Real-world costs of transvenous lead extraction: the challenge for reimbursement.

AIMS: Transvenous lead extraction is challenging, often requiring specialist equipment and prolonged hospital admission. A single tariff or itemized costs may be available for reimbursement. Due to limited data relating to the costs of transvenous extraction, it is unclear whether either form of reimbursement is adequate. We aim to describe accurately the total real-world costs of managing patients undergoing transvenous extraction at a single, large centre. We further aim to consider the additional costs of device reimplantation. METHODS AND RESULTS: At a single UK extraction centre, a retrospective, patient level service line analysis was undertaken, during a complete financial year. Seventy-four patients required transvenous extraction (47 infected and 27 non-infected; 156 leads). Sixty-nine procedures (93%) were performed under general anaesthesia, with a median time in theatre of 95 min [interquartile range (IQR) 71-120]. Specialist extraction tools were required for 130 leads (83%). The median hospitalization duration was 3 days (IQR 1-8). The mean cost of extraction was £9228 (±4099); infected £10 727 (±4178) and non-infected £6619 (±2269). With the additional costs of device reimplantation, the overall mean cost rose to £17 574 (±12 882); infected £22 615 (±13 343) and non-infected £8801 (±5007). At the time of this study, the UK NHS tariff was £2530 for elective and £4764 for non-elective extraction, covering barely half of the real costs. CONCLUSION: We demonstrated a substantial difference between the real-world cost of extraction and the UK NHS tariff. Extracting centres should scrutinize their practice, including the timing of reimplantation.

Foley catheterisation versus oral misoprostol for induction of labour in hypertensive women in India (INFORM): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Between 62 000 and 77 000 women die annually from pre-eclampsia and eclampsia. Prompt delivery, preferably by the vaginal route, is vital for good maternal and neonatal outcomes. Two low-cost interventions-low-dose oral misoprostol tablets and transcervical Foley catheterisation-are already used in low-resource settings. We aimed to compare the relative risks and benefits of these interventions. METHODS: We undertook this multicentre, open-label, randomised controlled trial in two public hospitals in Nagpur, India. Women (aged ≥18 years) who were at 20 weeks' gestation or later with a live fetus and required delivery as a result of pre-eclampsia or hypertension were randomly assigned (1:1), via computer-generated block randomisation (block sizes of four, six, and eight) with concealment by use of opaque, sequentially numbered, sealed envelopes, to receive labour induction with either oral misoprostol 25 µg every 2 h (maximum of 12 doses) or a transcervical Foley catheter (silicone, size 18 F with 30 mL balloon). Randomisation was stratified by study centre. The catheter remained in place until active labour started, the catheter fell out, or 12 h had elapsed. If the catheter did not fall out within 12 h, induction continued with artificial membrane rupture and oxytocin, administered through a micro-drip gravity infusion set. Fetal monitoring was by intermittent auscultation. The primary outcome was vaginal birth within 24 h. Due to the nature of the interventions, masking of participants, study investigators, and care providers to group allocation was not possible. We analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01801410. FINDINGS: Between Dec 20, 2013, and June 29, 2015, we randomly assigned 602 women to induction with misoprostol (n=302) or the Foley catheter (n=300; intention-to-treat population). Vaginal birth within 24 h was more common in women in the misoprostol group than in the Foley catheter group (172 [57·0%] vs 141 [47·0%] women; absolute risk difference 10·0%, 95% CI 2·0-17·9; p=0·0136). Rates of uterine hyperstimulation were low in both the misoprostol and Foley catheter groups (two [0·7%] vs one [0·3%] cases; absolute risk difference 0·3%, 95% CI -0·8 to 1·5; p=0·566) and neonatal deaths did not differ significantly between groups (six [2·0%] vs three [1·0%] neonatal deaths; 1·0, -1·04 to 2·97; p=0·322). 17 serious adverse events (3%) were reported during the study: one case of intrapartum convulsion and one case of disseminated intravascular coagulation (both in the Foley group); ten perinatal deaths, including two stillbirths (both in the Foley catheter group) and eight neonatal deaths (n=5 in the misoprostol group and n=3 in the Foley catheter group); and five of neonatal morbidity, comprising birth asphyxia (n=3), septicaemia (n=1), and neonatal convulsion (n=1). INTERPRETATION: Oral misoprostol was more effective than transcervical Foley catheterisation for induction of labour in women with pre-eclampsia or hypertension. Future studies are required to assess whether oxytocin augmentation following misoprostol can be replaced by regular doses of oral misoprostol tablets. FUNDING: Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials Scheme.

