hospitals. Recommendations for research Further research is needed to explore opportunities for developing and delivering an intervention to support patient involvement in care before hospital admission. Patients found the advice sheet for managing at home (a component of the YCNY intervention) to be the most useful. Further research is needed to develop a systems-integrated patient-friendly discharge summary. The methodology of fidelity assessments for complex healthcare interventions requires further development. Trial registration This trial is registered as Current Controlled Trials ISRCTN51154948 (WP5) and ISRCTN17062524 (WP6). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20017) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 4. See the NIHR Funding and Awards website for further award information.

Limited evidence on relative effectiveness is common in Health Technology Assessment (HTA), often due to sparse evidence on the population of interest or study-design constraints. When evidence directly relating to the policy decision is limited, the evidence base could be extended to incorporate indirectly related evidence. For instance, a sparse evidence base in children could borrow strength from evidence in adults to improve estimation and reduce uncertainty. In HTA, indirect evidence has typically been either disregarded (‘splitting’; no information-sharing) or included without considering any differences (‘lumping’; full information-sharing). However, sophisticated methods that impose moderate degrees of information-sharing have been proposed. We describe and implement multiple information-sharing methods in a case-study evaluating the effectiveness, cost-effectiveness and value of further research of intravenous immunoglobulin for severe sepsis and septic shock. We also provide metrics to determine the degree of information-sharing. Results indicate that method choice can have significant impact. Across information-sharing models, odds ratio estimates ranged between 0.55 and 0.90 and incremental cost-effectiveness ratios between £16,000–52,000 per quality-adjusted life year gained. The need for a future trial also differed by information-sharing model. Heterogeneity in the indirect evidence should also be carefully considered, as it may significantly impact estimates. We conclude that when indirect evidence is relevant to an assessment of effectiveness, the full range of information-sharing methods should be considered. The final selection should be based on a deliberative process that considers not only the plausibility of the methods’ assumptions but also the imposed degree of information-sharing.

Economic evaluation of antimicrobial resistance (AMR) interventions is complicated by the multisectoral, inter-temporal and international aspects of the problem, further hindered by a lack of available data and theoretical understanding of the emergence and transmission of AMR. Despite the substantial global focus on the problem, there is a lack of comprehensive economic evaluation literature on AMR policies. The goal of this work is to review the available literature on the economic evaluation of AMR interventions focusing on methods used to quantify the effects on AMR and the associated health consequences and costs. The studies included in the review were identified by a previous study by Painter et al. that included all full economic evaluations of AMR policies in the peer-reviewed and grey literature published between 2000 and 2020. The current review extracted additional information to (1) summarise the types and the key features of the AMR intervention economic evaluation literature available; (2) systemise the types of intervention effects on AMR quantified and describe these across the dimensions of AMR burden: time, space, wider pathogen pool and different sectors (One Health framework); and (3) categorise the methods used to derive these outcomes and how were these linked to health consequences and costs. Thirty-one studies were included within this review, of which 18 evaluated interventions that aimed to reduce infection rates and 11 evaluated interventions that aimed to optimise antimicrobial use. Almost all were conducted with a high-income and/or upper-middle income country perspective and focused on human health. Thirteen of 31 studies were cost-utility analyses. Fifteen of 31 and 7/31 studies estimated the AMR effects through decision tree and/or Markov models and transmission models, respectively. Transmission models and linkage of AMR outcomes to quality-adjusted life-years and costs were more common in evaluations of interventions aimed at reducing infection rates. Most of the included studies restricted the scope of evaluation to a short time horizon and a narrow geographical scope and did not consider the wider impact on other pathogens and other settings, potentially resulting in an incomplete capture of the effects of interventions. This review found limited available literature that mainly focused on high-income countries and infection prevention/reduction strategies. Most evaluations used a narrow study scope, which might have prevented the full capture of the costs and outcomes associated with interventions. Finally, despite the known complexities associated with quantifying AMR effects, and the corresponding methodological challenges, the implications of these choices were rarely discussed explicitly.

ObjectivesThe UK has recently established subscription-payment agreements for two antimicrobials: cefiderocol and ceftazidime-avibactam. This article summarises the novel value assessments that informed this process and lessons learned for future pricing and funding decisions.MethodsThe evaluations used decision modelling to predict population incremental net health effects (INHEs), informed by systematic reviews, evidence syntheses, national surveillance data and structured expert elicitation.ResultsSignificant challenges faced during the development of the evaluations led to profound uncertainty in the estimates of INHEs. The value assessment required definition of the population expected to receive the new antimicrobials; estimating value within this heterogenous population; assessing comparative efficacy using antimicrobial susceptibility data due to the absence of relevant clinical data; and predicting population-level benefits despite poor data on current numbers of drug-resistant infections and uncertainties around emerging resistance. Though both antimicrobials offer the potential to treat multi-drug resistant infections, the benefits estimated were modest due to the rarity of true pan-resistance, low life expectancy of the patient population and difficulty of identifying and quantifying additional sources of value.ConclusionsAssessing the population INHEs of new antimicrobials was complex and resource intensive. Future evaluations should continue to assemble evidence relating to areas of expected usage, patient numbers over time and comparative effectiveness and safety. Projections of patient numbers could be greatly enhanced by the development of national level linked clinical, prescribing and laboratory data. A practical approach to synthesising these data would be to combine expert assessments of key parameters with a simple generic decision model.

