Overcoming challenges in the economic evaluation of interventions to optimise antibiotic use.

Bacteria are becoming increasingly resistant to antibiotics, reducing our ability to treat infections and threatening to undermine modern health care. Optimising antibiotic use is a key element in tackling the problem. Traditional economic evaluation methods do not capture many of the benefits from improved antibiotic use and the potential impact on resistance. Not capturing these benefits is a major obstacle to optimising antibiotic use, as it fails to incentivise the development and use of interventions to optimise the use of antibiotics and preserve their effectiveness (stewardship interventions). Estimates of the benefits of improving antibiotic use involve considerable uncertainty as they depend on the evolution of resistance and associated health outcomes and costs. Here we discuss how economic evaluation methods might be adapted, in the face of such uncertainties. We propose a threshold-based approach that estimates the minimum resistance-related costs that would need to be averted by an intervention to make it cost-effective. If it is probable that without the intervention costs will exceed the threshold then the intervention should be deemed cost-effective.

What, Where, and How to Collect Real-World Data and Generate Real-World Evidence to Support Drug Reimbursement Decision-Making in Asia: A reflection Into the Past and A Way Forward.

BACKGROUND: Globally, there is increasing interest in the use of real-world data (RWD) and real-world evidence (RWE) to inform health technology assessment (HTA) and reimbursement decision-making. Using current practices and case studies shared by eleven health systems in Asia, a non-binding guidance that seeks to align practices for generating and using RWD/RWE for decision-making in Asia was developed by the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) Working Group, addressing a current gap and needs among HTA users and generators. METHODS: The guidance document was developed over two face-to-face workshops, in addition to an online survey, a face-to-face interview and pragmatic search of literature. The specific focus was on what, where and how to collect RWD/ RWE. RESULTS: All 11 REALISE member jurisdictions participated in the online survey and the first in-person workshop, 10 participated in the second in-person workshop, and 8 participated in the in-depth face-to-face interviews. The guidance document was iteratively reviewed by all working group members and the International Advisory Panel. There was substantial variation in: (a) sources and types of RWD being used in HTA, and (b) the relative importance and prioritization of RWE being used for policy-making. A list of national-level databases and other sources of RWD available in each country was compiled. A list of useful guidance on data collection, quality assurance and study design were also compiled. CONCLUSION: The REALISE guidance document serves to align the collection of better quality RWD and generation of reliable RWE to ultimately inform HTA in Asia.

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. METHODS: EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03332212.

How can we optimise health technology assessment and reimbursement decisions to accelerate access to new cardiovascular medicines?

Regulatory approvals of, and subsequent access to, innovative cardiovascular medications have declined. How much of this decline relates to the final step of gaining reimbursement for new treatments is unknown. Payers and health technology assessment (HTA) bodies look beyond efficacy and safety to assess whether a new drug improves patient outcomes, quality of life, or satisfaction at a cost that is affordable compared to existing treatments. HTA bodies work within a limited healthcare budget, and this is one of the reasons why only half of newly approved drugs are accepted for reimbursement, or receive restricted or "optimised" recommendations from HTA bodies. All stakeholders have the common goal of facilitating access to safe, effective, and affordable treatments to appropriate patients. An important strategy to expedite this is providing optimal data. This is demonstrably facilitated by early (and ongoing) discussions between all stakeholders. Many countries have formal programmes to provide collaborative regulatory and HTA advice to developers. Other strategies include aligning regulatory and HTA processes, increasing use of real-world evidence, formally defining the decision-making process, and educating stakeholders on the criteria for positive decision making. Industry should focus on developing treatments for unmet medical needs, seek early engagement with HTA and regulatory bodies, improve methodologies for optimal price setting, develop internal systems to collaborate with national and international stakeholders, and conduct post-approval studies. Patient involvement in all stages of development, including HTA, is critical to capture the lived experience and priorities of those whose lives will be impacted by new treatment approvals.

Real-world data for health technology assessment for reimbursement decisions in Asia: current landscape and a way forward.