Evaluating the use of plerixafor in stem cell mobilisation - an economic analysis of the PHANTASTIC trial.

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor-mobilised patients achieved the composite primary endpoint of ≥4 × 10(6) CD34+ cells kg(-1) in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. © 2015 Wiley Periodicals, Inc.

A Single-Center Randomized Trial of Intraoperative Zero-Balanced Ultrafiltration During Cardiopulmonary Bypass for Patients With Impaired Kidney Function Undergoing Cardiac Surgery.

OBJECTIVES: The authors investigated whether zero-balance ultrafiltration (Z-BUF) during bypass significantly improves clinical and cost outcomes or biomarkers of kidney injury for patients with preoperative kidney impairment (estimated glomerular filtration rate [eGFR]<60 mL/minute) undergoing cardiac surgery. DESIGN: A single-center randomized controlled trial recruited, patients between 2010 and 2013, with a 12-months follow-up. SETTING: Hospital. PARTICIPANTS: One hundred ninety-nine patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Patients were assigned randomly to receive zero-balance ultrafiltration (Z-BUF) or not, with stratification for degree of kidney dysfunction and diabetes. MEASUREMENTS AND MAIN RESULTS: The authors assessed clinical efficacy and kidney function biomarkers. Cumulative probability of discharge from the intensive care unit (ICU) was assessed by Kaplan-Meier plots and was found not to be significantly different between the two trial arms (p = 0.61). After adjusting for EuroSCORE, diabetes, eGFR, cardioplegia types and type of surgery in a Cox proportional hazard model, hazard ratios (HR) for ICU length of stay between the Z-BUF and no-Z-BUF groups was not significantly different: HR (95% CI): 0.89 (0.66, 1.20; p = 0.44). In contrast, significant reductions in postoperative chest infections and the composite of clinical endpoints (death, strokes, and myocardial infarctions) in the Z-BUF group were observed. In addition, Z-BUF significantly abrogated the rise in the kidney damage markers urinary NGAL/creatinine ratio, urea, creatinine and eGFR during CPB and adverse events risks. CONCLUSIONS: Z-BUF during bypass surgery is associated with significant reductions in morbidity and biomarkers of CPB-induced acute kidney injury soon after CPB, which are indicative of clearance of inflammatory/immune mediators from the circulation.

Induction of labour in pre-eclamptic women: a randomised trial comparing the Foley balloon catheter with oral misoprostol.

BACKGROUND: Between 40,000 and 80,000 pregnant women die annually from pre-eclampsia and eclampsia. Although magnesium sulphate and anti-hypertensive therapies can reduce the morbidity and mortality associated with pre-eclampsia, the only cure comes with delivery. Prompt delivery of the baby, preferably by vaginal route, is vital in order to achieve good maternal and neonatal outcomes. Induction of labour is therefore a critical intervention in order to prevent morbidity to both mother and baby. Two low cost interventions - oral misoprostol tablets and transcervical Foley catheterization - are already used by some in low resource settings, but their relative risks and benefits are not known. The trial will compare the risks, benefits, and trade-offs in efficacy, safety, acceptability and cost of misoprostol and Foley catheter for induction in women with preeclampsia or uncontrolled hypertension. METHODS/DESIGN: A total of 602 women with an ongoing pregnancy with a live fetus requiring delivery because of pre-eclampsia or uncontrolled hypertension will be randomly assigned to labor induction with a transcervical Foley catheter or oral misoprostol 25 micrograms. Women will be recruited at two hospitals in Nagpur, India. The misoprostol group will receive oral misoprostol 25 microgram every 2 hours for a maximum of 12 doses or until active labor commences. The Foley group will undergo induction using a Foley catheter (silicone, size 18 F with 30 ml balloon) which will remain until active labor starts, the Foley catheter falls out, or 12 hours have elapsed. The primary outcome will be the attainment of vaginal delivery within 24 hours. Providers administering the treatment and those assessing the outcomes will not be blinded to group assignment. TRIAL REGISTRATION: NCT01801410 (ClinicalTrials.gov).

