Cost of digital technologies and family-observed DOT for a shorter MDR-TB regimen: a modelling study in Ethiopia, India and Uganda.

BACKGROUND: In 2017, the WHO recommended the use of digital technologies, such as medication monitors and video observed treatment (VOT), for directly observed treatment (DOT) of drug-susceptible TB. The WHO's 2020 guidelines extended these recommendations to multidrug-resistant tuberculosis (MDR-TB), based on low evidence. The impact of COVID on health systems and patients underscored the need to use digital technologies in the management of MDR-TB. METHODS: A decision-tree model was developed to explore the costs of several potential DOT alternatives: VOT, 99DOTS (Directly-observed Treatment, Short-course) and family-observed DOT. Assuming a 9-month, all-oral regimen (as evaluated within the STREAM trial), we constructed base-case cost models for the standard-of-care DOTs in Ethiopia, India, and Uganda, as well as for the three alternative DOT approaches. The models were populated with STREAM Stage 2 clinical trial outcome and cost data, supplemented with market prices data for the digital DOT strategies. Sensitivity analyses were conducted on key parameters. RESULTS: Modelling suggested that the standard-of-care DOT approach is the most expensive DOT strategy from a societal perspective in all three countries evaluated (Ethiopia, India, Uganda), with considerable direct- and indirect-costs incurred by patients. The second most expensive DOT approach is VOT, with high health-system costs, largely caused by up-front technology expenditure. Each of VOT, 99DOTS and family-observed DOT would reduce by more than 90% patients' direct and indirect costs compared to standard of care DOT. Results were robust to the sensitivity analyses. CONCLUSIONS: While data on the costs and efficacy of alternative DOT approaches in the context of shorter MDR-TB treatment is limited, our modelling suggests alternative DOT approaches can significantly reduce patient costs in all three countries. Health system costs are higher for VOT and lower for 99DOTS and family-observed therapy when compared to standard of care DOT, as low smartphone penetration and internet availability requires the VOT health system to fund the cost of making them available to patients.

Competing treatments for migraine: a headache for decision-makers.

BACKGROUND: Migraine is the world's second most common disabling disorder, affecting 15% of UK adults and costing the UK over £1.5 billion per year. Several costly new drugs have been approved by National Institute for Health and Care Excellence. AIM: To assess the cost-effectiveness of drugs used to treat adults with chronic migraine. METHODS: We did a systematic review of placebo-controlled trials of preventive drugs for chronic migraine. We then assessed the cost-effectiveness of the currently prescribable drugs included in the review: Onabotulinum toxin A (BTA), Eptinezumab (100mg or 300mg), Fremanezumab (monthly or quarterly dose), Galcanezumab or Topiramate, each compared to placebo, and we evaluated them jointly. We developed a Markov (state-transition) model with a three-month cycle length to estimate the costs and quality-adjusted life years (QALYs) for the different medications from a UK NHS and Personal Social Services perspective. We used a two-year time horizon with a starting age of 30 years for the patient cohort. We estimated transition probabilities based on monthly headache days using a network meta-analysis (NMA) developed by us, and from published literature. We obtained costs from published sources and applied discount rates of 3.5% to both costs and outcomes. RESULTS: Deterministic results suggest Topiramate was the least costly option and generated slightly more QALYs than the placebo, whereas Eptinezumab 300mg was the more costly option and generated the most QALYs. After excluding dominated options, the incremental cost-effectiveness ratio (ICER) between BTA and Topiramate was £68,000 per QALY gained and the ICER between Eptinezumab 300mg and BTA was not within plausible cost-effectiveness thresholds. The cost-effectiveness acceptability frontier showed that Topiramate is the most cost-effective medication for any amount the decision maker is willing-to-pay per QALY. CONCLUSIONS: Among the various prophylactic medications for managing chronic migraine, only Topiramate was within typical cost-effectiveness threshold ranges. Further research is needed, ideally an economic evaluation alongside a randomised trial, to compare these newer, expensive CGRP MAbs with the cheaper oral medications.

