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STUDY QUESTION Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and MAIN RESULTS AND THE ROLE OF CHANCE Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S) NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors’ competing interests: none declared. TRIAL REGISTRATION NUMBER ISRCTN: 61225414. TRIAL REGISTRATION DATE 29 December 2015. DATE OF FIRST PATIENT’S ENROLMENT 16 February 2016.

Very few data are available to demonstrate the economic benefit of early paliperidone palmitate once-monthly long-acting injectable (PP1M) treatment in patients with schizophrenia or schizoaffective disorder.This study has retrospectively compared the healthcare utilization and associated costs of pre- and post-PPIM treatment in 413 patients with schizophrenia or schizoaffective disorder recruited from three major public hospitals providing psychiatric services in Hong Kong. Patients were categorized into early treatment (≤3 years since diagnosis) and chronic (3 years) groups, and also whether they were receiving polypharmacy (POP).It was found that patients who were started on early therapy with no POP had the most favourable outcomes. Overall results of the entire cohort, including both early and late treatments, indicate that there was a slight increase in annual in-patient days (IP) per patient and outpatient visit (OP) by 3.18 and 1.87, respectively, and a decrease in emergency room visit (ER) of 0.9 (p 0.05). For non-polypharmacy (NP) patients receiving early PP1M therapy, there was a significant decrease in IP and ER of 21.56 (p 0.05) and 1.15 (p 0.05), respectively, but an increase in OP of 1.88 (p 0.05). For patients with POP, there was an all-across increase in IP and all-across decrease in OP and ER. In monetary terms, a NP patient receiving early therapy may have an overall saving of HKD40,878 (USD5,241, 1USD = 7.8HKD) per year compared to HKD6,224 (USD798) in patients where therapy was given after 3 years. For patients with POP, there was an all-across increase in overall spending despite reductions in OP and ER.From the 413 patients studied, potential annual savings is higher by early administration of PPIM in patients with NP. Analysis using multivariate linear regression based on generalized estimating equations and sensitivity analysis using a linear mixed model supported the findings.

Background: Embryos created following in-vitro fertilisation (IVF) are usually replaced within the uterus within a few days (fresh embryo transfer). It has been suggested that elective freezing of all embryos followed by transfer at a later date (freeze-all) could make treatment safer and more effective. The aim of this trial was to compare the clinical and cost-effectiveness of a strategy of freeze-all versus fresh embryo transfer. Methods: A two arm, non-blinded, parallel group pragmatic randomised trial was conducted across 18 IVF clinics in the UK. Couples undergoing IVF, where the woman was

Background Antimicrobial resistance (AMR) is a global health problem requiring a reduction in inappropriate antibiotic prescribing. Point-of-Care C-Reactive Protein (POCCRP) tests could distinguish between bacterial and non-bacterial causes of fever in malaria-negative patients and thus reduce inappropriate antibiotic prescribing. However, the cost-effectiveness of POCCRP testing is unclear in low-income settings. Methods A decision tree model was used to estimate cost-effectiveness of POCCRP versus current clinical practice at primary healthcare facilities in Afghanistan. Data were analysed from healthcare delivery and societal perspectives. Costs were reported in 2019 USD. Effectiveness was measured as correctly treated febrile malaria-negative patient. Cost, effectiveness and diagnostic accuracy parameters were obtained from primary data from a cost-effectiveness study on malaria rapid diagnostic tests in Afghanistan and supplemented with POCCRP-specific data sourced from the literature. Incremental cost-effectiveness ratios (ICERs) reported the additional cost per additional correctly treated febrile malaria-negative patient over a 28-day time horizon. Univariate and probabilistic sensitivity analyses examined the impact of uncertainty of parameter inputs. Scenario analysis included economic cost of AMR per antibiotic prescription. Results The model predicts that POCCRP intervention would result in 137 fewer antibiotic prescriptions (6%) with a 12% reduction (279 prescriptions) in inappropriate prescriptions compared to current clinical practice. ICERs were $14.33 (healthcare delivery), $11.40 (societal), and $9.78 (scenario analysis) per additional correctly treated case. Conclusions POCCRP tests could improve antibiotic prescribing among malaria-negative patients in Afghanistan. Cost-effectiveness depends in part on willingness to pay for reductions in inappropriate antibiotic prescribing that will only have modest impact on immediate clinical outcomes but may have long-term benefits in reducing overuse of antibiotics. A reduction in the overuse of antibiotics is needed and POCCRP tests may add to other interventions in achieving this aim. Assessment of willingness to pay among policy makers and donors and undertaking operational trials will help determine cost-effectiveness and assist decision making. to current clinical practice. ICERs were $14.33 (healthcare delivery), $11.40 (societal), and $9.78 (scenario analysis) per additional correctly treated case. Conclusions POCCRP tests could improve antibiotic prescribing among malaria-negative patients in Afghanistan. Cost-effectiveness depends in part on willingness to pay for reductions in inappropriate antibiotic prescribing that will only have modest impact on immediate clinical outcomes but may have long-term benefits in reducing overuse of antibiotics. A reduction in the overuse of antibiotics is needed and POCCRP tests may add to other interventions in achieving this aim. Assessment of willingness to pay among policy makers and donors and undertaking operational trials will help determine cost-effectiveness and assist decision making.