Personalizing health care: feasibility and future implications.

Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer's perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.

Quantifying the relationship between disability progression and quality of life in patients treated for NMOSD: Insights from the SAkura studies.

BACKGROUND: To date, no specific scales have been developed to explore the impact of neuromyelitis optica spectrum disorder (NMOSD)-related disability on quality of life (QoL). The Expanded Disability Status Scale (EDSS) and the EuroQol 5-dimensions (EQ-5D) have been used to assess disability and QoL, respectively, in patients with NMOSD. However, there is limited evidence surrounding their use in this condition. We compared EDSS and EQ-5D data across two clinical trials to quantify the relationship between disability and QoL in patients with NMOSD. METHODS: SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279) were Phase 3, multicenter, randomized, international, double-blind, placebo-controlled, parallel-assignment studies of satralizumab, administered in combination with baseline immunosuppressants (SAkuraSky) or as monotherapy (SAkuraStar). EDSS and EQ-5D were assessed at baseline and at 24-week intervals thereafter. The relationship between disability and QoL was assessed by estimating EQ-5D utilities (UK tariff) for each incremental EDSS category. A repeated-measures linear model was used to regress health utilities on EDSS score-derived health states. RESULTS: Overall, 176 patients underwent at least one EDSS assessment and completed an EQ-5D survey and were included in this analysis. There was a clear association between mean EQ-5D score and EDSS score, with decreases in QoL being observed at each incremental increase in disability. The relationship between EDSS and EQ-5D score remained consistent across the different treatment groups. CONCLUSIONS: These results, generated from high-quality clinical trial data, demonstrated a strong and consistent relationship between disability and QoL in patients with NMOSD.

The Induction with Foley OR Misoprostol (INFORM) Study dataset. A dataset of 602 women with hypertensive disease in pregnancy, in India, randomised to either Foley catheter or oral misoprostol for induction of labour.

OBJECTIVES: Induction of labour (IOL), or starting labour artificially, can be a lifesaving intervention for pregnant women and their babies, and rates are rising significantly globally. As rates increase, it becomes increasingly important to fully evaluate all available data, especially that from low income settings where the potential benefits and harms are greater. The goal of this paper is to describe the datasets collected as part of the Induction with Foley OR Misoprostol (INFORM) Study, a randomised trial comparing two of the recommended methods of cervical ripening for labour induction, oral misoprostol and Foley catheter, in women being induced for hypertension in pregnancy, at two sites in India during 2013-15. DATA DESCRIPTION: This dataset includes comprehensive data on 602 women who underwent IOL for hypertensive disorders in pregnancy. Women were randomly assigned to cervical ripening with oral misoprostol or a transcervical Foley catheter in two government hospitals in India. The main dataset has 367 variables including monitoring during the induction of labour, medications administered, timing and mode of delivery, measures of neonatal morbidity and mortality, maternal mortality and morbidity, maternal satisfaction and health economic data. The dataset is anonymised and available on ReShare.

Risk sharing arrangements for pharmaceuticals: potential considerations and recommendations for European payers.

