Can Cyprus Afford Luspatercept? A Budget Impact Analysis of the Reimbursement of Luspatercept for the Management of Thalassaemia in Cyprus.

OBJECTIVE: This study aims to estimate the budget impact of luspatercept reimbursement as an adjuvant to the standard management of ß-thalassaemia major in Cyprus, from a societal perspective, and assess the financial feasibility of its inclusion in the ß-thalassaemia armamentarium. METHODS: A 5-year horizon budget impact model was developed to determine the budget impact of reimbursing luspatercept for the management of ß-thalassaemia major in Cyprus. Two treatment discontinuation scenarios were elaborated. In the first scenario, luspatercept is reimbursed complementary to best supportive care, and a dropout rate of 40% is assumed based on published real-world data, while for the second scenario a dropout rate of 25%, is assumed as per the clinical trial data. Input parameters were retrieved from the phase III clinical trial of luspatercept, literature, and expert opinion consensus. One-way sensitivity analyses were conducted for both scenarios. RESULTS: The addition of luspatercept to the standard management of ß-thalassaemia major in Cyprus imparted an incremental budget impact ranging from €21,300,643 to €25,834,368, depending on the drop-out rate scenario assumed. Results were sensitive to the number of eligible patients and dose per patient. CONCLUSION: The potential reimbursement of luspatercept will wield a substantial impact on Cyprus total pharmaceutical expenditure and it is therefore imperative to affix a reimbursement framework that will allow the payer to mitigate uncertainty stemming out of the scarce clinical data and the inherently complex therapeutic landscape of ß-thalassemia management.

Implementing a Managed Entry Agreement Framework in Cyprus.

INTRODUCTION: The aim of this study is to explore the current practice in Cyprus regarding the introduction and reimbursement of innovative pharmaceuticals through Managed Entry Agreements (MEA), assess its operational context, and suggest approaches toward spanning the knowledge gap consequential to these efforts, especially the barriers of a small country context. AREAS COVERED: The recent introduction of a National Health System (NHS), brought about fundamental reforms in Cyprus' Healthcare sector. Among such reforms, of particular interest, has been the introduction of a Managed Entry Agreements (MEA) mechanism. The first preliminary results indicate that despite being a small and unattractive market, Cyprus can apply a substantial MEA program. Concomitantly, it annotates the need to design an operational framework which should include, the definition of important technical parameters, clear demarcation of the scope, cooperation principles ensuring the effective operation of scientific committees, and clear delineation of what 'value' is. Moreover, in the context of the unified healthcare market, budget transfers should be considered, which could alleviate the inordinate budget impact of new products, which nevertheless will cut down on hospital expenditures. Narrative synthesis and health policy analysis-related resources were used. EXPERT OPINION: The implementation of MEA in Cyprus provides an ideal testing ground for innovative reimbursement approaches. This will streamline the country's efforts toward reimbursement of innovation, while concomitantly add to the collective MEA experience.

Is it a chimera? A systematic review of the economic evaluations of CAR-T cell therapy - an update.

INTRODUCTION: The new class of chimeric antigen receptor T-cell has emboldened health-care professionals and patients for a more effective treatment of hematological malignancies, indicatively lymphoma, acute lymphoblastic leukemia, and myeloma. Nevertheless, their burgeoning procurement costs comprise a litmus stress for health systems across the globe. In this context, this systematic review aims to update the current body of evidence assessing CAR-T economic evaluations and elucidate their financial efficiency. AREAS COVERED: A systematic review of the economic evaluations of tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel and brexucabtagene autoleucel was performed. EXPERT OPINION: The updated results corroborated the previously reported favorable cost-effectiveness ratio of CAR-T. They also pointed out differences among CAR-T agents. However, their budget impact emerges as a significant barrier in the reimbursement process. Any proposed Managed Entry Agreement must integrate the ingrained uncertainty of long-term efficacy and precede reimbursement decisions.

The economics of TAVI: A systematic review.

Objective: The scope of this systematic review is to update the existing body of evidence regarding the cost-effectiveness of transcatheter aortic valve implantation, stratified across all risk categories, and to assess their methodological quality. Methods: A systematic review was performed including published cost-effectiveness analyses of heart valve implantations. The quality was assessed with the Quality of Health Economics Tool. Results: We identified 33 economic evaluations of transcatheter aortic heart valve implantations. Results were not consistent, ranging from dominant to dominating. Moreover, the models were sensitive to an array of variables. The methodological quality of the studies was good. Conclusion: This systematic review led to inconclusive and inconsistent results pertinent to the economic profile of TAVI technology. It also highlighted areas which merit further research regarding the pillars of cost-effectiveness analysis such as modeling, the extrapolation of available data and the uncertainty of the evidence. A thorough assessment of the patient should proceed any decision-making.