Background It is estimated that around 30% of breast cancers in post-menopausal women are related to lifestyle. The breast cancer-pooling project demonstrated that sustained weight loss of 2 to 4.5 kg is associated with an 18% lower risk of breast cancer, highlighting the importance of small changes in body weight. Our study aimed to assess the effectiveness a volunteer-delivered, community based, weight management programme (ActWELL) for women with a BMI > 25 kg/m2 attending NHS Scotland Breast Screening clinics. Methods A multicentre, 1:1 parallel group, randomised controlled trial was undertaken in 560 women aged 50 to 70 years with BMI > 25 kg/m2. On completion of baseline measures, all participants received a breast cancer prevention leaflet. Intervention group participants received the ActWELL intervention which focussed on personalised diet advice and pedometer walking plans. The programme was delivered in leisure centres by (the charity) Breast Cancer Now volunteer coaches. Primary outcomes were changes between groups at 12 months in body weight (kg) and physical activity (accelerometer measured step count). Results Two hundred seventy-nine women were allocated to the intervention group and 281 to the comparison group. Twelve-month data were available from 240 (81%) intervention and 227 (85%) comparison group participants. Coaches delivered 523 coaching sessions and 1915 support calls to 279 intervention participants. Mean weight change was − 2.5 kg (95% CI − 3.1 to − 1.9) in the intervention group and − 1.2 kg (− 1.8 to 0.6) in the comparison group. The adjusted mean difference was − 1.3 kg (95% CI − 2.2 to − 0.4, P = 0.003). The odds ratio for losing 5% weight was 2.20 (95% CI 1.4 to 3.4, p = 0.0005) in favour of the intervention. The adjusted mean difference in step counts between groups was 483 steps/day (95% CI − 635 to 1602) (NS). Conclusions A community weight management intervention initiated at breast screening clinics and delivered by volunteer coaches doubled the likelihood of clinically significant weight loss at 12 months (compared with usual care) offering significant potential to decrease breast cancer risk. Trial registration Database of registration: ISCRTN. Registration number:11057518. Date trial registered:21.07.2017. Date of enrolment of first participant: 01.09.2017.

Background Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. Objectives The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. Design A parallel-group, double-blind, placebo-controlled randomised trial. Setting The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. Participants Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of Interventions Eligible participants were randomised 1 : 1 to oral sodium bicarbonate or matching placebo. Dosing started at 500 mg three times daily, increasing to 1 g three times daily if the serum bicarbonate concentration was Main outcome measures The primary outcome was the between-group difference in the Short Physical Performance Battery score at 12 months, adjusted for baseline. Other outcome measures included generic and disease-specific health-related quality of life, anthropometry, 6-minute walk speed, grip strength, renal function, markers of bone turnover, blood pressure and brain natriuretic peptide. All adverse events were recorded, including commencement of renal replacement therapy. For the health economic analysis, the incremental cost per quality-adjusted life-year was the main outcome. Results In total, 300 participants were randomised, 152 to bicarbonate and 148 to placebo. The mean age of participants was 74 years and 86 (29%) were female. Adherence to study medication was 73% in both groups. A total of 220 (73%) participants were assessed at the 12-month visit. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery score at 12 months (–0.4 points, 95% confidence interval –0.9 to 0.1 points; p = 0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 vs. 400). Time to commencement of renal replacement therapy was similar in both groups (hazard ratio 1.22, 95% confidence interval 0.74 to 2.02; p = 0.43). Health economic analysis showed higher costs and lower quality of life in the bicarbonate arm at 1 year, with additional costs of £564 (95% confidence interval £88 to £1154) and a quality-adjusted life-year difference of –0.05 (95% confidence interval –0.08 to –0.01); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. Limitations The trial population was predominantly white and male, limiting generalisability. The increment in serum bicarbonate concentrations achieved was small and a benefit from larger doses of bicarbonate cannot be excluded. Conclusions Oral sodium bicarbonate did not improve a range of health measures in people aged ≥ 60 years with chronic kidney disease category 4 or 5 and mild acidosis, and is unlikely to be cost-effective for use in the NHS in this patient group. Once other current trials of bicarbonate therapy in chronic kidney disease are complete, an individual participant meta-analysis would be helpful to determine which subgroups, if any, are more likely to benefit and which treatment regimens are more beneficial. Trial registration Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.