BACKGROUND: There has been an increase in 'risk sharing' schemes for pharmaceuticals between healthcare institutions and pharmaceutical companies in Europe in recent years as an additional approach to provide continued comprehensive and equitable healthcare. There is though confusion surrounding the terminology as well as concerns with existing schemes. METHODS: A literature review was undertaken to identify existing schemes supplemented with additional internal documents or web-based references known to the authors. This was combined with the extensive knowledge of health authority personnel from 14 different countries and locations involved with these schemes. RESULTS AND DISCUSSION: A large number of 'risk sharing' schemes with pharmaceuticals are in existence incorporating both financial-based models and performance-based/outcomes-based models. In view of this, a new logical definition is proposed. This is "risk sharing' schemes should be considered as agreements concluded by payers and pharmaceutical companies to diminish the impact on payers' budgets for new and existing schemes brought about by uncertainty and/or the need to work within finite budgets". There are a number of concerns with existing schemes. These include potentially high administration costs, lack of transparency, conflicts of interest, and whether health authorities will end up funding an appreciable proportion of a new drug's development costs. In addition, there is a paucity of published evaluations of existing schemes with pharmaceuticals. CONCLUSION: We believe there are only a limited number of situations where 'risk sharing' schemes should be considered as well as factors that should be considered by payers in advance of implementation. This includes their objective, appropriateness, the availability of competent staff to fully evaluate proposed schemes as well as access to IT support. This also includes whether systematic evaluations have been built into proposed schemes.

Ongoing pharmaceutical reforms in France: implications for key stakeholder groups.

The rapid rise in pharmaceutical costs in France has been driven by new technologies and the growing prevalence of chronic diseases as well as considerable prescribing freedom and choice of physician among patients. This has led to the introduction of a number of reforms and initiatives in an attempt to moderate expenditure whilst ensuring universal coverage and rewarding innovation. These reforms include accelerating access to and granting average European prices for new innovative drugs, delisting drugs where there are concerns over their value and instigating rebates for excessive prescribing. Alongside this, ongoing initiatives to improve the quality and efficiency of prescribing include programmes to enhance generic prescribing and dispensing as well as to reduce antibacterial and anxiolytic/hypnotic prescribing. However, there have been few publications documenting the impact of specific reforms on the overall costs and quality of care, which have been exacerbated by compartmentalization of budgets. Estimates suggest savings of over 27 million euro/year by decreasing antibacterial prescribing, 450 million euro/year by not reimbursing ineffective drugs, 670 million euro/year from pharmaceutical company rebates and approximately 1 billion euro/year from increased prescribing and dispensing of generics (year 2003-7 values). Additional savings of at least 1.5 billion euro/year are seen as being possible from increased use of generics such as generic proton pump inhibitors, statins (HMG-CoA reductase inhibitors) and ACE inhibitors instead of current branded products such as angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). Delisting drugs when there are concerns about their value provides an example to other countries with currently limited demand-side measures. Other possible examples include price : volume agreements and multifaceted campaigns to enhance generic prescribing and dispensing and reduce antibacterial prescribing. Possible future initiatives could include adopting more stringent criteria for categorizing new drugs as innovative as well as further reductions in the prices of generics. Other initiatives could include further enhancement of the quality and efficiency of prescribing, including formal auditing of physician prescribing, as well as increasing efforts to monitor the risk : benefit ratio of new drugs post-launch in real-world practice.

Proposal for a regulation on health technology assessment in Europe - opinions of policy makers, payers and academics from the field of HTA.