Budget impact analysis of daratumumab for light-chain amyloidosis in Cyprus.

OBJECTIVE: The aim of this study is to assess the budget impact of daratumumab for light-chain amyloidosis in Cyprus. METHODS: A budget impact model assessed the cost prior and after the introduction of daratumumab for light-chain amyloidosis. All related costs were set from the perspective of Cyprus NHS. Clinical data were extracted from the published trials. One-way sensitivity analysis was conducted. We reported incremental budget impact, per member per month, per year, and per treated member per month. RESULTS: The introduction of D-VCd led to a net budget impact of €254,264 in the first year, which escalated to €497,007 by fifth year. The PMPY was estimated at €0.2893 in the first year, reaching €0.5246 at fifth year, the PMPM were at €0.0241 at the first year escalating to €0.0437 at the fifth year, and the PTMPM costs were €2,379 at the first year and gauged to €4,435 by fifth year. Our results were sensitive to incidence of the disease, percentage of patients without cardiac involvement and daratumumab cost. CONCLUSIONS: The introduction of daratumumab for AL amyloidosis, with a 90% annual uptake over 5 years, leads to a substantial budget impact. Managed entry agreement schemes can be considered in order to mitigate the impact.

Comparison of validation protocols for blood pressure measuring devices in children and adolescents.

Accuracy of blood pressure (BP) measurement is important for the evaluation of hypertension in children and adolescents, and it is critically dependent upon the accuracy of the BP measuring device. A device that could pass validated protocols with reliable accuracy would be desirable in clinical and research settings. Several scientific organizations have published recommendations on the validation of different BP measuring devices. Most of them focus on adults but separate recommendations and validation criteria for BP devices intended for use in children and adolescents are included in some validation protocols. In this review, we compare the validation criteria for BP measuring devices among consensus documents from different scientific organizations focusing on the pediatric population and we discuss the evidence gaps targeting the needs for validated BP measuring devices in children and adolescents. We also highlight common pitfalls in the validation studies of BP measuring devices in children and adolescents using the example of office BP devices.

A systematic review of economic evaluations of enzyme replacement therapy in Lysosomal storage diseases.

OBJECTIVE: The objective of this paper is to assess the economic profile of enzyme replacement therapy (ERT) to symptomatic patients with Pompe, Fabry, Gaucher disease and Lysosomal acid lipase (LAL) deficiency. METHODS: A systematic search was performed to retrieve and critically assess economic evaluations of enzyme replacement therapy. Publications were screened according to predefined criteria and evaluated according to the Quality of Economic Studies. Data were narratively synthesized. RESULTS: The Incremental Cost-Effectiveness Ratio greatly exceeded willingness to pay thresholds. The cost of the medication dominated the sensitivity analysis. For Infantile-onset Pompe's disease, the incremental cost-effectiveness ratio (ICER) was estimated at €1.043.868 per Quality-adjusted life year (QALY) based on the dose of alglucosidase 40 mg/kg/ week, and €286.114 per QALY for 20 mg of alglucosidase/kg/2 weeks. For adults patients presenting with Pompe disease the reported was ICER € 1.8 million/ QALY. In the case of Fabry disease, the ICER per QALY amounts to 6.1 million Euros/QALY. Respectively for Gaucher's disease, the ICER /QALY was estimated at € 884,994 per QALY. Finally, for patients presenting LAL deficiency NCPE perpetuated an ICER of €2,701,000/QALY. DISCUSSION: ERT comprise a promising treatment modality for orphan diseases; nevertheless, it is interlaced with a substantial economic burden. Moreover, the available data on the cost-effectiveness ratio are scarce. For certain diseases, such as Fabry, a thorough selection of patients could exert a beneficial effect on the reported ICER. Steep price reductions are imperative for these products, in the conventional reimbursement pathway or a new assessment framework should be elaborated, which in principle, should target uncertainty.

Methodological considerations in injury burden of disease studies across Europe: a systematic literature review.