INTRODUCTION:Antimicrobial resistance (AMR) is a complex, inter-sectoral and international problem. Economic evaluation (EE) methods offer systematic, evidence-driven approaches to inform policy decisions about which AMR interventions to fund. EE of AMR interventions is complicated owing to diffuse effects, complex mechanics of the problem and high levels of uncertainty. Current AMR EE literature restricts the analytical scope, potentially resulting in omissions of effects that may limit the utility of EE to inform policy decisions. We aimed to systemise the key evolutionary and ecological processes of AMR to elucidate the paths through which AMR interventions impact population health and healthcare costs to support EE design and to support decision makers in understanding the limitations of EE evidence for decision-making. METHODS:A conceptual map and a corresponding tool were developed on the basis of a literature review in consultation with experts across the relevant disciplines of molecular biology, infectious disease modelling, health economics and ecology. RESULTS:The AMR development map: (1) distils the key AMR processes and process drivers behind AMR development and maps the available types of AMR interventions to AMR process drivers; (2) proposes a way to conceptualise the spatial scope of analysis through considering the connectivity of the wider ecosystem and (3) outlines the key dimensions that AMR burden and intervention effects could be measured across. An AMR development map tool was developed to support conceptual modelling, with the focus on the choice of scope in the EE of AMR interventions, and an illustrative case study was provided. DISCUSSION:This work summarises the key underlying biological principles of AMR development to provide mechanistical grounding for considering the scope of effects of AMR interventions and the appropriate system of analysis to support conceptual modelling in EE of AMR interventions. In addition, this map can facilitate the identification of effects that cannot be considered or quantified, thus enabling transparency about these omissions within decision-making.

Pricing should consider local value to ensure fair access and health system affordability

OBJECTIVES:This article aims to inform which pricing policies for new pharmaceuticals will benefit population health most, and which will not, by drawing out the implications of current pricing policy in Thailand for the value that new, branded pharmaceuticals bring to the population. METHODS:We quantify the lifecycle value in terms of net population health gains of 9 new, branded pharmaceutical and indication combinations by evaluating lifetime health gains and reimbursement costs, considering the availability of generics or biosimilars. We then analyze how the value is shared between the population and manufacturers. RESULTS:Two-thirds of the pharmaceutical and indication combinations generated net population health gains over their lifecycle, with more than 90% of the total potential net health effects benefiting patients within the Thai healthcare system. However, manufacturers received a low proportion of value. Key factors driving these outcomes included delayed adoption of new pharmaceuticals and entry of generics or biosimilars. Conversely, 2 pharmaceuticals that were approved despite being deemed cost-ineffective resulted in net losses to population health. CONCLUSIONS:Quantification of the lifecycle value of new pharmaceuticals can better inform policies that enhance population health. In Thailand, policies that could improve overall population health include earlier adoption of new pharmaceuticals alongside careful price regulation and expedited generic entry. These approaches could also provide mechanisms to signal research and development priorities effectively.

BACKGROUND:Hospital-to-home transitions are a critical component of effective healthcare delivery, especially for patients aged 75 and older. This study evaluates the cost-effectiveness of the 'Your Care Needs You' (YCNY) intervention, a patient-centred approach designed to empower older adults during discharge, compared to standard care. METHODS:The analysis adopts the perspective of the National Health Service (NHS) and Personal Social Services. Data were drawn from a cluster randomised controlled trial (cRCT) conducted within the UK NHS over a 90-day postdischarge follow-up period. Adjusted differences in costs and quality-adjusted life years (QALYs) were estimated using multilevel mixed-effects generalised linear models (MME-GLMs) to account for the hierarchical structure of the trial design. Alternatively, seemingly unrelated regression (SUR) models were employed to address potential correlations between costs and QALYs. Scenario analyses and probabilistic sensitivity analyses were conducted to assess the robustness of the results. RESULTS:The YCNY intervention reduced costs by £269 and achieved a QALY gain of 0.0057, resulting in a net health benefit (NHB) of 0.0246 QALYs at a £15,000/QALY threshold. It demonstrated an 89% probability of cost-effectiveness compared to standard care within the trial's time horizon. Findings remained robust across alternative scenarios and sensitivity analyses. CONCLUSION:The results suggest that YCNY is a potentially cost-effective strategy for improving hospital-to-home transitions for older adults. The study supports integrating patient-involved interventions like YCNY into routine NHS practice, with the potential to improve both efficiency and quality of healthcare delivery.