INTRODUCTION: In January 2018 the European Commission published a Proposal for a Regulation on Health Technology Assessment (HTA): 'Proposal for a Regulation on health technology assessment and amending Directive 2011/24/EU'. A number of stakeholders, including some Member States, welcomed this initiative as it was considered to improve collaboration, reduce duplication and improve efficiency. There were however a number of concerns including its legal basis, the establishment of a single managing authority, the preservation of national jurisdiction over HTA decision-making and the voluntary/mandatory uptake of joint assessments by Member States. Areas covered: This paper presents the consolidated views and considerations on the original Proposal as set by the European Commission of a number of policy makers, payers, experts from pricing and reimbursement authorities and academics from across Europe. Expert commentary: The Proposal has since been extensively discussed at Council and while good progress has been achieved, there are still divergent positions. The European Parliament gave a number of recommendations for amendments. If the Proposal is approved, it is important that a balanced, improved outcome is achieved for all stakeholders. If not approved, the extensive contribution and progress attained should be sustained and preserved, and the best alternative solutions found.

Having your cake and eating it: office of fair trading proposal for funding new drugs to benefit patients and innovative companies.

There are insufficient resources in the UK to fund all new technologies and new indications approved by the National Institute for Health and Clinical Excellence (NICE). Diverting funding from existing sources will have a detrimental effect on the provision of other priority services. The UK Office of Fair Trading (OFT) recently suggested a value-based pricing approach that appears workable but has generated considerable debate. Their proposal of a 25% premium for the originator product once generics are available is more generous than seen in a number of other European countries, where typically only the lowest priced product is reimbursed. The OFT proposal for a maximum 50% premium for patent-protected products, versus the prices of generics in a class or related classes, is also more generous than the proposed reforms for the pricing of proton pump inhibitors in Sweden or current reforms in Germany. In our opinion, the OFT proposals are persuasive and in accordance with the reforms seen in other European countries, and therefore should be adopted. The alternatives to fully funding new drugs or new indications as approved by NICE are either tightening the cost per QALY threshold, giving NICE an annual national budget to fund its advice alongside suggested areas for disinvestment, proactively switching patients from high-cost brand-name drugs to generics, or further delaying funding for new drugs and new indications approved by NICE. The majority of these suggestions are not in the best interests of patients or innovative pharmaceutical companies seeking to reap the rewards of their efforts.

Recent national and regional drug reforms in Sweden: implications for pharmaceutical companies in Europe.

With an aging population and increased prevalence of chronic diseases, such as obesity and diabetes mellitus, drug reforms are needed across Europe to ensure the continued provision of comprehensive healthcare. It is also a challenge, with the limited resources available, to fund new innovative drugs that significantly improve patient health. Recent national and regional reforms in Sweden have moderated the rate of increase in drug expenditure, despite increased volumes of drug use and the launch of new, expensive drugs. National reforms include the adoption of economic principles when assessing the value and subsequent reimbursement of new and existing drugs, as well as reforms to obtain low prices for generic drugs. Regional reforms aim to encourage the rational use of medicines through the establishment of drug and therapeutic committees, development of guidelines, academic detailing, continuous benchmarking of prescribing patterns, and financial incentives. Some of these reforms provide examples to other European countries, whilst others duplicate existing measures. As such, we believe other European countries can benefit from an analysis of the Swedish reforms. We believe the pharmaceutical industry can also benefit from this analysis by working with key regional payers involved with developing and implementing the reforms as they moderate and refine their future activities, including finding acceptable ways of introducing new expensive drugs.

Cost effectiveness of asthma treatment with a breath-actuated inhaler: how has the story changed?