BACKGROUND: Calculating the disease burden due to injury is complex, as it requires many methodological choices. Until now, an overview of the methodological design choices that have been made in burden of disease (BoD) studies in injury populations is not available. The aim of this systematic literature review was to identify existing injury BoD studies undertaken across Europe and to comprehensively review the methodological design choices and assumption parameters that have been made to calculate years of life lost (YLL) and years lived with disability (YLD) in these studies. METHODS: We searched EMBASE, MEDLINE, Cochrane Central, Google Scholar, and Web of Science, and the grey literature supplemented by handsearching, for BoD studies. We included injury BoD studies that quantified the BoD expressed in YLL, YLD, and disability-adjusted life years (DALY) in countries within the European Region between early-1990 and mid-2021. RESULTS: We retrieved 2,914 results of which 48 performed an injury-specific BoD assessment. Single-country independent and Global Burden of Disease (GBD)-linked injury BoD studies were performed in 11 European countries. Approximately 79% of injury BoD studies reported the BoD by external cause-of-injury. Most independent studies used the incidence-based approach to calculate YLDs. About half of the injury disease burden studies applied disability weights (DWs) developed by the GBD study. Almost all independent injury studies have determined YLL using national life tables. CONCLUSIONS: Considerable methodological variation across independent injury BoD assessments was observed; differences were mainly apparent in the design choices and assumption parameters towards injury YLD calculations, implementation of DWs, and the choice of life table for YLL calculations. Development and use of guidelines for performing and reporting of injury BoD studies is crucial to enhance transparency and comparability of injury BoD estimates across Europe and beyond.

A Systematic Review of the Economic Evaluations of Belimumab in Systemic Lupus Erythematosus.

OBJECTIVES: Systemic lupus erythematosus is a heterogeneous, multisystem autoimmune disease. These attributes cause lupus to be a challenging condition to adequately manage, which is further aggravated by the lack of treatment modalities. Belimumab is a full human monoclonal antibody, and its safety and efficacy in lupus management have been demonstrated in a number of randomized clinical trials. However, these gains come at a high cost in an era that is demarcated by soaring pharmaceutical expenditure. Therefore, the objective of this paper is to critically assess the economic evaluations of belimumab. METHODS: A systematic review was performed for economic evaluations of belimumab and the retrieved studies were assessed with the quality of health economic studies questionnaire. RESULTS: A total of 3 studies and 5 abstracts were retrieved. Belimumab demonstrated a consistent favorable economic profile across Spain, Italy, Portugal, Greece, Hong Kong, Canada, and Greece. The sensitivity analyses revealed that the effectiveness of treatment and the discontinuation rate had the greatest effect on the outcome. CONCLUSION: Current data underscore a favorable cost-effectiveness ratio of belimumab in the treatment of systemic lupus erythematosus. Results are consistent across Spain, Italy, Portugal, Greece, Hong Kong, Canada, and Greece, countries for which an economic evaluation was available. Nevertheless, the low number of assessments, along with concerns regarding its long-term effectiveness, underpin areas that necessitate further research.

Economic Evaluation of Monoclonal Antibodies in Metastatic Colorectal Cancer: A Systematic Review.

INTRODUCTION: Colorectal cancer (CRC) is one of the major causes of mortality and morbidity worldwide. The median overall survival (OS) of patients with metastatic CRC (mCRC) has doubled over the last 20 years partly due to the introduction of advanced biologic therapies. However, these treatment modalities bear significant costs on healthcare systems globally, and may jeopardize their fiscal sustainability. The aim of this systematic review was to critically appraise the economic evaluations of monoclonal antibodies in mCRC. METHODOLOGY: A literature search was performed in the electronic databases of: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, EMBASE, EMBASE Alert, PUBMED, NHS Economic Evaluation and Health Technology Assessment Database for full articles published from 1 January 2013 to 31 December 2020. RESULTS: Twenty economic analyses were identified in the literature that fulfilled the inclusion criteria and evaluated the cost-effectiveness of (a) bevacizumab as first-line treatment for mCRC and as maintenance treatment, (b) cetuximab as first-line treatment, (c) panitumumab versus bevacizumab and cetuximab versus bevacizumab as first-line treatment, (d) aflibercept and ramucirumab as second-line treatment, (e) cetuximab and panitumumab as third-line treatment, (f) cetuximab versus panitumumab as later lines of treatment, and (g) RAS testing prior to anti-epidermal growth factor receptor (EGFR) treatment. CONCLUSIONS: Bevacizumab in combination with chemotherapy is cost-effective as neither first-line treatment nor maintenance treatment. Sequential treatment with bevacizumab in first-line and second-line treatment was also not cost-effective. Testing for KRAS and extended RAS mutations is cost-effective and should be performed prior to anti-EGFR treatment. In the RAS wild-type subgroup of mCRCs the use of anti-EGFR (panitumumab or cetuximab) in first-line treatment leads to a more favorable cost-effectiveness profile than the corresponding anti-VEGF (bevacizumab). Cetuximab is not cost-effective as a first-line treatment. Anti-EGFR administration is not a cost-effective strategy in third-line treatment, even for RAS wild-type mCRCs, compared to best supportive care. Aflibercept was superior to ramucirumab and costed less, but neither were cost-effective compared to standard care.

A Comprehensive Molecular Epidemiological Analysis of SARS-CoV-2 Infection in Cyprus from April 2020 to January 2021: Evidence of a Highly Polyphyletic and Evolving Epidemic.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in an extraordinary global public health crisis. In early 2020, Cyprus, among other European countries, was affected by the SARS-CoV-2 epidemic and adopted lockdown measures in March 2020 to limit the initial outbreak on the island. In this study, we performed a comprehensive retrospective molecular epidemiological analysis (genetic, phylogenetic, phylodynamic and phylogeographic analyses) of SARS-CoV-2 isolates in Cyprus from April 2020 to January 2021, covering the first ten months of the SARS-CoV-2 infection epidemic on the island. The primary aim of this study was to assess the transmissibility of SARS-CoV-2 lineages in Cyprus. Whole SARS-CoV-2 genomic sequences were generated from 596 clinical samples (nasopharyngeal swabs) obtained from community-based diagnostic testing centers and hospitalized patients. The phylogenetic analyses revealed a total of 34 different lineages in Cyprus, with B.1.258, B.1.1.29, B.1.177, B.1.2, B.1 and B.1.1.7 (designated a Variant of Concern 202012/01, VOC) being the most prevalent lineages on the island during the study period. Phylodynamic analysis showed a highly dynamic epidemic of SARS-CoV-2 infection, with three consecutive surges characterized by specific lineages (B.1.1.29 from April to June 2020; B.1.258 from September 2020 to January 2021; and B.1.1.7 from December 2020 to January 2021). Genetic analysis of whole SARS-CoV-2 genomic sequences of the aforementioned lineages revealed the presence of mutations within the S protein (L18F, ΔH69/V70, S898F, ΔY144, S162G, A222V, N439K, N501Y, A570D, D614G, P681H, S982A and D1118H) that confer higher transmissibility and/or antibody escape (immune evasion) upon the virus. Phylogeographic analysis indicated that the majority of imports and exports were to and from the United Kingdom (UK), although many other regions/countries were identified (southeastern Asia, southern Europe, eastern Europe, Germany, Italy, Brazil, Chile, the USA, Denmark, the Czech Republic, Slovenia, Finland, Switzerland and Pakistan). Taken together, these findings demonstrate that the SARS-CoV-2 infection epidemic in Cyprus is being maintained by a continuous influx of lineages from many countries, resulting in the establishment of an ever-evolving and polyphyletic virus on the island.

Assessing the pricing and benefits of oncology products: an update.

Introduction: Oncology expenditure is outperforming all other health care sectors. In particular, the cost of oncology pharmaceuticals is soaring as it is fueled both by incremental costs and the introduction rate of new products. Due to the particularities of cancer as a disease, a significant multilayer of pressure is exerted toward the reimbursement of new treatments. Nevertheless, if the expenditure increase is left unattended, it may hamper the viability of any health care system worldwide.Areas covered: A literature review of the expenditure on oncology pharmaceuticals and the exploration of the root causes for the increase in expenditure was performed.Expert commentary: The surging oncology expenditure demonstrates a multi-layer causality that encompasses prices, the uncertainty of clinical trials, the specificities of cancer as a disease, and the artificial monopoly of oncology modalities. Moreover, laxity in the regulatory approval of new products was noted. In addition, the study design should be adequately justified. Finally, new reimbursement schemes, that explicitly reward and promote clinically meaningful and measurable outcomes, are also imperative.

The 2019 introduction of the new National Healthcare System in Cyprus.

In 2019, Cyprus launched its new National Healthcare System (NHS) as one of the major structural reforms required by the bail-out agreement with the International Monetary Fund, the European Commission and the European Central Bank (known as the Troika) which averted Cyprus bankruptcy in 2011. This paper presents the key features of the new NHS: A National Health Insurance Fund operated by the Health Insurance Organisation pays for services provided by a mix of public and private providers. A prerequisite for the establishment of this new quasi-market was the transfer of public hospitals from the Ministry of Health to the new State Health Services Organisation, thus establishing a purchaser-provider and regulator split. The first implementation phase started in June 2019 and introduced coverage of outpatient healthcare services for the entire population, providing access - with relatively small user charges - to family physicians, outpatient specialists, pharmaceuticals and laboratories. The second implementation phase began in June 2020 with the inclusion of hospital care, followed by the inclusion of specialty pharmaceuticals in September and was completed in December 2020. The reform is a vital achievement as it is a major step towards the goal of universal health coverage, reducing the excessive reliance on out-of-pocket payment and glaring inequities in access to care.