There is growing interest globally in using real-world data (RWD) and real-world evidence (RWE) for health technology assessment (HTA). Optimal collection, analysis, and use of RWD/RWE to inform HTA requires a conceptual framework to standardize processes and ensure consistency. However, such framework is currently lacking in Asia, a region that is likely to benefit from RWD/RWE for at least two reasons. First, there is often limited Asian representation in clinical trials unless specifically conducted in Asian populations, and RWD may help to fill the evidence gap. Second, in a few Asian health systems, reimbursement decisions are not made at market entry; thus, allowing RWD/RWE to be collected to give more certainty about the effectiveness of technologies in the local setting and inform their appropriate use. Furthermore, an alignment of RWD/RWE policies across Asia would equip decision makers with context-relevant evidence, and improve timely patient access to new technologies. Using data collected from eleven health systems in Asia, this paper provides a review of the current landscape of RWD/RWE in Asia to inform HTA and explores a way forward to align policies within the region. This paper concludes with a proposal to establish an international collaboration among academics and HTA agencies in the region: the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) working group, which seeks to develop a non-binding guidance document on the use of RWD/RWE to inform HTA for decision making in Asia.

In primary care, is measuring free-thyroxine plus thyroid-stimulating hormone to detect hypopituitarism cost-effective? A cost utility analysis using Markov chain models.

OBJECTIVE: We examined whether it is cost-effective to measure free thyroxine (FT4) in addition to thyrotropin (thyroid-stimulating hormone (TSH)) on all requests for thyroid function tests from primary care on adult patients. BACKGROUND: Hypopituitarism occurs in about 4 people per 100 000 per year. Loss of thyrotropin (TSH) secretion may lead to secondary hypothyroidism with a low TSH and low FT4, and this pattern may help to diagnose hypopituitarism that might otherwise be missed. DESIGN: Markov model simulation. PRIMARY OUTCOME MEASURE: Incremental cost-effectiveness ratio (ICER), the ratio of cost in pounds to benefit in quality-adjusted life years of this strategy. RESULTS: The ICER for this strategy was £71 437. Factors with a large influence on the ICER were the utilities of the treated hypopituitary state, the likelihood of going to the general practitioner (GP) and of the GP recognising a hypopituitary patient. The ICER would be below £20 000 at a cost to the user of an FT4 measurement of £0.61. CONCLUSION: With FT4 measurements at their present cost to the user, routine inclusion of FT4 in a thyroid hormone profile is not cost-effective.

Longitudinal medical resources and costs among type 2 diabetes patients participating in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

AIMS: TECOS, a cardiovascular safety trial (ClinicalTrials.gov identifier: NCT00790205) involving 14 671 patients with type 2 diabetes and cardiovascular disease, demonstrated that sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome when added to best usual care. This study tested hypotheses that medical resource use and costs differed between these 2 treatment strategies. MATERIALS AND METHODS: Information concerning medical resource use was collected on case report forms throughout the trial and was valued using US costs for: Medicare payments for hospitalizations, medical procedures and outpatient visits, and wholesale acquisition costs (WAC) for diabetes-related medications. Hierarchical generalized linear models were used to compare resource use and US costs, accounting for variable intercountry practice patterns. Sensitivity analyses included resource valuation using English costs for a UK perspective. RESULTS: There were no significant differences in hospitalizations, inpatient days, medical procedures, or outpatient visits during follow-up (mean and median 3.0 years in both groups). Hospitalization rates appeared to diverge after 2 years, with lower rates among sitagliptin-treated vs placebo patients after 2.5 years (relative rate, 0.90 [95% CI, 0.83-0.97]; P = .01). Mean medical costs, exclusive of study medication, were 11 937 USD in the sitagliptin arm and 12 409 USD in the placebo arm (P = .06). Mean sitagliptin costs based on undiscounted WAC were 9978 USD per patient. Differential UK total costs including study drug costs were smaller (911 GBP), primarily because of lower mean costs for sitagliptin (1072 GBP). CONCLUSIONS: Lower hospitalization rates across time with sitagliptin slightly offset sitagliptin treatment costs over 3 years in type 2 diabetes patients at high risk for cardiovascular events.

Economic evaluation of type 2 diabetes prevention programmes: Markov model of low- and high-intensity lifestyle programmes and metformin in participants with different categories of intermediate hyperglycaemia.

BACKGROUND: National guidance on preventing type 2 diabetes mellitus (T2DM) in the UK recommends low-intensity lifestyle interventions for individuals with intermediate categories of hyperglycaemia defined in terms of impaired fasting glucose (IFG) or 'at-risk' levels of HbA1c. In a recent systematic review of economic evaluations of such interventions, most studies had evaluated intensive trial-based lifestyle programmes in participants with impaired glucose tolerance (IGT). This study examines the costs and effects of different intensity lifestyle programmes and metformin in participants with different categories of intermediate hyperglycaemia. METHODS: We developed a decision tree and Markov model (50-year horizon) to compare four approaches, namely (1) a low-intensity lifestyle programme based on current NICE guidance, (2) a high-intensity lifestyle programme based on the US Diabetes Prevention Program, (3) metformin, and (4) no intervention, modelled for three different types of intermediate hyperglycaemia (IFG, IGT and HbA1c). A health system perspective was adopted and incremental analysis undertaken at an individual and population-wide level, taking England as a case study. RESULTS: Low-intensity lifestyle programmes were the most cost-effective (£44/QALY, £195/QALY and £186/QALY compared to no intervention in IGT, IFG and HbA1c, respectively). Intensive lifestyle interventions were also cost-effective compared to no intervention (£2775/QALY, £6820/QALY and £7376/QALY, respectively, in IGT, IFG and HbA1c). Metformin was cost-effective relative to no intervention (£5224/QALY, £6842/QALY and £372/QALY in IGT, IFG and HbA1c, respectively), but was only cost-effective relative to other treatments in participants identified with HbA1c. At a willingness-to-pay threshold of £20,000/QALY, low- and high-intensity lifestyle programmes were cost-effective 98%, 99% and 98% and 81%, 81% and 71% of the time in IGT, IFG and HbA1c, respectively. An England-wide programme for 50-59 year olds could reduce T2DM incidence by < 3.5% over 50 years and would cost 0.2-5.2% of the current diabetes budget for 2-9 years. DISCUSSION: This analysis suggests that current English national policy of low-intensity lifestyle programmes in participants with IFG or HbA1c will be cost-effective and have the most favourable budget impact, but will prevent only a fraction of cases of T2DM. Additional approaches to prevention need to be investigated urgently.

Unrelated Future Costs and Unrelated Future Benefits: Reflections on NICE Guide to the Methods of Technology Appraisal.

In this editorial, we consider the vexing issue of 'unrelated future costs' (for example, the costs of caring for people with dementia or kidney failure after preventing their deaths from a heart attack). The National Institute of Health and Care Excellence (NICE) guidance is not to take such costs into account in technology appraisals. However, standard appraisal practice involves modelling the benefits of those unrelated technologies. We argue that there is a sound principled reason for including both the costs and benefits of unrelated care. Changing this practice would have material consequences for decisions about reimbursing particular technologies, and we urge future research to understand this better. Copyright © 2016 John Wiley & Sons, Ltd.

Diagnostic accuracy of urine dipstick testing in screening for microalbuminuria in type 2 diabetes: a cohort study in primary care.

BACKGROUND: Clinical guidelines recommend annual screening for microalbuminuria in diabetes. Detection of microalbuminuria is important because it is associated with increased morbidity and mortality. Dipstick tests for microalbuminuria may be convenient, but their accuracy is uncertain. OBJECTIVE: To assess the utility of urine dipstick testing for microalbuminuria in type 2 diabetes. METHODS: In a 6-week cohort study in four general practices in Oxfordshire, UK, first-pass urine samples were obtained at two weekly intervals from patients with type 2 diabetes and tested in the practice using Micral-Test and Microalbustix urine dipsticks. Parallel samples were sent for laboratory albumin-creatinine ratio (ACR) assay. Results of single dipstick tests and sequences of dipstick and laboratory tests were compared with a clinical testing strategy based on current guidelines to assess the accuracy and estimate costs of testing. RESULTS: The prevalence of microalbuminuria was 12.5% (n = 88). Mean (standard deviation) age was 68 (10) years, 56 (57%) were men. Median (interquartile range) diabetes duration was 6.2 (2.0-10.0) years. The sensitivity and specificity, respectively, of a single Micral-Test were 91.7% and 44.0% and of a Microalbustix test 33.3% and 92.0%. Testing strategies involving dipstick and laboratory ACR measurements or dipstick tests had similar accuracy. The costs of using dipstick tests were overall lower than laboratory ACR-based testing. CONCLUSIONS: Dipstick testing in this study did not reliably identify diabetes patients with microalbuminuria. Although dipstick testing would decrease testing costs, it could either fail to diagnose most patients with microalbuminuria or increase the numbers of patients retested depending on the dipstick used.