OBJECTIVES: A database analysis evaluating the comparative costs and outcomes of asthma treatment with breath-actuated inhalers (BAIs) and metered-dose inhalers (MDIs) has previously been undertaken in 2001. This analysis found that, despite the higher acquisition cost associated with BAIs, economies elsewhere meant that the overall cost associated with BAIs was lower than MDIs. Between 2001 and 2007, the comparative price of MDIs was significantly reduced thus widening the gap between the comparative acquisition cost of MDIs and BAIs. Furthermore, the introduction of specific targets for asthma review included a requirement for regular checks on inhaler technique. Such initiatives may be expected to enhance the overall effectiveness of MDIs. Given the potential impact of such changes, it appeared to be timely to update the original database analysis to assess the extent to which the original findings have been altered by changes in the clinical and economic environment over the past 5 years. METHODS: As in all chronic diseases, it is important that economic analyses evaluate cost effectiveness over as long a period as possible, and so the 2006 analysis was conducted over a 12- and a 24-month time period. RESULTS: The results emphasised that the clinical benefits associated with BAIs for certain patients can still be translated into greater cost effectiveness, but that altered cost structures required a longer time period for the greater cost effectiveness of BAIs to become evident. CONCLUSION: Since completing this study, the reimbursement costs for beclometasone MDIs have increased significantly (since October 2007) due to the discontinuation of Becotide and Becloforte. As a consequence of this higher acquisition cost for MDI inhalers, the current cost-effectiveness advantages of BAI compared to MDI can be expected to be even greater than that identified in the study.

Utilization and Expenditure of Anti-cancer Medicines in Kosovo: Findings and Implications.

BACKGROUND AND OBJECTIVE: The Ministry of Health (MoH) leads and organizes health policy in Kosovo, which includes procurement and provision of medicines, including anti-cancer medicines, which compose a special group of medicines. However, there has been limited analysis of the utilization and expenditure on anti-cancer medicines in Kosovo; consequently, the objective of this study is to undertake research to provide future guidance on the use of anti-cancer medicines. METHOD: National drug utilization data is available in Kosovo. Utilization and expenditure on anti-cancer medicines [Anatomical Therapeutic Chemical (ATC) code L], initially from 2011 to 2013, especially for anti-cancer medicines on the essential medicines list was analysed from national data. In addition, current systems for procuring and managing anti-cancer medicines in Kosovo was documented. RESULTS: There was appreciable variability in the utilization of anti-cancer medicines over the years, with low or limited use of some anti-cancer medicines on the Essential Medicine List. This is a concern in view of their essential medicine status. From 2011 to 2013, €16.49 million was spent on anti-cancer medicines (ATC L). The process of selection of new medicines begins with suggestions from doctors at the University Clinical Centre in Kosovo. CONCLUSION: The analysis has shown appreciable variation with current utilization patterns for anti-cancer medicines in Kosovo. This needs to be addressed as part of improving the drug management process to optimize patient care within available resources. Future years and reforms need to be assessed to improve current utilization and expenditure patterns.

Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies.

Overexpression of the HER2 gene is predictive of treatment benefit with trastuzumab therapy for breast cancer (BC) patients. The study objective was to investigate whether all eligible patients with HER2-positive BC initiated trastuzumab therapy. A systematic search was conducted through PubMed, Web of Science PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library. From 2651 studies identified, 107 observational studies were included for full text review, of which 26 met the inclusion criteria and an additional 7 studies were identified through citation searching. Two independent reviewers extracted data for accuracy and completeness. From 33 observational studies, 14,644 patients were exposed to trastuzumab therapy. Age range varied across studies; the youngest cohort had a median age of 50 and the oldest had a median age of 84. Sample sizes ranged from 11 to 1928 and included patients from 10 countries. Studies were heterogenous and few studies accounted for confounders. We identified large variability in uptake of trastuzumab in HER2-positive early BC patients (9.1-100%) and metastatic BC patients (50.8-84.0%). The pooled uptake was 71.3% (95% CI 64.6-77.9%), with high heterogeneity (I2 = 99.05%). The most conservative predictors of higher uptake included younger age (OR 2.09; 95% CI 1.36-3.20) and lower Charlson Comorbidity Index of patients (OR 1.62; 95% CI 1.32-1.99). In addition, tumour characteristics including higher tumour grade (OR 1.73; 95% CI 1.23-2.45), larger tumour size (OR 1.80; 95% CI 1.54-2.10), advanced tumour stage (OR 2.07; 95% CI 1.44-2.96) and hormone receptor negative tumor (OR 1.54; 95% CI 1.35-1.77) were associated with higher uptake. The uptake of trastuzumab therapy varied widely between studies and across subgroups suggesting that there may be some inequalities in the use of this agent. However, our findings should be interpreted with caution due to study heterogeneity and potential confounding, and thus additional studies of individual level data which control for confounders are needed to understand more about inequalities in uptake.