Clinical effectiveness of pharmacological interventions for managing chronic migraine in adults: a systematic review and network meta-analysis.

BACKGROUND: Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication is the most effective. We present a network meta-analysis to determine the effectiveness and rank of preventive drugs for chronic migraine in adults. METHODS: We identified, reviewed, and extracted data from randomised controlled trials (RCTs) of preventive drugs for chronic migraine with at least 200 participants. Data were analysed using network meta-analysis. FINDINGS: We included 12 RCTs of six medications (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Onabotulinumtoxin A, and Topiramate) compared to placebo or each other. All drugs effectively reduced monthly headache and migraine days compared with placebo. The most effective drug for monthly headache days was Eptinezumab 300mg, with a mean difference of -2.46 days, 95% Credible Interval (CrI): -3.23 to -1.69. On the Surface Under the Cumulative Ranking Area (SUCRA) analysis, the probability that Eptinezumab 300mg was ranked highest was 0.82. For monthly migraine days, the most effective medication was Fremanezumab-monthly, with a mean difference: -2.77 days, 95% CrI: -3.36 to -2.17, and 0.98 probability of being ranked the highest. All included drugs, except Topiramate, improved headache-related quality of life. No eligible studies were identified for the other common preventive oral medications such as Amitriptyline, Candesartan, and Propranolol. The main reasons were that the studies did not define chronic migraine, were undertaken before the definition of chronic migraine, or were too small. INTERPRETATION: All six medications were more effective than the placebo on monthly headache and migraine days. The absolute differences in the number of headache/migraine days are, at best, modest. No evidence was found to determine the relative effectiveness of the six included drugs with other oral preventive medications. REGISTRATION: PROSPERO (number CRD42021265990).

The use of composite time trade-off and discrete choice experiment methods for the valuation of the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS): a think-aloud study.

PURPOSE: To identify patterns and problems in completing composite time trade-off (C-TTO) and discrete choice experiment (DCE) exercises for the valuation of the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) to inform the optimisation of a valuation protocol. METHODS: Fourteen cognitive interviews were conducted in the UK using concurrent and retrospective think-aloud and probing techniques. Each participant completed 8 C-TTO tasks and 8 DCE tasks within a computer-assisted personal interview setting. Verbal information was transcribed verbatim. Axial coding and thematic analysis were used to organise the qualitative data and identify patterns and problems with the completion of tasks. RESULTS: While participants found the tasks generally manageable, five broad themes emerged to explain and optimise the response to the tasks. (1) Format and structure: attention to the design of practice examples, instructions, and layout were needed. (2) Items and levels: underlying relationships were discovered across different combinations of levels of SWEMWBS items. (3) Decision heuristics: participants engaged in diverse strategies to assist trade-off decisions. (4) Valuation feasibility: certain states were difficult to imagine, compare and quantify. (5) Valuation outcome: the data quality was affected by participants' discriminatory ability across states and their time trade-off decisions. CONCLUSION: The interviews contributed insights regarding the robustness of the proposed methods. The application of C-TTO and DCE valuation techniques was practical and suitable for capturing individual attitudes towards different mental well-being scenarios. A modified protocol informed by the results is being tested in a larger sample across the UK.

Key informants' perspectives on policy- and service-level challenges and opportunities for delivering adolescent and youth-friendly health services in public health facilities in a Nigerian setting.

BACKGROUND: Integrating the care of adolescents and young people into existing public health facilities requires deliberate efforts to address challenges related to policy and service provision. This study assessed key informants' perspectives on policy- and service-level challenges, and opportunities, for implementing a strategic framework for adolescent and youth-friendly health services (AYFHS) in public health facilities in a Nigerian setting. METHODS: Seventeen key informants were interviewed including members of the Adolescent sexual and reproductive health (ASRH) Technical Working Group (TWG), program managers of non-governmental organizations (NGO), State and local level health officials, and youth representatives, in Ogun State, Southwest Nigeria. RESULT: Findings from this study indicate that some health workers continue to have a negative attitude toward young people's sexual and reproductive health. There was some level of inclusion of adolescents and young people living with disabilities in ASRH programming which is welcome and extremely important. Some of the challenges in ASRH service provision included insufficient coordination of activities of donors/partners working in the adolescent health space. Also found was the missed opportunity to strengthen policy implementation with research, and the need for increased focus on mental health, substance use, and other aspects of adolescent and young people's health. There was noted the opportunity to explore the Basic Health Care Provisions Funds (BHCPF) as a new source of funding for health services for AYP in Nigeria. CONCLUSION: This study provided the context of the implementation of a strategic framework for adolescent reproductive health in a Nigerian setting from the perspectives of policy and service-level stakeholders. Opportunities for improving program delivery identified include ensuring research-based policy implementation and seeking program sustainability through tapping into new sources of funding.

Attributes development for a discrete choice experiment on preferences in sexual and reproductive health services for adolescents and young people in Nigeria.

BACKGROUND: A major component of the validity of the discrete choice experiment (DCE) research design lies in the correct specification of attributes and levels relevant to the research focus. In this paper, we set out the validation steps we took in designing the tool for a DCE on preferences in sexual and reproductive health (SRH) services for adolescents and young people. METHODOLOGY: This study was carried out among adolescents and young people (AYP) in Ogun State, Southwest Nigeria. We used a three-step mixed-methods process in developing the attributes and attribute-levels for our DCE tool. The first was to conduct a series of 16 focus group discussions (FGD) with AYP ensuring maximal variation (by age group, sex, marital status, and location). The FGD included a priority listing process in which participants were asked to list and rank the most important characteristics of optimal SRH services for AYP. The lists were harmonized and items were scored. The main (highest scoring) themes emerging from the harmonized priority list were converted into an initial set of attributes and the subthemes as level. These initial attributes and levels were presented to a panel of methods and content experts in a virtual modified Delphi process. This was for deciding on the importance of the attributes in providing optimum sexual and reproductive health services for young people, and the appropriateness of the levels. The same set of attributes was presented to another set of AYP in a series of four FGD to clarify meanings, and test whether the wordings were well understood. We applied some decision rules for including and excluding attributes and levels in the different phases of the development process. RESULTS: We extracted an initial set of nine attributes with 2-4 levels each from the first FGD sessions. These were revised to a final set of seven attributes with 2-4 levels each based on findings from the expert review and final validation FGDs with AYP. The final attributes were: the type of staff, physical environment, health worker attitude, cost, waiting time, contraceptive availability, and opening hours. CONCLUSION: The final set of attributes covered those relating to the services provided, the health workers providing the services, and the AYP. Our three-step process which included both quantitative and qualitative approaches ensured a rigorous process that produced a reliable combination of attributes and levels. Although we had to trade off some competing attributes to come to a final list, our decision rules helped us to conduct a transparent and reproducible process.

The long term effect of pulmonary tuberculosis on income and employment in a low income, urban setting.

BACKGROUND: Mitigating the socioeconomic impact of tuberculosis (TB) is key to the WHO End TB Strategy. However, little known about socioeconomic well-being beyond TB-treatment completion. In this mixed-methods study, we describe socioeconomic outcomes after TB-disease in urban Blantyre, Malawi, and explore pathways and barriers to financial recovery. METHODS: Adults ≥15 years successfully completing treatment for a first episode of pulmonary TB under the National TB Control Programme were prospectively followed up for 12 months. Socioeconomic, income, occupation, health seeking and cost data were collected. Determinants and impacts of ongoing financial hardship were explored through illness narrative interviews with purposively selected participants. RESULTS: 405 participants were recruited from February 2016 to April 2017. Median age was 35 years (IQR: 28-41), 67.9% (275/405) were male, and 60.6% (244/405) were HIV-positive. Employment and incomes were lowest at TB-treatment completion, with limited recovery in the following year: fewer people were in paid work (63.0% (232/368) vs 72.4% (293/405), p=0.006), median incomes were lower (US$44.13 (IQR: US$0-US$106.15) vs US$72.20 (IQR: US$26.71-US$173.29), p<0.001), and more patients were living in poverty (earning

Psychiatric hospital reform in low- and middle-income countries: a systematic review of literature.

PURPOSE: Psychiatric hospitals or mental asylums grew across the world in the colonial era. Despite concerns over quality of care and human rights violations, these hospitals continue to provide the majority of mental health care in most low- and middle-income countries (LMICs). We sought to review the evidence of reform of mental hospitals and associated patient outcomes. METHODS: We adopted an integrative review methodology by including experimental and non-experimental research. The review protocol was registered on PROSPERO (CRD42019130399). A range of databases and systematic hand searches were conducted by two independent reviewers. Research conducted between 1980 and May 2019, that focused on any aspect of reform in mental hospitals for adults (age 18 and upwards) with severe mental illness and published in English, were considered. RESULTS: 16 studies were included in the review. 12 studies met inclusion criteria, and four additional reports emerged from the hand search. Studies covered-India, China, South Africa, Grenada, Georgia, Sri Lanka, Argentina and Brazil. Key findings emphasise the role of judicial intervention as a critical trigger of reform. Structural reform composed of optimisation of resources and renovations of colonial structures to cater to diverse patient needs. Process reforms include changes in medical management, admission processes and a move from closed to open wards. Staff engagement and capacity building have also been used as a modality of reform in mental hospital settings. CONCLUSION: There is some documentation of reform in psychiatric hospitals. However, poor methodological quality and variation in approach and outcomes measured, make it challenging to extrapolate specific findings on process or outcomes of reform. Despite being integral service providers, psychiatric hospitals still do not adopt patient centric, recovery-oriented processes. Hence, there is an urgent need to generate robust evidence on psychiatric reform and its effect on patient outcomes.

Delivery of long-term-injectable agents for TB by lay carers: pragmatic randomised trial.

BACKGROUND: People with recurrent or drug-resistant TB require long courses of intramuscular injections. We evaluate a novel system in which patient-nominated lay carers were trained to deliver intramuscular injections to patients in their own homes. METHODS: A pragmatic, individually randomised non-inferiority trial was conducted at two hospitals in Malawi. Adults starting TB retreatment were recruited. Patients randomised to the intervention received home-based care from patient-nominated lay people trained to deliver intramuscular streptomycin. Patients receiving standard care were admitted to hospital for 2 months of streptomycin. The primary outcome was successful treatment (alive and on treatment) at the end of the intervention. RESULTS: Of 456 patients screened, 204 participants were randomised. The trial was terminated early due to futility. At the end of the intervention, 97/101 (96.0%) in the hospital arm were still alive and on treatment compared with 96/103 (93.2%) in the home-based arm (risk difference -0.03 (95% CI -0.09 to 0.03); p value 0.538). There were no differences in the proportion completing 8 months of anti-TB treatment; or the proportion experiencing 2-month sputum culture conversion. The mean cost of hospital-based management was US$1546.3 per person, compared to US$729.2 for home-based management. Home-based care reduced risk of catastrophic household costs by 84%. CONCLUSIONS: Although this trial failed to meet target recruitment, the available data demonstrate that training patient-nominated lay people has potential to provide a feasible solution to the operational challenges associated with delivering long-term-injectable drugs to people with recurrent or drug-resistant TB in resource-limited settings, and substantially reduce costs. Further data under operational conditions are required. TRIAL REGISTRATION NUMBER: ISRCTN05815615.

Economic evaluation of short treatment for multidrug-resistant tuberculosis, Ethiopia and South Africa: the STREAM trial.

OBJECTIVE: To investigate cost changes for health systems and participants, resulting from switching to short treatment regimens for multidrug-resistant (MDR) tuberculosis. METHODS: We compared the costs to health systems and participants of long (20 to 22 months) and short (9 to 11 months) MDR tuberculosis regimens in Ethiopia and South Africa. Cost data were collected from participants in the STREAM phase-III randomized controlled trial and we estimated health-system costs using bottom-up and top-down approaches. A cost-effectiveness analysis was performed by calculating the incremental cost per unfavourable outcome avoided. FINDINGS: Health-care costs per participant in South Africa were 8340.7 United States dollars (US$) with the long and US$ 6618.0 with the short regimen; in Ethiopia, they were US$ 6096.6 and US$ 4552.3, respectively. The largest component of the saving was medication costs in South Africa (67%; US$ 1157.0 of total US$ 1722.8) and social support costs in Ethiopia (35%, US$ 545.2 of total US$ 1544.3). In Ethiopia, trial participants on the short regimen reported lower expenditure for supplementary food (mean reduction per participant: US$ 225.5) and increased working hours (i.e. 667 additional hours over 132 weeks). The probability that the short regimen was cost-effective was greater than 95% when the value placed on avoiding an unfavourable outcome was less than US$ 19 000 in Ethiopia and less than US$ 14 500 in South Africa. CONCLUSION: The short MDR tuberculosis treatment regimen was associated with a substantial reduction in health-system costs and a lower financial burden for participants.

Cost-effectiveness of adrenaline for out-of-hospital cardiac arrest.

BACKGROUND: The 'Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration In Cardiac Arrest' (PARAMEDIC2) trial showed that adrenaline improves overall survival, but not neurological outcomes. We sought to determine the within-trial and lifetime health and social care costs and benefits associated with adrenaline, including secondary benefits from organ donation. METHODS: We estimated the costs, benefits (quality-adjusted life years (QALYs)) and incremental cost-effectiveness ratios (ICERs) associated with adrenaline during the 6-month trial follow-up. Model-based analyses explored how results altered when the time horizon was extended beyond 6 months and the scope extended to include recipients of donated organs. RESULTS: The within-trial (6 months) and lifetime horizon economic evaluations focussed on the trial population produced ICERs of £1,693,003 (€1,946,953) and £81,070 (€93,231) per QALY gained in 2017 prices, respectively, reflecting significantly higher mean costs and only marginally higher mean QALYs in the adrenaline group. The probability that adrenaline is cost-effective was less than 1% across a range of cost-effectiveness thresholds. Combined direct economic effects over the lifetimes of survivors and indirect economic effects in organ recipients produced an ICER of £16,086 (€18,499) per QALY gained for adrenaline with the probability that adrenaline is cost-effective increasing to 90% at a £30,000 (€34,500) per QALY cost-effectiveness threshold. CONCLUSIONS: Adrenaline was not cost-effective when only directly related costs and consequences are considered. However, incorporating the indirect economic effects associated with transplanted organs substantially alters cost-effectiveness, suggesting decision-makers should consider the complexity of direct and indirect economic impacts of adrenaline. TRIAL REGISTRATION: ISRCTN73485024 . Registered on 13 March 2014.

Effect of Incisional Negative Pressure Wound Therapy vs Standard Wound Dressing on Deep Surgical Site Infection After Surgery for Lower Limb Fractures Associated With Major Trauma: The WHIST Randomized Clinical Trial.

Importance: Following surgery to treat major trauma-related fractures, deep wound infection rates are high. It is not known if negative pressure wound therapy can reduce infection rates in this setting. Objective: To assess outcomes in patients who have incisions resulting from surgery for lower limb fractures related to major trauma and were treated with either incisional negative pressure wound therapy or standard wound dressing. Design, Setting, and Participants: A randomized clinical trial conducted at 24 trauma hospitals representing the UK Major Trauma Network that included 1548 patients aged 16 years or older who underwent surgery for a lower limb fracture caused by major trauma from July 7, 2016, through April 17, 2018, with follow-up to December 11, 2018. Interventions: Incisional negative pressure wound therapy (n = 785), which involved a specialized dressing used to create negative pressure over the wound, vs standard wound dressing not involving negative pressure (n = 763). Main Outcomes and Measures: The primary outcome measure was deep surgical site infection at 30 days diagnosed according to the criteria from the US Centers for Disease Control and Prevention. A preplanned secondary analysis of the primary outcome was performed at 90 days. The secondary outcomes were patient-reported disability (Disability Rating Index), health-related quality of life (EuroQol 5-level EQ-5D), surgical scar assessment (Patient and Observer Scar Assessment Scale), and chronic pain (Douleur Neuropathique Questionnaire) at 3 and 6 months, as well as other local wound healing complications at 30 days. Results: Among 1548 participants who were randomized (mean [SD] age, 49.8 [20.3] years; 561 [36%] were aged ≤40 years; 583 [38%] women; and 881 [57%] had multiple injuries), 1519 (98%) had data available for the primary outcome. At 30 days, deep surgical site infection occurred in 5.84% (45 of 770 patients) of the incisional negative pressure wound therapy group and in 6.68% (50 of 749 patients) of the standard wound dressing group (odds ratio, 0.87 [95% CI, 0.57 to 1.33]; absolute risk difference, -0.77% [95% CI, -3.19% to 1.66%]; P = .52). There was no significant difference in the deep surgical site infection rate at 90 days (11.4% [72 of 629 patients] in the incisional negative pressure wound therapy group vs 13.2% [78 of 590 patients] in the standard wound dressing group; odds ratio, 0.84 [95% CI, 0.59 to 1.19]; absolute risk difference, -1.76% [95% CI, -5.41% to 1.90%]; P = .32). For the 5 prespecified secondary outcomes reported, there were no significant differences at any time point. Conclusions and Relevance: Among patients who underwent surgery for major trauma-related lower limb fractures, use of incisional negative pressure wound therapy, compared with standard wound dressing, resulted in no significant difference in the rate of deep surgical site infection. The findings do not support the use of incisional negative pressure wound therapy in this setting, although the event rate at 30 days was lower than expected. Trial Registration: isrctn.org Identifier: ISRCTN12702354.

Patterns, trends and methodological associations in the measurement and valuation of childhood health utilities.

PURPOSE: To systematically assess patterns and temporal changes in the measurement and valuation of childhood health utilities and associations between methodological factors. METHODS: Studies reporting childhood health utilities using direct or indirect valuation methods, published by June 2017, were identified through PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL, Cochrane Library and PEDE. The following were explored: patterns in tariff application; linear trends in numbers of studies/samples and paediatric cost-utility analyses (CUAs) and associations between them; changes in proportions of studies/samples within characteristic-based categories over pre-specified periods; impact of National Institute for Health and Care Excellence (NICE) guidance on primary UK research and associations between valuation method, age and methodological factors. RESULTS: 335 studies with 3974 samples covering all ICD-10 chapters, 23 valuation methods, 12 respondent types and 42 countries were identified by systematic review. 34.0% of samples using indirect methods compatible with childhood applied childhood-derived tariffs. There was no association between numbers of studies/samples and numbers of CUAs. Compared to 1990-2008, 2009-June 2017 saw a significant fall in the proportion of studies using case series; significant compositional changes across ICD-10 chapters and significantly higher sample proportions using childhood-specific and adult-specific indirect valuation methods, and based on pre-adolescents, self-assessment, self-administration and experienced health states. NICE guidance was weakly effective in promoting reference methods. Associations between valuation method, age and methodological factors were significant. CONCLUSION: 1990-2017 witnessed significant changes in primary research on childhood health utilities. Health technology assessment agencies should note the equivocal effect of methodological guidance on primary research.

Adult mental health provision in England: a national survey of acute day units.

BACKGROUND: Acute Day Units (ADUs) exist in some English NHS Trusts as an alternative to psychiatric inpatient admission. However, there is a lack of information about the number, configuration, and functioning of such units, and about the extent to which additional units might reduce admissions. This cross-sectional survey and cluster analysis of ADUs aimed to identify, categorise, and describe Acute Day Units (ADUs) in England. METHODS: English NHS Mental Health Trusts with ADUs were identified in a mapping exercise, and a questionnaire was distributed to ADU managers. Cluster analysis was used to identify distinct models of service, and descriptive statistics are given to summarise the results of the survey questions. RESULTS: Two types of service were identified by the cluster analysis: NHS (n = 27; and voluntary sector services (n = 18). Under a third of NHS Trusts have access to ADUs. NHS services typically have multi-disciplinary staff teams, operate during office hours, offer a range of interventions (medication, physical checks, psychological interventions, group sessions, peer support), and had a median treatment period of 30 days. Voluntary sector services had mostly non-clinically qualified staff, and typically offered supportive listening on a one-off, drop-in basis. Nearly all services aim to prevent or reduce inpatient admissions. Voluntary sector services had more involvement by service users and carers in management and running of the service than NHS services. CONCLUSIONS: The majority of NHS Trusts do not provide ADUs, despite their potential to reduce inpatient admissions. Further research of ADUs is required to establish their effectiveness and acceptability to service users, carers, and staff.

A realist approach to the evaluation of complex mental health interventions.

Conventional approaches to evidence that prioritise randomised controlled trials appear increasingly inadequate for the evaluation of complex mental health interventions. By focusing on causal mechanisms and understanding the complex interactions between interventions, patients and contexts, realist approaches offer a productive alternative. Although the approaches might be combined, substantial barriers remain.Declaration of interestAll authors had financial support from the National Institute for Health Research Health Services and Delivery Research Programme while completing this work. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the National Health Service, the National Institute for Health Research, the Medical Research Council, Central Commissioning Facility, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre, the Health Services and Delivery Research Programme or the Department of Health. S.P.S. is part funded by Collaboration for Leadership in Applied Health Research and Care West Midlands. K.B. is editor of the British Journal of Psychiatry.

Value of information methods to design a clinical trial in a small population to optimise a health economic utility function.

BACKGROUND: Most confirmatory randomised controlled clinical trials (RCTs) are designed with specified power, usually 80% or 90%, for a hypothesis test conducted at a given significance level, usually 2.5% for a one-sided test. Approval of the experimental treatment by regulatory agencies is then based on the result of such a significance test with other information to balance the risk of adverse events against the benefit of the treatment to future patients. In the setting of a rare disease, recruiting sufficient patients to achieve conventional error rates for clinically reasonable effect sizes may be infeasible, suggesting that the decision-making process should reflect the size of the target population. METHODS: We considered the use of a decision-theoretic value of information (VOI) method to obtain the optimal sample size and significance level for confirmatory RCTs in a range of settings. We assume the decision maker represents society. For simplicity we assume the primary endpoint to be normally distributed with unknown mean following some normal prior distribution representing information on the anticipated effectiveness of the therapy available before the trial. The method is illustrated by an application in an RCT in haemophilia A. We explicitly specify the utility in terms of improvement in primary outcome and compare this with the costs of treating patients, both financial and in terms of potential harm, during the trial and in the future. RESULTS: The optimal sample size for the clinical trial decreases as the size of the population decreases. For non-zero cost of treating future patients, either monetary or in terms of potential harmful effects, stronger evidence is required for approval as the population size increases, though this is not the case if the costs of treating future patients are ignored. CONCLUSIONS: Decision-theoretic VOI methods offer a flexible approach with both type I error rate and power (or equivalently trial sample size) depending on the size of the future population for whom the treatment under investigation is intended. This might be particularly suitable for small populations when there is considerable information about the patient population.

Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages.

BACKGROUND: We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-ß) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages. METHODS: We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-ß and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. RESULTS: We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. CONCLUSIONS: Meta-analyses confirmed that IFN-ß and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. REVIEW REGISTRATION: PROSPERO CRD42016043278 .

Approaches to sample size calculation for clinical trials in rare diseases.

We discuss 3 alternative approaches to sample size calculation: traditional sample size calculation based on power to show a statistically significant effect, sample size calculation based on assurance, and sample size based on a decision-theoretic approach. These approaches are compared head-to-head for clinical trial situations in rare diseases. Specifically, we consider 3 case studies of rare diseases (Lyell disease, adult-onset Still disease, and cystic fibrosis) with the aim to plan the sample size for an upcoming clinical trial. We outline in detail the reasonable choice of parameters for these approaches for each of the 3 case studies and calculate sample sizes. We stress that the influence of the input parameters needs to be investigated in all approaches and recommend investigating different sample size approaches before deciding finally on the trial size. Highly influencing for the sample size are choice of treatment effect parameter in all approaches and the parameter for the additional cost of the new treatment in the decision-theoretic approach. These should therefore be discussed extensively.

Timely Digital Patient-Clinician Communication in Specialist Clinical Services for Young People: A Mixed-Methods Study (The LYNC Study).

BACKGROUND: Young people (aged 16-24 years) with long-term health conditions can disengage from health services, resulting in poor health outcomes, but clinicians in the UK National Health Service (NHS) are using digital communication to try to improve engagement. Evidence of effectiveness of this digital communication is equivocal. There are gaps in evidence as to how it might work, its cost, and ethical and safety issues. OBJECTIVE: Our objective was to understand how the use of digital communication between young people with long-term conditions and their NHS specialist clinicians changes engagement of the young people with their health care; and to identify costs and necessary safeguards. METHODS: We conducted mixed-methods case studies of 20 NHS specialist clinical teams from across England and Wales and their practice providing care for 13 different long-term physical or mental health conditions. We observed 79 clinical team members and interviewed 165 young people aged 16-24 years with a long-term health condition recruited via case study clinical teams, 173 clinical team members, and 16 information governance specialists from study NHS Trusts. We conducted a thematic analysis of how digital communication works, and analyzed ethics, safety and governance, and annual direct costs. RESULTS: Young people and their clinical teams variously used mobile phone calls, text messages, email, and voice over Internet protocol. Length of clinician use of digital communication varied from 1 to 13 years in 17 case studies, and was being considered in 3. Digital communication enables timely access for young people to the right clinician at the time when it can make a difference to how they manage their health condition. This is valued as an addition to traditional clinic appointments and can engage those otherwise disengaged, particularly at times of change for young people. It can enhance patient autonomy, empowerment and activation. It challenges the nature and boundaries of therapeutic relationships but can improve trust. The clinical teams studied had not themselves formally evaluated the impact of their intervention. Staff time is the main cost driver, but offsetting savings are likely elsewhere in the health service. Risks include increased dependence on clinicians, inadvertent disclosure of confidential information, and communication failures, which are mostly mitigated by young people and clinicians using common-sense approaches. CONCLUSIONS: As NHS policy prompts more widespread use of digital communication to improve the health care experience, our findings suggest that benefit is most likely, and harms are mitigated, when digital communication is used with patients who already have a relationship of trust with the clinical team, and where there is identifiable need for patients to have flexible access, such as when transitioning between services, treatments, or lived context. Clinical teams need a proactive approach to ethics, governance, and patient safety.

Determination of the optimal sample size for a clinical trial accounting for the population size.

The problem of choosing a sample size for a clinical trial is a very common one. In some settings, such as rare diseases or other small populations, the large sample sizes usually associated with the standard frequentist approach may be infeasible, suggesting that the sample size chosen should reflect the size of the population under consideration. Incorporation of the population size is possible in a decision-theoretic approach either explicitly by assuming that the population size is fixed and known, or implicitly through geometric discounting of the gain from future patients reflecting the expected population size. This paper develops such approaches. Building on previous work, an asymptotic expression is derived for the sample size for single and two-arm clinical trials in the general case of a clinical trial with a primary endpoint with a distribution of one parameter exponential family form that optimizes a utility function that quantifies the cost and gain per patient as a continuous function of this parameter. It is shown that as the size of the population, N, or expected size, N∗ in the case of geometric discounting, becomes large, the optimal trial size is O(N1/2) or O(N∗1/2). The sample size obtained from the asymptotic expression is also compared with the exact optimal sample size in examples with responses with Bernoulli and Poisson distributions, showing that the asymptotic approximations can also be reasonable in relatively small sample sizes.