Evidence Following Conditional NICE Technology Appraisal Recommendations: A Critical Analysis of Methods, Quality and Risk of Bias.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) may approve health technologies on condition of more evidence generated only in research (OiR) or only with research (OwR). NICE specifies the information needed to comply with its request, although it may not necessarily guarantee good quality and timely evidence for re-appraisal, before reaching a final decision. AIM: This study aimed to critically appraise the methods, quality and risk of bias of evidence generated in response to NICE OiR and OwR technology appraisal (TA) and highly specialised technologies (HSTs) recommendations. METHODS: NICE TAs (between March 2000 and September 2020) and HST evaluations (to October 2023) of medicines were reviewed. Conditional recommendations were analysed to identify the evidence requested by NICE for re-appraisal. The new evidence was analysed for compliance with NICE's request and assessed using the Cochrane Collaboration's tools for risk of bias in randomised trials and the ROBINS-I tool for non-randomised evidence. RESULTS: NICE made 54 conditional recommendations from TAs (13 OiR and 41 OwR) and five conditional recommendations for HSTs (all OwR). Of these, 16 TAs presented additional evidence for re-appraisal (9 OiR [69%] and 7 OwR [17%]) and three HSTs (3 OwR [60%]). Two of the nine re-appraised TAs with OiR recommendation and four of the seven OwR complied fully with NICE's request for further evidence, while all three from the HSTs complied. The majority of re-appraised TAs and HSTs included evidence that was deemed to be at serious, high, moderate or unclear risk of bias. Among the 26 randomised controlled trials from TAs assessed, eight were categorised as having low risk of bias in all domains and ten had at least one domain as a high risk of bias. Reporting was unclear for the remainder. Twenty-two non-randomised studies, primarily single-arm studies, were susceptible to biases mostly due to the selection of participants and to confounding. Two HSTs provided evidence from randomised controlled trials which were classified as unclear or high risk of bias. All non-randomised evidence from HSTs were categorised as moderate or serious risk of bias. CONCLUSIONS: There is widespread non-compliance with agreed data requests and important variation in the quality of evidence submitted in response to NICE conditional approval recommendations. Quality standards ought to be stipulated in respect to evidence contributing to re-appraisals following NICE conditional approval recommendations.

The experiences and perspectives of people with gout on urate self-monitoring.

INTRODUCTION: Gout management remains suboptimal despite safe and effective urate-lowering therapy. Self-monitoring of urate may improve gout management, however, the acceptability of urate self-monitoring by people with gout is unknown. The aim of this study was to explore the experiences of urate self-monitoring in people with gout. METHODS: Semistructured interviews were conducted with people taking urate-lowering therapy (N = 30) in a 12-month trial of urate self-monitoring in rural and urban Australia. Interviews covered the experience of monitoring and its effect on gout self-management. Deidentified transcripts were analysed thematically. RESULTS: Participants valued the ability to self-monitor and gain more understanding of urate control compared with the annual monitoring ordered by their doctors. Participants indicated that self-monitoring at home was easy, convenient and informed gout self-management behaviours such as dietary modifications, hydration, exercise and medication routines. Many participants self-monitored to understand urate concentration changes in response to feeling a gout flare was imminent or whether their behaviours, for example, alcohol intake, increased the risk of a gout flare. Urate concentrations were shared with doctors mainly when they were above target to seek management support, and this led to allopurinol dose increases in some cases. CONCLUSION: Urate self-monitoring was viewed by people with gout as convenient and useful for independent management of gout. They believed self-monitoring achieved better gout control with a less restricted lifestyle. Urate data was shared with doctors at the patient's discretion and helped inform clinical decisions, such as allopurinol dose changes. Further research on implementing urate self-monitoring in routine care would enable an evaluation of its impact on medication adherence and clinical outcomes, as well as inform gout management guidelines. PATIENT OR PUBLIC CONTRIBUTION: One person with gout, who was not a participant, was involved in the study design by providing feedback and pilot testing the semistructured interview guide. In response to their feedback, subsequent modifications to the interview guide were made to improve the understandability of the questions from a patient perspective. No additional questions were suggested.

Patient-Led Urate Self-Monitoring to Improve Clinical Outcomes in People With Gout: A Feasibility Study.

OBJECTIVE: Self-monitored point-of-care urate-measuring devices are an underexplored strategy to improve adherence to urate-lowering therapy and clinical outcomes in gout. This study observed patient-led urate self-monitoring practice and assessed its influence on allopurinol adherence, urate control, and health-related quality of life. METHODS: People with gout (n = 31) and prescribed allopurinol self-monitored their urate concentrations (HumaSens2.0plus) at baseline and thereafter monthly for 12 months (3 months per quarter). Adherence to allopurinol was measured using medication event monitoring technology (Medication Event Monitoring System cap). Time spent below the target urate concentration (<0.36 mmol/L) was determined. Health-related quality of life was measured using a survey (EuroQoL EQ-5D-5L). Gout flares were recorded. Two-tailed Spearman correlation and the Wilcoxon matched-pairs signed-rank test (P < 0.05) were used for statistical comparisons. RESULTS: Most participants were male (94%) and had urate concentrations below the target (74%) at baseline. Overall, seven participants demonstrated repeated periods of "missed doses" (two or fewer allopurinol doses missed consecutively) and "drug holidays" (three or more missed doses). Most participants (94%) persisted with allopurinol. Time spent within the target urate concentration increased 1.3-fold (from 79% to 100%; P = 0.346), and the incidence of gout flares decreased 1.6-fold (from 8 to 5; P = 0.25) in the final quarter compared to that in the first quarter of the study. Health-related quality of life was reduced for participants reporting at least one gout flare (median utility values 0.9309 vs 0.9563, P = 0.04). CONCLUSION: Patient-led urate self-monitoring may support the maintenance of allopurinol adherence and improve urate control, thus reducing the incidence of gout flares. Further research on patient-led urate self-monitoring in a randomized controlled study is warranted.

Supporting people with type 2 diabetes in effective use of their medicine through mobile health technology integrated with clinical care (SuMMiT-D pilot): results of a feasibility randomised trial.

BACKGROUND: The purpose of this 6-month intervention pilot feasibility randomised trial was to test sending brief messages using mobile phones to promote self-management through taking medication as prescribed to people with type 2 diabetes. This was to inform the design and conduct of a future large-scale United Kingdom-based clinical trial and establish the feasibility of recruitment, the technology used, follow-up, and data collection. METHODS: A multicentre individually randomised, controlled parallel group trial in primary care, recruiting adults (≥ 35 years) with type 2 diabetes in England. Consenting participants were randomly allocated to receive short message system text messages up to four times a week, or usual care, for a period of 6 months; messages contained behavioural change techniques targeting medication use. The primary outcome was the rate of recruitment to randomisation of participants to the trial with a planned rate of 22 participants randomised per month. The study also aimed to establish the feasibility of follow-up at 6 months, with an aim of retaining more than 80% of participants. Data, including patient-reported measures, were collected at baseline and the end of the 6-month follow-up period, and a notes review was completed at 24 months. RESULTS: The trial took place between 26 November 2018 and 30 September 2019. In total 209 participants were randomly allocated to intervention (n = 103) or usual care (n = 106). The maximum rate of monthly recruitment to the trial was 60-80 participants per month. In total, 12,734 messages were sent to participants. Of these messages, 47 were identified as having failed to be sent by the service provider. Participants sent 2,864 messages to the automated messaging system. Baseline data from medical records were available for > 90% of participants with the exception of cholesterol (78.9%). At 6 months, a further HbA1c measurement was reported for 67% of participants. In total medical record data were available at 6 months for 207 (99.0%) of participants and completed self-report data were available for 177 (84.7%) of participants. CONCLUSION: The feasibility of a large-scale randomised evaluation of brief message intervention for people with type 2 diabetes appears to be high using this efficient design. Failure rate of sending messages is low, rapid recruitment was achieved among people with type 2 diabetes, clinical data is available on participants from routine medical records and self-report of economic measures was acceptable. TRIAL REGISTRATION: ISCTRN ISRCTN13404264. Registered on 10 October 2018.

Appropriate design and reporting of superiority, equivalence and non-inferiority clinical trials incorporating a benefit-risk assessment: the BRAINS study including expert workshop.

Background: Randomised controlled trials are designed to assess the superiority, equivalence or non-inferiority of a new health technology, but which trial design should be used is not always obvious in practice. In particular, when using equivalence or non-inferiority designs, multiple outcomes of interest may be important for the success of a trial, despite the fact that usually only a single primary outcome is used to design the trial. Benefit-risk methods are used in the regulatory clinical trial setting to assess multiple outcomes and consider the trade-off of the benefits against the risks, but are not regularly implemented in publicly funded trials. Objectives: The aim of the project is to aid the design of clinical trials with multiple outcomes of interest by defining when each trial design is appropriate to use and identifying when to use benefit-risk methods to assess outcome trade-offs (qualitatively or quantitatively) in a publicly funded trial setting. Methods: A range of methods was used to elicit expert opinion to answer the project objectives, including a web-based survey of relevant researchers, a rapid review of current literature and a 2-day consensus workshop of experts (in 2019). Results: We created a list of 19 factors to aid researchers in selecting the most appropriate trial design, containing the following overarching sections: population, intervention, comparator, outcomes, feasibility and perspectives. Six key reasons that indicate a benefit-risk method should be considered within a trial were identified: (1) when the success of the trial depends on more than one outcome; (2) when important outcomes within the trial are in competing directions (i.e. a health technology is better for one outcome, but worse for another); (3) to allow patient preferences to be included and directly influence trial results; (4) to provide transparency on subjective recommendations from a trial; (5) to provide consistency in the approach to presenting results from a trial; and (6) to synthesise multiple outcomes into a single metric. Further information was provided to support the use of benefit-risk methods in appropriate circumstances, including the following: methods identified from the review were collated into different groupings and described to aid the selection of a method; potential implementation of methods throughout the trial process were provided and discussed (with examples); and general considerations were described for those using benefit-risk methods. Finally, a checklist of five pieces of information that should be present when reporting benefit-risk methods was defined, with two additional items specifically for reporting the results. Conclusions: These recommendations will assist research teams in selecting which trial design to use and deciding whether or not a benefit-risk method could be included to ensure research questions are answered appropriately. Additional information is provided to support consistent use and clear reporting of benefit-risk methods in the future. The recommendations can also be used by funding committees to confirm that appropriate considerations of the trial design have been made. Limitations: This research was limited in scope and should be considered in conjunction with other trial design methodologies to assess appropriateness. In addition, further research is needed to provide concrete information about which benefit-risk methods are best to use in publicly funded trials, along with recommendations that are specific to each method. Study registration: The rapid review is registered as PROSPERO CRD42019144882. Funding: Funded by the Medical Research Council UK and the National Institute for Health and Care Research as part of the Medical Research Council-National Institute for Health and Care Research Methodology Research programme.

Randomised controlled trials are considered the best way to gather evidence about potential NHS treatments. They can be designed from different perspectives depending whether the aim is to show that a new treatment is better than, equal to or no worse than the current best available treatment. The selection of this design relates to the single most important outcome; however, often multiple outcomes can be affected by a treatment. For example, a new treatment may improve disease management but increase side effects. Patients want a treatment to work but not at the price of poor quality of life; therefore, a trade-off must be made, and the recommended treatment depends on this trade-off. Benefit­risk methods can assess the trade-off between multiple outcomes and can include patient preference. These methods could improve the way that decisions are made about treatments in the NHS, but there is currently limited research about the use of these methods in publicly funded trials. The aim of this report is to improve the design of clinical trials by helping researchers to select the most appropriate trial design and to decide when to include a benefit­risk method. The recommendations were created using the opinions of experts within the field and consisted of a survey, review of the literature and a workshop. The project created a list of 19 factors that can assist researchers to select the most appropriate trial design. Furthermore, six key areas were identified in which researchers may consider including a benefit­risk method within a trial. Finally, if a benefit­risk assessment is being used, a checklist of items has been created that identifies the information important to include in reports. This report is, however, limited in its applicability and further research should extend this work, as well as provide more detail on individual methods that are available.

Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data.

BACKGROUND: There is uncertainty about the best treatment option for children/adolescents with uncontrolled asthma despite inhaled corticosteroids (ICS) and international guidelines make different recommendations. We evaluated the pharmacological treatments to reduce asthma exacerbations and symptoms in uncontrolled patients age <18 years on ICS. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, Web of Science, National Institute for Health and Care Excellence Technology Appraisals, National Institute for Health and Care Research Health Technology Assessment series, World Health Organization International Clinical Trials Registry, conference abstracts and internal clinical trial registers (1 July 2014 to 5 May 2023) for randomised controlled trials of participants age <18 years with uncontrolled asthma on any ICS dose alone at screening. Studies before July 2014 were retrieved from previous systematic reviews/contact with authors. Patients had to be randomised to any dose of ICS alone or combined with long-acting ß2-agonists (LABA) or combined with leukotriene receptor antagonists (LTRA), LTRA alone, theophylline or placebo. Primary outcomes were exacerbation and asthma control. The interventions evaluated were ICS (low/medium/high dose), ICS+LABA, ICS+LTRA, LTRA alone, theophylline and placebo. RESULTS: Of the 4708 publications identified, 144 trials were eligible. Individual participant data were obtained from 29 trials and aggregate data were obtained from 19 trials. Compared with ICS Low, ICS Medium+LABA was associated with the lowest odds of exacerbation (OR 0.44, 95% credibility interval (95% CrI) 0.19-0.90) and with an increased forced expiratory volume in 1 s (mean difference 0.71, 95% CrI 0.35-1.06). Treatment with LTRA was the least preferred. No apparent differences were found for asthma control. CONCLUSIONS: Uncontrolled children/adolescents on low-dose ICS should be recommended a change to medium-dose ICS+LABA to reduce the risk for exacerbation and improve lung function.

Costs of orphan medicinal products: longitudinal analysis of expenditure in Wales.

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

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

BACKGROUND: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. OBJECTIVE: This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. METHODS: Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. RESULTS: We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. CONCLUSIONS: We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46710.

A framework for understanding sources of bias in medication adherence research.

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.

Value of improving patient safety: health economic considerations for rapid response systems-a rapid review of the literature and expert round table.

OBJECTIVES: Failure to rescue deteriorating patients in hospital is a well-researched topic. We aimed to explore the impact of safer care on health economic considerations for clinicians, providers and policymakers. DESIGN: We undertook a rapid review of the available literature and convened a round table of international specialists in the field including experts on health economics and value-based healthcare to better understand health economics of clinical deterioration and impact of systems to reduce failure to rescue. RESULTS: Only a limited number of publications have examined the health economic impact of failure to rescue. Literature examining this topic lacked detail and we identified no publications on long-term cost outside the hospital following a deterioration event. The recent pandemic has added limited literature on prevention of deterioration in the patients' home.Cost-effectiveness and cost-efficiency are dependent on broader system effects of adverse events. We suggest including the care needs beyond the hospital and loss of income of patients and/or their informal carers as well as sickness of healthcare staff exposed to serious adverse events in the analysis of adverse events. They are likely to have a larger health economic impact than the direct attributable cost of the hospital admission of the patient suffering the adverse event. Premorbid status of a patient is a major confounder for health economic considerations. CONCLUSION: In order to optimise health at the population level, we must limit long-term effects of adverse events through improvement of our ability to rapidly recognise and respond to acute illness and worsening chronic illness both in the home and the hospital.

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS.

AIMS: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS. MATERIALS AND METHODS: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method. RESULTS: The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058). CONCLUSIONS: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings. CLINICALTRIALS.GOV IDENTIFIER: NCT03160898.

The impact of parent treatment preference and other factors on recruitment: lessons learned from a paediatric epilepsy randomised controlled trial.

BACKGROUND: In paediatric epilepsy, the evidence of effectiveness of antiseizure treatment is inconclusive for some types of epilepsy. As with other paediatric clinical trials, researchers undertaking paediatric epilepsy clinical trials face a range of challenges that may compromise external validity MAIN BODY: In this paper, we critically reflect upon the factors which impacted recruitment to the pilot phase of a phase IV unblinded, randomised controlled 3×2 factorial trial examining the effectiveness of two antiseizure medications (ASMs) and a sleep behaviour intervention in children with Rolandic epilepsy. We consider the processes established to support recruitment, public and patient involvement and engagement (PPIE), site induction, our oversight of recruitment targets and figures, and the actions we took to help us understand why we failed to recruit sufficient children to continue to the substantive trial phase. The key lessons learned were about parent preference, children's involvement and collaboration in decision-making, potential and alternative trial designs, and elicitation of stated preferences pre-trial design. Despite pre-funding PPIE during the trial design phase, we failed to anticipate the scale of parental treatment preference for or against antiseizure medication (ASMs) and consequent unwillingness to be randomised. Future studies should ensure more detailed and in-depth consultation to ascertain parent and/or patient preferences. More intense engagement with parents and children exploring their ideas about treatment preferences could, perhaps, have helped predict some recruitment issues. Infrequent seizures or screening children close to natural remission were possible explanations for non-consent. It is possible some clinicians were unintentionally unable to convey clinical equipoise influencing parental decision against participation. We wanted children to be involved in decisions about trial participation. However, despite having tailored written and video information to explain the trial to children we do not know whether these materials were viewed in each consent conversation or how much input children had towards parents' decisions to participate. Novel methods such as parent/patient preference trials and/or discrete choice experiments may be the way forward. CONCLUSION: The importance of diligent consultation, the consideration of novel methods such as parent/patient preference trials and/or discrete choice experiments in studies examining the effectiveness of ASMs versus no-ASMs cannot be overemphasised even in the presence of widespread clinician equipoise.

Psychometric Properties of an Adapted Stigma Scale and Experiences of Stigma Associated with HIV Pre-exposure Prophylaxis Use Among Men Who have Sex with Men: A Mixed Methods Study.

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

Between- and Within-Individual Sociodemographic and Psychological Determinants of PrEP Adherence Among Men Who have Sex with Men Prescribed a Daily PrEP Regimen in Wales.

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

Methodological considerations on estimating medication adherence from self-report, electronic monitoring and electronic healthcare databases using the TEOS framework.

AIMS: Measuring adherence to medication is complex due to the diversity of contexts in which medications are prescribed, dispensed and used. The Timelines-Events-Objectives-Sources (TEOS) framework outlined a process to operationalize adherence. We aimed to develop practical recommendations for quantification of medication adherence using self-report (SR), electronic monitoring (EM) and electronic healthcare databases (EHD) consistent with the TEOS framework for adherence operationalization. METHODS: An adherence methodology working group of the International Society for Medication Adherence (ESPACOMP) analysed implications of the process of medication adherence for all data sources and discussed considerations specific to SR, EM and EHD regarding the information available on the prescribing, dispensing, recommended and actual use timelines, the four events relevant for distinguishing the adherence phases, the study objectives commonly addressed with each type of data, and the potential sources of measurement error and quality criteria applicable. RESULTS: Four key implications for medication adherence measurement are common to all data sources: adherence is a comparison between two series of events (recommended and actual use); it refers to one or more specific medication(s); it applies to regular repeated events coinciding with known recommended dosing; and it requires separate measurement of the three adherence phases for a complete picture of patients' adherence. We propose recommendations deriving from these statements, and aspects to be considered in study design when measuring adherence with SR, EM and EHD using the TEOS framework. CONCLUSION: The quality of medication adherence estimates is the result of several design choices that may optimize the data available.

Adverse drug reactions, multimorbidity and polypharmacy: a prospective analysis of 1 month of medical admissions.

OBJECTIVE: To ascertain the burden and associated cost of adverse drug reactions (ADRs), polypharmacy and multimorbidity through a prospective analysis of all medical admissions to a large university teaching hospital over a 1-month period. DESIGN: Prospective observational study. SETTING: Liverpool University Hospital Foundation National Health Service (NHS) Trust, England. PARTICIPANTS: All medical admissions with greater than 24-hour stay over a 1-month period. MAIN OUTCOME MEASURES: Prevalence of admissions due to an ADR and associated mortality, prevalence and association of multimorbidity and polypharmacy with ADRs, and estimated local financial cost of admissions where an ADR was a contributing or main reason for admission with projected costs for NHS in England. RESULTS: There were 218 identified patient admissions with an ADR giving a prevalence of 18.4%. The majority of these (90.4%) were ADRs that directly resulted in or contributed to admission. ADRs thus accounted for 16.5% of total admissions. Those with an ADR were on average taking more medicines (10.5 vs 7.8, p<0.01) and had more comorbidities than those without an ADR (6.1 vs 5.2, p<0.01). Drugs most commonly implicated were diuretics, steroid inhalers, anticoagulants and antiplatelets, proton pump inhibitors, chemotherapeutic agents and antihypertensives. 40.4% of ADRs were classified avoidable or possibly avoidable. The mortality rate due to an ADR was 0.34%. The average length of stay for those with an ADR was 6 days. Direct 1-month cost to the Trust from ADR admissions was £490 716. Extrapolated nationally, the projected annual cost to the NHS in England is 2.21 billion. CONCLUSION: The local prevalence of admission and mortality from ADRs is higher than previously reported. Important factors that could be contributing to this include polypharmacy and multimorbidity. ADRs place a significant burden on patients and healthcare services with associated financial implications. Reducing inappropriate polypharmacy should be a major aim for preventing ADRs.

Supply-Side Cost-Effectiveness Thresholds: Questions for Evidence-Based Policy.

There is growing interest in cost-effectiveness thresholds as a tool to inform resource allocation decisions in health care. Studies from several countries have sought to estimate health system opportunity costs, which supply-side cost-effectiveness thresholds are intended to represent. In this paper, we consider the role of empirical estimates of supply-side thresholds in policy-making. Recent studies estimate the cost per unit of health based on average displacement or outcome elasticity. We distinguish the types of point estimates reported in empirical work, including marginal productivity, average displacement, and outcome elasticity. Using this classification, we summarise the limitations of current approaches to threshold estimation in terms of theory, methods, and data. We highlight the questions that arise from alternative interpretations of thresholds and provide recommendations to policymakers seeking to use a supply-side threshold where the evidence base is emerging or incomplete. We recommend that: (1) policymakers must clearly define the scope of the application of a threshold, and the theoretical basis for empirical estimates should be consistent with that scope; (2) a process for the assessment of new evidence and for determining changes in the threshold to be applied in policy-making should be created; (3) decision-making processes should retain flexibility in the application of a threshold; and (4) policymakers should provide support for decision-makers relating to the use of thresholds and the implementation of decisions stemming from their application.

Methods for Extrapolating Survival Analyses for the Economic Evaluation of Advanced Therapy Medicinal Products.

There are two significant challenges for analysts conducting economic evaluations of advanced therapy medicinal products (ATMPs): (1) estimating long-term treatment effects in the absence of mature clinical data and (2) capturing potentially complex hazard functions. This review identifies and critiques a variety of methods that can be used to overcome these challenges. The narrative review is informed by a rapid literature review of methods used for the extrapolation of survival analyses in the economic evaluation of ATMPs. There are several methods that are more suitable than traditional parametric survival modeling approaches for capturing complex hazard functions, including, cure-mixture models and restricted cubic spline models. In the absence of mature clinical data, analysts may augment clinical trial data with data from other sources to aid extrapolation, however, the relative merits of applying methods for including data from different sources is not well understood. Given the high and potentially irrecoverable costs of making incorrect decisions concerning the reimbursement or commissioning of ATMPs, it is important that economic evaluations are correctly specified, and that both parameter and structural uncertainty associated with survival extrapolations are considered. Value of information analyses allow for this uncertainty to be expressed explicitly, and in monetary terms.

Experiences of men who have sex with men when initiating, implementing and persisting with HIV pre-exposure prophylaxis.

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