Incidence, aetiology, and sequelae of viral meningitis in UK adults: a multicentre prospective observational cohort study.

BACKGROUND: Viral meningitis is increasingly recognised, but little is known about the frequency with which it occurs, or the causes and outcomes in the UK. We aimed to determine the incidence, causes, and sequelae in UK adults to improve the management of patients and assist in health service planning. METHODS: We did a multicentre prospective observational cohort study of adults with suspected meningitis at 42 hospitals across England. Nested within this study, in the National Health Service (NHS) northwest region (now part of NHS England North), was an epidemiological study. Patients were eligible if they were aged 16 years or older, had clinically suspected meningitis, and either underwent a lumbar puncture or, if lumbar puncture was contraindicated, had clinically suspected meningitis and an appropriate pathogen identified either in blood culture or on blood PCR. Individuals with ventricular devices were excluded. We calculated the incidence of viral meningitis using data from patients from the northwest region only and used these data to estimate the population-standardised number of cases in the UK. Patients self-reported quality-of-life and neuropsychological outcomes, using the EuroQol EQ-5D-3L, the 36-Item Short Form Health Survey (SF-36), and the Aldenkamp and Baker neuropsychological assessment schedule, for 1 year after admission. FINDINGS: 1126 patients were enrolled between Sept 30, 2011, and Sept 30, 2014. 638 (57%) patients had meningitis: 231 (36%) cases were viral, 99 (16%) were bacterial, and 267 (42%) had an unknown cause. 41 (6%) cases had other causes. The estimated annual incidence of viral meningitis was 2·73 per 100 000 and that of bacterial meningitis was 1·24 per 100 000. The median length of hospital stay for patients with viral meningitis was 4 days (IQR 3-7), increasing to 9 days (6-12) in those treated with antivirals. Earlier lumbar puncture resulted in more patients having a specific cause identified than did those who had a delayed lumbar puncture. Compared with the age-matched UK population, patients with viral meningitis had a mean loss of 0·2 quality-adjusted life-years (SD 0·04) in that first year. INTERPRETATION: Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services. FUNDING: Meningitis Research Foundation and UK National Institute for Health Research.

An assessment of the impact of pharmacogenomics on health disparities: a systematic literature review.

This review assessed evidence of disparities in benefits of pharmacogenomics related to 'model performance' in subgroups of patients and studies which reported impact on health inequalities. 'Model performance' refers to the ability of algorithms including clinical, environmental and genetic information to guide treatment. A total of 4978 abstracts were screened by one reviewer and 30% (1494) were double screened by a second independent reviewer, after which data extraction was performed. Additional forward and backward citation searching of reference lists was conducted. Investigators independently double rated study quality and applicability of included studies. Only five individual studies were identified which met our inclusion criteria, but were contradictory in their conclusions. While three studies of genotype-guided dosing of warfarin reported that ethnic disparities in healthcare may widen, two other studies (one reporting on warfarin and reporting on clopidogrel) suggested that disparities in healthcare may reduce. There is a paucity of studies which evaluates the impact of pharmacogenomics on health disparities. Further work is required not only to evaluate health disparities between ethnic groups and countries but also within ethnic groups in the same country and solutions need to be identified to overcome these disparities.

The Implementation of Managed Entry Agreements in Central and Eastern Europe: Findings and Implications.

BACKGROUND: Managed entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available. METHOD: We conducted a survey on the implementation of MEAs in CEE between January and March 2017. RESULTS: Sixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC)-L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%). CONCLUSIONS: Experience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation.

Adaptive Pathways: Possible Next Steps for Payers in Preparation for Their Potential Implementation.

Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The "introduction" of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers.