The cost of ischaemic stroke in Croatia.

Objective: The aim of this analysis was to estimate 1 year and long-term cost and quality of life of ischaemic stroke patients in Croatia. In addition, we aimed to identify and estimate key categories of costs and outcomes driving the burden of stroke in Croatian healthcare system. Methods: Data were derived from analysis of the RES-Q Registry for Croatia in 2018 and supplemented with clinical expert opinion and relevant medical, clinical and economic literature to estimate the course of the disease and treatment patterns in Croatian healthcare system. The health economic model was comprised of a one-year discrete event simulation (DES) mapping real life patient experience and a 10-year Markov model built on existing literature. Cost and health resources use were obtained using Croatian tariffs. Health utilities were mapped to EQ5D from the Barthel Index utilising previously published studies. Results: The key aspects determining costs and quality of life were rehabilitation, discharge to residential care (currently 13% of patients in Croatia) and recurrent stroke. Total 1 year cost per patient was 18,221 EUR having 0.372 QALYs. Conclusion: Direct costing structure of ischaemic stroke in Croatia is above the value of upper-middle income countries. Our study showed that post stroke rehabilitation seems to be a strong modifier of future post-stroke costs and further research into various models of post-stroke care and rehabilitation could be the answer into more successful rehabilitation that could increase QALY and reduce the economic burden of stroke. Further investment in rehabilitation research and provision might bring promising opportunities to improve long term patient outcomes.

The time is now: Achieving FH paediatric screening across Europe - The Prague Declaration.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

The Use of Evidence-Informed Deliberative Processes for Health Benefit Package Design in Kazakhstan.

Kazakhstan strives to obtain Universal Health Coverage (UHC) by using health technology assessment (HTA) for determining their health benefit package. This paper reports on employing evidence-informed deliberative processes (EDPs), a practical and stepwise approach to enhance legitimate health benefit package design in Kazakhstan. METHODS: The Ministry of Health of Kazakhstan approved the operationalization and application of EDPs during March 2019 and December 2020. We used a combination of desk research, conducting HTA, online surveys as well as a face-to-face workshop in Nur-Sultan, Kazakhstan, and two online workshops to prioritize 25 selected health technologies. During the latter, we tested two alternative approaches to prioritization: quantitative multicriteria decision analysis (MCDA) and the use of decision rules. RESULTS: For each of the HTA reports, evidence summaries were developed according to the decision criteria (safety, social priority disease, severity of disease, effectiveness, cost-effectiveness, level of evidence, financial risk protection and budget impact). When appraising the evidence, the advisory committee preferred using quantitative MCDA, and only when this would result in any controversy could decision rules be applied. CONCLUSIONS: Despite several challenges, including a partial disruption because of the COVID-19 pandemic, implementation of the process will likely play a key role in determining an evidence-informed and transparent health benefit package.

The Expiry of Humira® Market Exclusivity and the Entry of Adalimumab Biosimilars in Europe: An Overview of Pricing and National Policy Measures.

Background: From October 2018, adalimumab biosimilars could enter the European market. However, in some countries, such as Netherlands, high discounts reported for the originator product may have influenced biosimilar entry. Objectives: The aim of this paper is to provide a European overview of (list) prices of originator adalimumab, before and after loss of exclusivity; to report changes in the reimbursement status of adalimumab products; and discuss relevant policy measures. Methods: Experts in European countries received a survey consisting of three parts: 1) general financing/co-payment of medicines, 2) reimbursement status and prices of originator adalimumab, and availability of biosimilars, and 3) policy measures related to the use of adalimumab. Results: In May 2019, adalimumab biosimilars were available in 24 of the 30 countries surveyed. Following introduction of adalimumab biosimilars, a number of countries have made changes in relation to the reimbursement status of adalimumab products. Originator adalimumab list prices varied between countries by a factor of 2.8 before and 4.1 after loss of exclusivity. Overall, list prices of originator adalimumab decreased after loss of exclusivity, although for 13 countries list prices were unchanged. When reported, discounts/rebates on originator adalimumab after loss of exclusivity ranged from 0% to approximately 26% (Romania), 60% (Poland), 80% (Denmark, Italy, Norway), and 80-90% (Netherlands), leading to actual prices per pen or syringe between €412 (Finland) and €50 - €99 (Netherlands). To leverage competition following entry of biosimilar adalimumab, only a few countries adopted measures specifically for adalimumab in addition to general policies regarding biosimilars. In some countries, a strategy was implemented even before loss of exclusivity (Denmark, Scotland), while others did not report specific measures. Conclusion: Even though originator adalimumab is the highest selling product in the world, few countries have implemented specific policies and practices for (biosimilar) adalimumab. Countries with biosimilars on the market seem to have competition lowering list or actual prices. Reported discounts varied widely between countries.

Oxidative stress biomarkers in amniotic fluid of pregnant women with hypothyroidism.

Purpose: Hypothyroidism in pregnancy is the serious state that may lead to fetal morbidity and mortality. Oxidative stress biomarkers in the amniotic fluid can provide important information on the health, development and maturation of the fetus during pregnancy. In this study, we examined whether maternal hypothyroidism contributes to increased oxidative stress biomarkers in the amniotic fluid during the first trimester of pregnancy. Materials and methods: The study was conducted on healthy pregnant women and pregnant women with hypothyroidism (gestational age: 16-18 weeks). Oxidative stress biomarkers, such as superoxide anion (O2•-), hydrogen peroxide (H2O2), nitric oxide (NO), peroxynitrite (ONOO-), lipid peroxide (LPO), reduced glutathione (GSH) and oxidized glutathione (GSSG) were assayed in the amniotic fluid. Results: The results of this study indicated that concentrations of O2•- and NO are significantly higher, while the concentration of H2O2 is significantly lower in the amniotic fluid of pregnant women with hypothyroidism in comparison to healthy pregnant women. There were no differences in concentrations of LPO, GSH and GSSG among tested groups. Also, we found that amniotic fluid concentration of O2•- is negatively correlated with the body weight and Apgar score values of the newborns. Conclusion: These results suggest that pregnancy hypothyroidism is characterized by the amniotic fluid oxidative stress. Incorporation of the oxidative stress biomarkers measurement in the amniotic fluid may be of clinical importance in the management of pregnancy hypothyroidism.

Barriers for Access to New Medicines: Searching for the Balance Between Rising Costs and Limited Budgets.

Introduction: There is continued unmet medical need for new medicines across countries especially for cancer, immunological diseases, and orphan diseases. However, there are growing challenges with funding new medicines at ever increasing prices along with funding increased medicine volumes with the growth in both infectious diseases and non-communicable diseases across countries. This has resulted in the development of new models to better manage the entry of new medicines, new financial models being postulated to finance new medicines as well as strategies to improve prescribing efficiency. However, more needs to be done. Consequently, the primary aim of this paper is to consider potential ways to optimize the use of new medicines balancing rising costs with increasing budgetary pressures to stimulate debate especially from a payer perspective. Methods: A narrative review of pharmaceutical policies and implications, as well as possible developments, based on key publications and initiatives known to the co-authors principally from a health authority perspective. Results: A number of initiatives and approaches have been identified including new models to better manage the entry of new medicines based on three pillars (pre-, peri-, and post-launch activities). Within this, we see the growing role of horizon scanning activities starting up to 36 months before launch, managed entry agreements and post launch follow-up. It is also likely there will be greater scrutiny over the effectiveness and value of new cancer medicines given ever increasing prices. This could include establishing minimum effectiveness targets for premium pricing along with re-evaluating prices as more medicines for cancer lose their patent. There will also be a greater involvement of patients especially with orphan diseases. New initiatives could include a greater role of multicriteria decision analysis, as well as looking at the potential for de-linking research and development from commercial activities to enhance affordability. Conclusion: There are a number of ongoing activities across countries to try and fund new valued medicines whilst attaining or maintaining universal healthcare. Such activities will grow with increasing resource pressures and continued unmet need.

Effects of maternal subclinical hypothyroidism on amniotic fluid cells oxidative status.

In this study, we researched the effects of maternal subclinical hypothyroidism on the amniotic fluid cells oxidative metabolism during the first trimester of pregnancy. Oxidative stress and damage biomarkers were assayed in the amniotic fluid cells of healthy and pregnant women with subclinical hypothyroidism. Obtained results show that amniotic fluid cells of pregnant women with subclinical hypothyroidism have significantly higher concentrations of oxidative stress biomarkers (superoxide anion, nitric oxide, peroxynitrite) and oxidative damage (lipid peroxide and micronuclei frequency), but lower concentrations of hydrogen peroxide and oxidized glutathione in comparison to healthy pregnant women. We also showed that oxidative stress biomarkers were positively correlated with micronuclei frequency and lipid peroxide concentration in amniotic fluid cells of pregnant women with subclinical hypothyroidism. The present study provides the first evidence for prooxidative effects of maternal subclinical hypothyroidism on the fetus obtained by the estimating oxidative metabolism in the amniotic fluid cells.

The value of innovation in decision-making in health care in Central Eastern Europe - The Sixth International Conference, 2 June 2017, Belgrade, Serbia.

The Pharmacoeconomics Section of the Pharmaceutical Association of Serbia organised a one day international conference on the value of innovation in decision-making in health care in Central and Eastern Europe. The focus of the conference was on reimbursement decisions for medicines using health technology assessment and the use of managed entry agreements (MEAs). The objectives of this conference were firstly to discuss the challenges and opportunities with the use of MEAs in Central and Eastern European countries; secondly the role of patient registries especially with outcome based schemes, and finally new approaches to improve accessibility to new medicines including better managing their entry.

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.

Addressing challenges for sustainable healthcare in Central and Eastern Europe.

All European countries face increasing challenges in the provision of equitable and comprehensive healthcare for their citizens in view of a number of factors. These include changing demographics and the continual launch of new premium priced medicines. The challenges are even more difficult among Central and Eastern European healthcare systems. Consequently, there is a need for countries to learn from each other to help address some of these challenges and to maintain sustainable systems. This was the basis of the 2-day conference, The Fifth International Conference: Challenges for Efficient Healthcare in Central and Eastern Europe, 9-10 October 2015, Belgrade, Serbia.

Evaluating the Serbian version of the KIDSCREEN quality-of-life questionnaires: reliability, validity, and agreement between children's and parents' ratings.

PURPOSE: To evaluate the psychometric properties of the Serbian set of the KIDSCREEN questionnaires: KIDSCREEN-52, KIDSCREEN-27, and KIDSCREEN-10 index. METHODS: The study included 330 children (8-18 years) and 314 parents. All completed the KIDSCREEN and KINDL questionnaires. Psychometric analyses included internal consistency reliability (Cronbach's coefficient), criterion, convergent and discriminant validity, and agreement between children and parents (the intraclass correlation coefficient-ICC). RESULTS: Cronbach's α of 0.7 and above was found for all except for the self-perception scale of the KIDSCREEN-52, being 0.58 for the child and 0.63 for the parent version. Correlations between similar scales in the KIDSCREEN and KINDL were substantial (ranging 0.45-65) and higher than correlations between theoretically different scales. Moderate to excellent agreement existed between children's and parents' ratings in all KIDSCREEN scales (ICC ranged 0.44-0.63), except for the moods and emotions from the longer (ICC = 0.34) and the social support and peers from the shorter version (ICC = 0.38). CONCLUSIONS: Levels of internal consistency reliability and validity of all KIDSCREEN questionnaires in Serbian are appropriate, as well as agreement between children's and parents' ratings.

Correlation between serum biochemical markers and early amniocentesis in diagnosis of congenital fetal anomalies.

A combined test performed at the 12th week of gestation enables us to classify the pregnancy as high risk (risk higher than 1:300) or low risk (risk lower than 1:300) for congenital foetal anomalies, with great accuracy of 85 - 90%. According to the available data, the frequency of false positive results is estimated at around 5%. The objective of the study was to examine possible correlation between the serum marker values and amniocentesis results in prenatal diagnostics of congenital foetal anomalies. The study included 745 pregnant women monitored by the Genetic Counselling Service of the Clinic of Gynaecology and Obstetrics of the Clinics Centre Kragujevac. The subjects were included in the study under condition that CRL (embryonic crown-rump length) was from 45 to 84 mm and that the gestational age was at 11-13+6 weeks. Free beta HCG and PAPP-A were determined from venous blood using commercial DPS-USA tests. Tests were based on the analytic principle of the immuno-chemiluminescence technique and were performed by application of the automatic Immulite 2000 analyzer by DPC-USA. The foetal nuchal translucency thickness (NT) and CRL were measured by Colour Doppler. The chromosome identification was performed after a certain number of cell divisions by stopping the cell division in metaphase of mitosis when the chromosomes were the most distinguishable. The foetal karyotype was prepared using G bands. In the total sample of pregnant women (n=745), there were six cases of pathological foetal karyotype. A statistical paradox in the frequency of congenital foetal anomalies in favour of younger population was noticed. A high coefficient of Spearman's rank correlation suggests great importance of the combined test in the detection of congenital foetal anomalies (p<0,05). A high consistency was also proved for components of biochemical screening and ultrasonographic markers. The combined test, as a method of prenatal screening in the first trimester of pregnancy, if used at 11 - 13+6 weeks' gestation and for CRL of 45-84 mm, has a great importance in the detection of congenital foetal anomalies.