Background Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations Methods Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of 2, not receiving dialysis, with serum bicarbonate concentration Results We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB: bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect − 0.4 (95% CI − 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI − 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400). Conclusions Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group. Trial registration European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012.

OBJECTIVE Studies found a strong association between allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and the HLA-B*58:01 allele. HLA-B*58:01 screening-guided therapy may mitigate the risk of allopurinol-induced SJS/TEN. This study aimed to evaluate the cost-effectiveness of HLA-B*58:01 screening before allopurinol therapy initiation compared with the current practice of no screening for Malaysian patients with chronic gout in whom a hypouricemic agent is indicated. METHODS This cost-effectiveness analysis adopted a societal perspective with a lifetime horizon. A decision tree model coupled with Markov models were developed to estimate the costs and outcomes, represented by quality-adjusted life years (QALYs) gained, of three treatment strategies: (a) current practice (allopurinol initiation without HLA-B*58:01 screening); (b) HLA-B*58:01 screening before allopurinol initiation; and (c) alternative treatment (probenecid) without HLA-B*58:01 screening. The model was populated with data from literature review, meta-analysis, and published government documents. Cost values were adjusted for the year 2016, with costs and health outcomes discounted at 3% per annum. A series of sensitivity analysis including probabilistic sensitivity analysis were carried out to determine the robustness of the findings. RESULTS Both HLA-B*58:01 screening and probenecid prescribing were dominated by current practice. Compared with current practice, HLA-B*58:01 screening resulted in 0.252 QALYs loss per patient at an additional cost of USD 322, whereas probenecid prescribing resulted in 1.928 QALYs loss per patient at an additional cost of USD 2203. One SJS/TEN case would be avoided for every 556 patients screened. At the cost-effectiveness threshold of USD 8695 per QALY, the probability of current practice being the best choice is 99.9%, in contrast with 0.1 and 0% in HLA-B*58:01 screening and probenecid prescribing, respectively. This is because of the low incidence of allopurinol-induced SJS/TEN in Malaysia and the lower efficacy of probenecid compared with allopurinol in gout control. CONCLUSION This analysis showed that HLA-B*58:01 genetic testing before allopurinol initiation is unlikely to be a cost-effective intervention in Malaysia.

SummaryBackground A strong association has been documented between HLA-B*15:02 and carbamazepine-induced severe cutaneous adverse reactions (SCARs) in Asians. Human leucocyte antigen testing is potentially valuable in many countries to facilitate early recognition of patient susceptibility to SCARs. Objectives To determine the cost-effectiveness of universal HLA-B*15:02 screening in preventing carbamazepine-induced Stevens–Johnson syndrome/toxic epidermal necrolysis in an ethnically diverse Malaysian population. Methods A hybrid model of a decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed epilepsy among adults: (i) carbamazepine initiation without HLA-B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to carbamazepine initiation; and (iii) alternative treatment [sodium valproate (VPA)] prescribing without HLA-B*15:02 screening. Base-case analysis and sensitivity analyses were performed over a lifetime time horizon. Incremental cost-effectiveness ratios were calculated. Results Both universal HLA-B*15:02 screening and VPA prescribing were dominated by current practice. Compared with current practice, universal HLA-B*15:02 screening resulted in a loss of 0·0255 quality-adjusted life years (QALYs) at an additional cost of 707 U.S. dollars (USD); VPA prescribing resulted in a loss of 0·2622 QALYs at an additional cost of USD 4127, owing to estimated differences in antiepileptic treatment efficacy. Conclusions Universal HLA-B*15:02 screening is unlikely to be a cost-effective intervention in Malaysia. However, with the emergence of an ethnically diverse population in many other countries, this may render HLA-B*15:02 screening a viable intervention when an increasing proportion of the population is at risk and an equally effective yet safer antiepileptic drug is available.

Aims A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. Methods The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration–time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R0), a measure of transmissibility, was linked by reduction of viral shedding duration. The number of infected patients per population of 100 000 susceptible individuals was simulated for a series of pandemic scenarios, varying oseltamivir dose, R0 (1.9 vs. 2.7), and drug uptake (25%, 50%, and 80%). The number of infected patients for each scenario was entered into the health economics module, a decision analytic model populated with branch probabilities, disease utility, costs of hospitalized patients developing complications, and case-fatality rates. Change in quality-adjusted life years was determined relative to base case. Results Oseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios. Conclusion This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework.

Background/Aims: Economic evaluation is integral to informed public health decision-making in the rapidly growing field of precision and personalized medicine (PM); however, this research requires specialized expertise and significant resources. Generic models are a novel innovation to efficiently address a critical PM evidence shortage and implementation barrier by enabling use of population-specific input values. This is a generic PM economic evaluation model proof-of-concept study for a pharmacogenomic use case. Methods: An 8-step generic economic model development process was applied to the use case of human leukocyte antigen (HLA)-B*15:02genotyping for prediction of carbamazepine-induced cutaneous reactions, with a user-friendly decision-making tool relying on user-provided input values. This generic model was transparently documented and validated, including cross-validation comparing cost-effectiveness results with 3 country-specific models. Results: A generic pharmacogenomic use case cost-effectiveness model with decision-making tool was successfully developed and cross-validated using input values for 6 populations which produced consistent results for HLA-B*15:02 screening at country-specific cost-effectiveness threshold values. Differences between the generic and country-specific model results were largely due to differences in model structure and assumptions. Conclusion: This proof on concept demonstrates the feasibility of generic models to provide useful PM economic evidence, supporting their use as a pragmatic and timely approach to address a growing need.

Background Medication non-adherence is one of the major challenges in treating patients with depression. This systematic review aims to determine the clinical and economic outcomes of non-adherence in depression. Methods A systematic search was performed across the following databases: PubMed, EMBASE, DARE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews; from database inception to March 31, 2015. Studies must report on the association between adherence and outcomes, and English full texts needed to be available. The quality of each study was assessed using the Newcastle-Ottawa scale. Results A total of 11 articles were included, with eight reporting on clinical outcomes, two reporting on economic outcomes, and one reporting on both. The majority of studies were retrospective cohort studies. The mean quality of all included studies was 7, with a range from 3 to 9. Results clearly indicate that patients who were non-adherent were more likely to experience increased risks of relapse and/or recurrence, emergency department visits, and hospitalization rates; increased severity of depression, and a decrease in response and remission rates. The worsening of clinical outcomes in patients who were non-adherent subsequently translated to an increase in healthcare utilization and charges. Limitations No standardized adherence measurement tools were used, and few studies looked at the economic impact of non-adherence in depression. Conclusion There is a strong association between non-adherence to antidepressants and a worsening of patients’ clinical and economic outcomes. Cost-effective interventions should be directed to this group of patients to improve medication adherence.

Background The emergence of personalized medicine (PM) has raised some tensions in healthcare systems. PM is expensive and health budgets are constrained - efficient healthcare delivery is therefore critical. Notwithstanding the cost, many countries have started to adopt this novel technology, including resource-limited Southeast Asia (SEA) countries. This study aimed to describe the status of PM adoption in SEA, highlight the challenges and to propose strategies for future development. Methods The study included scoping review and key stakeholder interviews in four focus countries – Indonesia, Malaysia, Singapore, and Thailand. The current landscape of PM adoption was evaluated based on an assessment framework of six key themes – healthcare system, governance, access, awareness, implementation, and data. Six PM programs were evaluated for their financing and implementation mechanisms. Results The findings revealed SEA has progressed in adopting PM especially Singapore and Thailand. A regional pharmacogenomics research network has been established. However, PM policies and programs vary significantly. As most PM programs are champion-driven and the available funding is limited, the current PM distribution has the potential to widen existing health disparities. Low PM awareness in the society and the absence of political support with financial investment are fundamental barriers. There is a clear need to broaden opportunities for critical discourse about PM especially for policymakers. Multi-stakeholder, multi-country strategies need to be prioritized in order to leverage resources and expertise. Conclusions Adopting PM remains in its infancy in SEA. To achieve an effective PM adoption, it is imperative to balance equity issues across diverse populations while improving efficiency in healthcare. Electronic supplementary material The online version of this article (10.1186/s12920-018-0420-4) contains supplementary material, which is available to authorized users.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) – dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients’ quality of life. Integrating PK/PD–EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

Objective To compare the effectiveness of various treatments used for lower pole renal calculi. Methods We searched PubMed, EMBASE, CINAHL, the Cochrane Collaboration's Database of Systematic Reviews, the Cochrane Collaboration Central Register of Controlled Clinical Trials as well as ClinicalTrials.gov for reports up to 1 April 2014. The search was supplemented with abstract reports from various urology conferences. All randomised, ‘blinded’ clinical studies including patients treated for lower pole renal calculi of

Siew Li Teoh,1 Huey Yi Chong,1 Salina Abdul Aziz,2 Norliza Chemi,2 Abdul Razak Othman,2 Nurzuriana Md Zaki,2 Possatorn Vanichkulpitak,3 Nathorn Chaiyakunapruk1,4–6 1School of Pharmacy, Monash University Malaysia, Selangor, 2Department of Psychiatry and Mental Health, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 3Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 4Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; 5School of Pharmacy, University of Wisconsin, Madison, WI, USA; 6Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Selangor, MalaysiaIntroduction: Schizophrenia (SCZ) is a highly debilitating disease despite its low prevalence. The economic burden associated with SCZ is substantial and mainly attributed to productivity loss. To improve the understanding of economic burden of SCZ in the low- and middle-income country regions, we aimed to determine the economic burden of SCZ in Malaysia.Methods: A retrospective study was conducted using a prevalence-based approach from a societal perspective in Malaysia with a 1 year period from 2013. We used micro-costing technique with bottom-up method and included direct medical cost, direct non-medical cost, and indirect cost. The main data source was medical chart review which was conducted in Hospital Kuala Lumpur (HKL). The medical charts were identified electronically by matching the unique patient’s identification number registered under the National Mental Health Schizophrenia Registry and the list of patients in HKL in 2013. Other data sources were government documents, literatures, and local websites. To ensure robustness of result, probabilistic sensitivity analysis was conducted.Results: The total estimated number of treated SCZ cases in Malaysia in 2015 was 15,104 with the total economic burden of USD 100 million (M) which was equivalent to 0.04% of the national gross domestic product. On average, the mean cost per patient was USD 6,594. Of the total economic burden of SCZ, 72% was attributed to indirect cost, costing at USD 72M, followed by direct medical cost (26%), costing at USD 26M, and direct non-medical cost (2%), costing at USD 1.7M.Conclusion: This study highlights the magnitude of economic burden of SCZ and informs the policy-makers that there is an inadequate support for SCZ patients. More resources should be allocated to improve the condition of SCZ patients and to reduce the economic burden.Keywords: economic burden, schizophrenia, Malaysia, cost of illness, lower-income countries, middle-income countries, societal perspective

Background. The efficacy of antimicrobial central venous catheters (CVCs) remains questionable. In this network meta-analysis, we aimed to assess the comparative efficacy of antimicrobial CVC impregnations in reducing catheter-related infections in adults. Methods. We searched 4 electronic databases (Medline, the Cochrane Central Register of Controlled Trials, Embase, CINAHL) and internet sources for randomized controlled trials, ongoing clinical trials, and unpublished studies up to August 2016. Studies that assessed CVCs with antimicrobial impregnation with nonimpregnated catheters or catheters with another impregnation were included. Primary outcomes were clinically diagnosed sepsis, catheter-related bloodstream infection (CRBSI), and all-cause mortality. We performed a network meta-analysis to estimate risk ratio (RR) with 95% confidence interval (CI). Results. Sixty studies with 17 255 catheters were included. The effects of 14 impregnations were investigated. Both CRBSI and catheter colonization were the most commonly evaluated outcomes. Silver-impregnated CVCs significantly reduced clinically diagnosed sepsis compared with silver-impregnated cuffs (RR, 0.54 [95% CI, .29-.99]). When compared to no impregnation, significant CRBSI reduction was associated with minocycline-rifampicin (RR, 0.29 [95% CI, .16-.52]) and silver (RR, 0.57 [95% CI, .38-.86]) impregnations. No impregnations significantly reduced all-cause mortality. For catheter colonization, significant decreases were shown by miconazole-rifampicin (RR, 0.14 [95% CI, .05-.36]), 5-fluorouracil (RR, 0.34 [95% CI, .14-.82]), and chlorhexidine-silver sulfadiazine (RR, 0.60 [95% CI, .50-.72]) impregnations compared with no impregnation. None of the studies evaluated antibiotic/ antiseptic resistance as the outcome. Conclusions. Current evidence suggests that the minocycline-rifampicin-impregnated CVC appears to be the most effective in preventing CRBSI. However, its overall benefits in reducing clinical sepsis and mortality remain uncertain. Surveillance for antibiotic resistance attributed to the routine use of antimicrobial-impregnated CVCs should be emphasized in future trials.

The emergence of personalised medicine (PM) indicates a potential transformative point to a greater efficiency in Southeast Asia (SEA)’s healthcare. This research aims to provide PM-related evidence to policymakers, to facilitate an informed adoption decision and improve policies underpinning PM adoption in SEA. Cost-effectiveness evidence was generated for two PM interventions, and the current PM adoption landscape in SEA was described. Adopting PM remains in its infancy in SEA. Local health technology assessment should consider cost-effectiveness evidence and broader societal impacts of PM for an informed decision-making. Substantial future work is needed to support an efficient, equitable PM adoption.

A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios.The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration-time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (ROseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios.This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework.

Background Seven-valent pneumococcal conjugate vaccines (PCV7) have been used in children for more than a decade. Given the observed increase in disease caused by pneumococcal serotypes not covered by PCV7, an increasing number of countries are switching from 7-valent to 10- and 13-valent PCVs (“PCV10” and “PCV13”). Economic evaluations are important tools to inform decisions and price negotiations to make such a switch. Objective This review aims to provide a critical assessment of economic evaluations involving PCV10 or PCV13, published since 2006. Methods We searched Scopus, ISI Web of Science (SCI and SSCI) and Pubmed to retrieve, select and review relevant studies, which were archived between 1st January 2006 and 31st January 2014. The review protocol involved standard extraction of assumptions, methods, results and sponsorships from the original studies. Results Sixty-three economic evaluations on PCVs published since January 2006 were identified. About half of these evaluated PCV10 and/or PCV13, the subject of this review. At current prices, both PCV13 and PCV10 were likely judged preferable to PCV7. However, the combined uncertainty related to price differences, burden of disease, vaccine effectiveness, herd and serotype replacement effects determine the preference base for either PCV10 or PCV13. The pivotal assumptions and results of these analyses also depended on which manufacturer sponsored the study. Conclusion A more thorough exploration of uncertainty should be made in future analyses on this subject, as we lack understanding to adequately model herd and serotype replacement effects to reliably predict the population impact of PCVs. The introduction of further improved PCVs in an environment of evolving antibiotic resistance and under the continuing influence of previous PCVs implies that the complexity and data requirements for relevant analyses will further increase. Decision makers using these analyses should not just rely on an analysis from a single manufacturer.

Introduction Pharmacogenetic (PGx) test is a useful tool for guiding physician on an initiation of an optimal warfarin dose. To implement of such strategy, the evidence on the economic value is needed. This study aimed to determine the cost-effectiveness of PGx-guided warfarin dosing compared with usual care (UC). Methods A decision analytic model was used to compare projected lifetime costs and quality-adjusted life years (QALYs) accrued to warfarin users through PGx or UC for a hypothetical cohort of 1,000 patients. The model was populated with relevant information from systematic review, and electronic hospital-database. Incremental cost-effectiveness ratios (ICERs) were calculated based on healthcare system and societal perspectives. All costs were presented at year 2013. A series of sensitivity analyses were performed to determine the robustness of the findings. Results From healthcare system perspective, PGx increases QALY by 0.002 and cost by 2,959 THB (99 USD) compared with UC. Thus, the ICER is 1,477,042 THB (49,234 USD) per QALY gained. From societal perspective, PGx results in 0.002 QALY gained, and increases costs by 2,953 THB (98 USD) compared with UC (ICER 1,473,852 THB [49,128 USD] per QALY gained). Results are sensitive to the risk ratio (RR) of major bleeding in VKORC1 variant, the efficacy of PGx-guided dosing, and the cost of PGx test. Conclusion Our finding suggests that PGx-guided warfarin dosing is unlikely to be a cost-effective intervention in Thailand. This evidence assists policy makers and clinicians in efficiently allocating scarce resources.