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This study aimed to investigate the transferability of novel artificial intelligence (AI) methods for prediction modelling of diabetes based on real-world data (RWD) between early and late adopters of emerging health technologies from the perspective of developers and health technology assessment (HTA) experts. A two-step approach was used. Developers of the new AI methods within HTx consortium completed a survey about the benefits, usability, barriers associated with implementing the new prediction models in routine HTA practices. Then, HTA experts from Central and Eastern European (CEE) countries participated in a focus group discussion. Developers generally expressed optimism regarding the transferability of the methods, while acknowledging potential disparities across CEE countries. Key benefits that were identified included enhanced understanding of diabetes, improved cost-effectiveness modelling, and refined patient stratification, all of which could contribute to clinical and reimbursement decisions across various jurisdictions. The focus group underscored the value of real-world data for diabetes prediction modelling, serving as a beneficial resource for both clinicians and HTA agencies. However, there was a recognized need to clarify the processes of integrating randomized clinical trial data with real-world data. For the other stakeholders, the advancement of the methodology will improve the diagnosis and therapy during the process of decision making. Experts from CEE countries recognized the potential of artificial intelligence-based methods employing real-world data for diabetes modelling. These methods are seen as instrumental in elucidating the heterogeneous nature of the disease, supporting clinician decision-making and holding promises for HTA purposes.

Objectives: The aim of this study was to characterize the reimbursement policy for orphan drugs (ODs) in Central and Eastern European (CEE) countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedure, selected economic indicators, and the drug type according to indications.Materials and methods: A list of authorized medicines with orphan designation and information about active substance, Anatomical Therapeutic Chemical (ATC) classification, and therapeutic area was extracted from the web-based register of the European Medicines Agency (EMA). A country-based questionnaire survey was performed between September 2021 and January 2022 in a group of selected experts from nine CEE countries (an invitation was sent to 11 countries). A descriptive and statistical analysis was conducted to determine statistical significance, correlations, between the drug or country characteristic and the positive recommendation or reimbursement of ODs.Results: The proportion of reimbursed orphan drugs differed between countries, ranging from 17.7% in Estonia to 49.6% in Hungary (p < 0.001). The odds that ODs were reimbursed were reduced in countries with a “strong” level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), the presence of other additional specific clinical aspects (e.g., genomic data) considered in the reimbursement decision (p < 0.001) and mandatory (without exception) safety assessments (p=0.004). The probability that ODs were reimbursed was increased in countries with a “moderate” level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), when reimbursement decisions are dependent on the EMA registration status and orphan drug designation (p < 0.001), the presence of the “positive HTA recommendation guarantees reimbursement” policy (p < 0.001), higher GDP per inhabitant (p=0.003), and higher healthcare expenditure (p < 0.001).Conclusion: We found that there are differences among CEE countries in the reimbursement of orphan drugs, and we identified aspects that may influence these differences. Safety, efficacy, and specific clinical aspect issues significantly influenced reimbursement decisions. Antineoplastic and immunomodulating agents drugs were the largest group of ODs and increased the chance of getting a positive recommendation. The higher GDP per inhabitant and healthcare expenditures per inhabitant were positively linked to the chance that an OD receives reimbursement.

Introduction: As in other chronic conditions, medication adherence is important in the treatment of peripheral arterial disease (PAD). Our study aimed at a) analysing non-adherence to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in groups of older ACEI and ARB users with PAD, and b) identifying characteristics associated with non-adherence.Methods: We focused on the implementation phase of adherence (i.e., after treatment initiation and before possible discontinuation of treatment). The study cohort included ACEI/ARB users aged ≥65 years in whom PAD was newly diagnosed during 2012. Non-adherence was defined as Proportion of Days Covered (PDC) < 80%.Results: Among 7,080 ACEI/ARB users (6,578 ACEI and 502 ARB users), there was no significant difference in the overall proportion of non-adherent patients between ACEI and ARB users (13.9% and 15.3%, respectively). There were differences in factors associated with non-adherence between the groups of persistent and non-persistent (i.e., discontinued treatment at some point during follow-up) ACEI and ARB users. Increasing age, dementia and bronchial asthma were associated with non-adherence in persistent ACEI users. General practitioner as index prescriber was associated with adherence in the groups of non-persistent ACEI users and persistent ARB users.Conclusion: Identified factors associated with non-adherence may help in determining the groups of patients who require increased attention.

IntroductionMeaningful patient involvement in health technology assessment (HTA) is essential in ensuring that the interests of the affected patient population, their families, and the general public are accurately reflected in coverage and reimbursement decisions. Central and Eastern European (CEE) countries are generally at less advanced stages of implementing HTA, which is particularly true for patient involvement activities. As part of the Horizon2020 HTx project, this research aimed to form recommendations for critical barriers to patient involvement in HTA in CEE countries.MethodsBuilt on previous research findings on potential barriers, a prioritisation survey was conducted online with CEE stakeholders. Recommendations for prioritised barriers were formed through a face-to-face workshop by CEE stakeholders and HTx experts.ResultsA total of 105 stakeholders from 13 CEE countries completed the prioritisation survey and identified 12 of the 22 potential barriers as highly important. The workshop had 36 participants representing 9 CEE countries, and 5 Western European countries coming together to discuss solutions in order to form recommendations based on best practices, real-life experience, and transferability aspects. Stakeholder groups involved in both phases included HTA organisation representatives, payers, patients, caregivers, patient organisation representatives, patient experts, health care providers, academic and non-academic researchers, health care consultants and health technology manufacturers/providers. As a result, 12 recommendations were formed specified to the CEE region’s context, but potentially useful for a broader geographic audience.ConclusionIn this paper, we present 12 recommendations for meaningful, systematic, and sustainable patient involvement in HTA in CEE countries. Our hope is that engaging more than a hundred CEE stakeholders in the study helped to spread awareness of the importance and potential of patient involvement and that the resulting recommendations provide tangible steps for the way forward. Future studies shall focus on country-specific case studies of the implemented recommendations.

Background: In the past few years, COVID-19 became the leading cause of morbidity and mortality worldwide. Although the World Health Organization has declared an end to COVID-19 as a public health emergency, it can be expected, that the emerging new cases at the top of previous ones will result in an increasing number of patients with post-COVID-19 sequelae. Despite the fact that the majority of patients recover, severe acute lung tissue injury can in susceptible individuals progress to interstitial pulmonary involvement. Our goal is to provide an overview of various aspects associated with the Post-COVID-19 pulmonary fibrosis with a focus on its potential pharmacological treatment options.Areas covered: We discuss epidemiology, underlying pathobiological mechanisms, and possible risk and predictive factors that were found to be associated with the development of fibrotic lung tissue remodelling. Several pharmacotherapeutic approaches are currently being applied and include anti-fibrotic drugs, prolonged use or pulses of systemic corticosteroids and non-steroidal anti-inflammatory and immunosuppressive drugs. In addition, several repurposed or novel compounds are being investigated. Fortunately, clinical trials focused on pharmacological treatment regimens for post-COVID-19 pulmonary fibrosis have been either designed, completed or are already in progress. However, the results are contrasting so far. High quality randomised clinical trials are urgently needed with respect to the heterogeneity of disease behaviour, patient characteristics and treatable traits.Conclusion: The Post-COVID-19 pulmonary fibrosis contributes to the burden of chronic respiratory consequences among survivors. Currently available pharmacotherapeutic approaches mostly comprise repurposed drugs with a proven efficacy and safety profile, namely, corticosteroids, immunosuppressants and antifibrotics. The role of nintedanib and pirfenidone is promising in this area. However, we still need to verify conditions under which the potential to prevent, slow or stop progression of lung damage will be fulfilled.

BackgroundArtificial intelligence (AI) has attracted much attention because of its enormous potential in healthcare, but uptake has been slow. There are substantial barriers that challenge health technology assessment (HTA) professionals to use AI-generated evidence for decision-making from large real-world databases (e.g., based on claims data). As part of the European Commission-funded HTx H2020 (Next Generation Health Technology Assessment) project, we aimed to put forward recommendations to support healthcare decision-makers in integrating AI into the HTA processes. The barriers, addressed by the paper, are particularly focusing on Central and Eastern European (CEE) countries, where the implementation of HTA and access to health databases lag behind Western European countries.MethodsWe constructed a survey to rank the barriers to using AI for HTA purposes, completed by respondents from CEE jurisdictions with expertise in HTA. Using the results, two members of the HTx consortium from CEE developed recommendations on the most critical barriers. Then these recommendations were discussed in a workshop by a wider group of experts, including HTA and reimbursement decision-makers from both CEE countries and Western European countries, and summarized in a consensus report.ResultsRecommendations have been developed to address the top 15 barriers in areas of (1) human factor-related barriers, focusing on educating HTA doers and users, establishing collaborations and best practice sharing; (2) regulatory and policy-related barriers, proposing increasing awareness and political commitment and improving the management of sensitive information for AI use; (3) data-related barriers, suggesting enhancing standardization and collaboration with data networks, managing missing and unstructured data, using analytical and statistical approaches to address bias, using quality assessment tools and quality standards, improving reporting, and developing better conditions for the use of data; and (4) technological barriers, suggesting sustainable development of AI infrastructure.ConclusionIn the field of HTA, the great potential of AI to support evidence generation and evaluation has not yet been sufficiently explored and realized. Raising awareness of the intended and unintended consequences of AI-based methods and encouraging political commitment from policymakers is necessary to upgrade the regulatory and infrastructural environment and knowledge base required to integrate AI into HTA-based decision-making processes better.

Introduction: The COVID-19 pandemic has resulted in more than 6.5 million deaths worldwide yet. Vaccination against the SARS-CoV-2 virus is a reliable way out of the pandemic, however, vaccination rate reaches only 58% in the Slovak Republic. Concerns about the adverse reactions of vaccines are one of the reasons for the low vaccination rate.Objective: The aim of our analysis was to review reported suspicions of adverse reactions (ARs) of registered COVID-19 vaccines (Comirnaty, Vaxzevria, Spikevax), which State Institute for Drug Control received from healthcare professionals and patients in the period from 1 January 2021 to 31 May 2021.Methods: Data were collected from the State Institute for Drug Control database, a retrospective analysis was carried out focusing on trends in the number of all reports of suspicions of adverse reactions sent to the State Institute for Drug Control during the previously mentioned period. We analysed the Retrieved data were analysed with the usage of descriptive statistics and comparison to historical data on drug adverse reactions in Slovakia was performed.Results: During the evaluation period, 5,763 reported suspicions of adverse reactions were analysed, overall, there was a significant (p < 0.0001) increase in the number of reported adverse reactions fivefold. 93% of ARs (n = 5,346) were reported for COVID-19 vaccines. In comparison of the extentof all adverse reactions, there is clearly a statistically significant difference between all types of vaccines administered at that time (p ≤ 0.0001). No statistically significant difference (p ≤ 0.238) was identified between Spikevax and Comirnaty in the proportion of serious adverse reactions. However, a significantly higher (p ≤ 0.00001) proportion of reported suspicions of serious adverse reactions was observed after the administration of Vaxzevria.Conclusion: This is the first analysis conducted in Slovakia aimed to reported adverse reactions in relation to the administration of COVID-19 vaccines. The rate of spontaneously reported suspected adverse reactions has been insufficient in the past for a long time; during the period from January to May 2021 the reporting rate increased due active calls for adverse reactions reporting. In concordance with European data, Vaxzevria had a significantly higher ratio of reported suspicions of serious adverse reactions.

Abstract Background The reimbursement of orphan drugs (OD) is an increasingly important for country policymakers, and still insufficiently understood, especially in Central and Eastern Europe. The aim of this research was to provide a comprehensive description of country-specific health technology assessment (HTA) policies as well as evaluate the percentage of HTA recommendations and reimbursement decisions for oncology OD. In addition, the study was designed to elucidate the impact of reimbursement of these drugs on the public budget and the agreement between HTA recommendations and reimbursement decisions in the analysed countries. A questionnaire survey was used to collect data on the reimbursement status, HTA recommendation, marketing authorisation, and public expenses on reimbursement in 2014, 2015, and 2016 for all oncology drugs with an orphan designation by the European Medicine Agency in 2017 in Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, and Slovakia. The agreement between the HTA recommendation and reimbursement status was assessed using the kappa coefficient. The Pearson’s correlation was used to analyse the relationship between gross domestic product (GDP) and GDP per capita and reimbursement expenses. Results A total of 36 drugs were analysed (25% conditionally approved; 5.56% approved under exceptional circumstances). The share of reimbursed drugs ranged from 11.11% in Latvia to 41.67% in Poland. The highest share of positive recommendations was observed for Bulgaria and Estonia (36.11%), and the lowest, for Latvia (11.11%). The agreement varied from 0.4 for Poland to 1 for Latvia, Hungary, and Slovakia. Expenses were correlated with GDP (0.95 [0.81–0.99]), and not with GDP per capita (0.54 [− 0.136 to 0.873]). Expenses per capita were not correlated with GDP per capita (0.52 [− 0.15 to 0.87]). Conclusions In Hungary, Latvia, and Slovakia, a positive recommendation was associated with a reimbursement, and a negative one, with the lack of reimbursement. The reimbursement of oncology OD is associated with a growing burden for public budget, and the expenses are correlated with the total GDP. The highest share of drugs with any recommendation was observed in Poland, and the lowest, in Latvia and Romania. The share of reimbursed drugs was the lowest in Latvia and the highest in Poland.

Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) are recommended in the treatment of arterial hypertension in patients with peripheral arterial disease (PAD). The aims of our study were: (a) to analyse the extent of reinitiation and subsequent discontinuation in older hypertensive PAD patients non-persistent with ACEIs/ARBs; (b) to determine patient and medication factors associated with reinitiation and subsequent discontinuation; and (c) to compare these factors between prevalent and new users. The analysis of reinitiation was performed on a sample of 1642 non-persistent patients aged ≥65 years with PAD newly diagnosed in 2012. Patients reinitiating ACEIs/ARBs were used for the analysis of subsequent discontinuation identified according to the treatment gap period of at least 6 months without any prescription of ACEI/ARB. In the group of non-persistent patients, 875 (53.3%) patients reinitiated ACEIs/ARBs during a follow-up (24.8 months on average). Within this group, subsequent discontinuation was identified in 414 (47.3%) patients. Being a new user was associated with subsequent discontinuation, but not with reinitiation. Myocardial infarction during non-persistence and after reinitiation was associated with reinitiation and lower likelihood of subsequent discontinuation, respectively. Being a prevalent or a new user is associated with the use of medication also after initial discontinuation.

Background: The aim of this study was to investigate the impact of selected legislative initiatives and their implementation for off-patent medicinal products in Slovakia compared with the rest of the Visegrád Group (V4 countries).Methods: We analyzed the development of applications for the reimbursement of generic and biosimilar drugs. Particular emphasis was placed on a) the availability and penetration of biosimilars from 2006 to 2020 in Slovakia, b) a comparative analysis of biosimilars in V4 countries based on the national reimbursement lists of medicinal products for August 2021. Data relating to the sales of generic and biosimilar medicines in Czechia, Hungary, Poland, and Slovakia were based on the IQVIA MIDAS MAT July 2021.Results: The number of applications for the reimbursement of generic drugs decreased from 296 in 2016 to 165 in 2020. In financial terms, the sales of generic medicines in Slovakia increased from 21.7% in 2015 to 22.3% in 2020. Over the same period, the sales of generic drugs in Poland fell from 40.4% in 2015 to 35.0% in 2020, from 26.2 to 22.1% in Hungary, and from 29.6 to 20.4% in Czechia. When considering the 66 biosimilars registered by the European Medicines Agency 38 drugs (58%) were available on the Slovak market as of August 1, 2021; this compared to 32 drugs (48%) in Poland, 38 drugs (58%) in Hungary, and 40 drugs (61%) in Czechia. In financial terms, the sales of biosimilars in Slovakia increased from 0.94% in 2015 to 2.00% in 2020. Over the same period, the sales of biosimilars in Poland increased from 0.59% in 2015 to 1.29% in 2020, from 0.72 to 2.23% in Hungary, and from 0.76 to 2.15% in Czechia.Conclusion: To intensify the use of generic and biosimilar medicines, we suggest the comprehensive re-evaluation of combinations of the three-threshold entry, the amount of mandatory price reductions, and external reference pricing requirements (as the average of the three lowest prices among the official prices of a medicinal product in other Member States) for generic and biosimilar drugs. We also suggest cancellation of the exception from the fixed co-payment of the insured.

Introduction: Antiplatelet therapy needs to be administered life-long in patients with peripheral arterial disease (PAD). Our study was aimed at 1) the analysis of non-persistence with antiplatelet medication in older PAD patients and 2) identification of patient- and medication-related characteristics associated with non-persistence.Methods: The study data was retrieved from the database of the General Health Insurance Company. The study cohort of 9,178 patients aged ≥ 65 years and treated with antiplatelet medications was selected from 21,433 patients in whom PAD was newly diagnosed between 01/2012 and 12/2012. Patients with a 6 months treatment gap without antiplatelet medication prescription were classified as non-persistent. Characteristics associated with non-persistence were identified using the Cox regression.Results: At the end of the 5 years follow-up, 3,032 (33.0%) patients were non-persistent. Age, history of ischemic stroke or myocardial infarction, clopidogrel or combination of aspirin with clopidogrel used at the index date, higher co-payment, general practitioner as index prescriber and higher overall number of medications were associated with persistence, whereas female sex, atrial fibrillation, anxiety disorders, bronchial asthma/chronic obstructive pulmonary disease, being a new antiplatelet medication user (therapy initiated in association with PAD diagnosis), and use of anticoagulants or antiarrhythmic agents were associated with non-persistence.Conclusion: In patients with an increased probability of non-persistence, an increased attention should be paid to improvement of persistence.

The beneficial effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in hypertensive patients with peripheral arterial disease (PAD) depends on long-term persistence. The aims of our study were to analyse gender differences in non-persistence with ACEIs/ARBs, and to identify the characteristics associated with the likelihood of non-persistence. Our study cohort included 7080 hypertensive patients (4005 women and 3075 men) aged ≥65 years, treated with ACEIs/ARBs, in whom PAD was diagnosed between 1 January and 31 December 2012. Non-persistence was identified according to a treatment gap of 6 months without ACEI/ARB prescriptions. The characteristics associated with non-persistence were identified using the Cox regression model. At the end of the 5-year follow-up, 23.2% of the whole study cohort, 22.3% of men, and 23.9% of women were non-persistent with ACEIs/ARBs, with no significant gender differences in persistence. While a number of characteristics were associated with non-persistence, only three characteristics had consistent, statistically significant associations in both genders: being a new ACEI/ARB user increased the likelihood of non-persistence, and general practitioner as index prescriber and increasing the overall number of medications decreased the likelihood of non-persistence. Information on the differences in characteristics that are associated with non-persistence between genders may help to better identify patients for whom special attention should be paid to improve their persistence.

Objectives: To analyse the market shares of biosimilars in Slovakia and to calculate the potential cost-savings from the use of biosimilars in Slovakia based on two different data sources.Methods: National reimbursement lists from the Czech Republic, Hungary, Poland and Slovakia were used for analyzing the availability of biosimilars with public funding. In addition, the reimbursement dossiers of biosimilars, the justifications of reimbursement decisions by the Slovak Ministry of Health, and final reimbursement decrees, which are published on the webpage of the Slovak Ministry of Health, were utilized for this study. Reimbursement decisions regarding biosimilars by the Slovak Ministry of Health from 2006 to August 2019 were considered and the detailed utilization of biosimilars in 2018 was analyzed based on data from the State Institute for Drug Control. The study was validated based on data from the Slovak National Health Information Center.Results: Fifty four biosimilars were approved by the European Medicines Agency (EMA) in August 2019. Of the total group of licensed biosimilars on the market, 29 biosimilars (54%) were available in the Czech Republic, 28 biosimilars (52%) were available in Poland, and 27 biosimilars (50%) were available in Hungary and 24 biosimilars (44%) were available in Slovakia. Our analysis, based on the data provided by distributors of medicinal products to the State Institute for Drug Control, revealed that the health fund in Slovakia could have saved 35 to 50 million euros per year if biosimilars with marketing authorisations had been available on the Slovak market. The calculations assumed a 25–35% price decrease against the original biological medical products, and that there would be no increase in the utilization of biosimilars in Slovakia.Conclusions: To achieve significant improvement in patient access to biosimilars in Slovakia, a top-down approach establishing targets and quotas for the procurement of biosimilars should be applied.

Secondary prevention of peripheral arterial disease (PAD) includes administration of antiplatelet agents, and adherence to medication is a requirement for an effective treatment. The aim of this study was to analyse adherence measured using the proportion of days covered (PDC) index separately in persistent and non-persistent patients, and to identify patient- and medication-related characteristics associated with non-adherence in these patient groups. The study cohort of 9178 patients aged ≥ 65 years in whom PAD was diagnosed in 1/–12/2012 included 6146 persistent and 3032 non-persistent patients. Non-adherence was identified as PDC < 80%. Characteristics associated with non-adherence were determined using the binary logistic regression model. In the group of persistent patients, 15.3% of subjects were identified as non-adherent, while among non-persistent patients, 26.9% of subjects were non-adherent to antiplatelet medication. Administration of dual antiplatelet therapy (aspirin and clopidogrel) and a general practitioner as index prescriber were associated with adherence in both patient groups. Our study revealed a relatively high proportion of adherent patients not only in the group of persistent patients but also in the group of non-persistent patients before discontinuation. These results indicate that most non-persistent PAD patients discontinue antiplatelet treatment rapidly after a certain period of adherence.

The successful treatment of peripheral arterial disease (PAD) depends on adequate adherence to medications including antiplatelet agents. The aims of this study were (a) to identify the proportion of nonpersistent patients who reinitiated antiplatelet therapy and how many of them discontinued therapy after reinitiation, and (b) to identify patient- and medication-related characteristics associated with the likelihood of reinitiation and discontinuation among reinitiators. The analysis of reinitiation was conducted on 3032 nonpersistent users of antiplatelet agents aged ≥65 years, with PAD newly diagnosed in 2012. Discontinuation (i.e., a treatment gap of ≥6 months without antiplatelet medication prescription) was analysed in 2006 reinitiating patients. To identify factors associated with the likelihood of reinitiation and discontinuation, Cox regression with time-dependent covariates was used. Reinitiation was recorded in 2006 (66.2%) of 3032 patients who had discontinued antiplatelet medication. Among these 2006 reinitiators, 1078 (53.7%) patients discontinued antiplatelet therapy again. Ischemic stroke and myocardial infarction during nonpersistence and bronchial asthma/chronic obstructive pulmonary disease were associated with an increased likelihood of reinitiation. University education was associated with discontinuation among reinitiators. Factors associated with the probability of reinitiation and discontinuation in reinitiators make it possible to identify older PAD patients in whom “stop-starting” behaviour may be expected.

This paper aims to analyse the consumption of antibiotics in the Slovak health care system from 2011 to 2020. The data source on the consumption of antibiotics is sales data from SUKL and NCZI. The study employed the ATC/DDD Index and focused on the consumption of antibiotics in the primary care sector. Total antibiotic consumption decreased from 19.21 DID in 2011 to 13.16 DID in 2020. Consumption of beta-lactamase-sensitive penicillins, expressed as a percentage of the total consumption of antibiotics, decreased from 8.4% in 2011 to 4.2% in 2020. Consumption of the combination of penicillins, including beta-lactamase inhibitor, expressed as a percentage of the total consumption of antibiotics, increased from 16.2% in 2011 to 17.9% in 2020. Consumption of third- and fourth-generation cephalosporins, expressed as the percentage of the total consumption of antibiotics, increased from 2.0% in 2011 to 4.6% in 2020. Consumption of fluoroquinolones, expressed as the percentage of the total consumption of antibiotics, decreased from 10.7% in 2011 to 8.6% in 2020. Overall, antibiotic consumption significantly changed in Slovakia from 2011 to 2020. The ratio of the consumption of broad-spectrum to the consumption of narrow-spectrum penicillins, cephalosporins and macrolides decreased from 14.98 in 2011 to 13.38 in 2020.

Abstract Background Despite a variety of efficient and cost-effective antihypertensive medication, hypertension remains a serious health and economic burden. High consumption of cardiovascular drugs in the Slovak Republic does result neither in better hypertension control nor in significant decrease in cardiovascular mortality. At the same time, Slovakia has alarmingly low patients’ adherence to medication intake. Studies have shown the efficiency of short messaging service (SMS) reminders to improve patients’ adherence and health outcomes at low costs. Since SMS is popular among Slovaks, this approach may be feasible also in Slovakia. The primary objective is to assess if daily SMS reminders of antihypertensive medication intake provided by pharmacists in addition to the standard pharmaceutical care increase the proportion of adherent older hypertensive ambulatory patients. Methods The SPPA trial is a pragmatic randomized parallel group (1:1) trial in 300 older hypertensive patients carried out in community pharmacies in Slovakia. Trial pharmacies will be selected from all main regions of Slovakia. Trial intervention comprises daily personalized SMS reminders of medication intake embedded into usual pharmaceutical practice. The primary outcome is a combined adherence endpoint consisting of subjective self-reported medication adherence via the eight-item Morisky Medication Adherence Scale (MMAS-8) and objective pill count rate. Secondary outcomes include: change in the MMAS-8; comparison of adherence rates using pill count; change in systolic blood pressure; and patient satisfaction. Also, direct treatment costs will be evaluated and a cost-effectiveness analysis will be carried out. Discussion The SPPA trial engages community pharmacists and mobile health (mHealth) technologies via evidence-based pharmaceutical care to efficiently and cost-effectively addresses current main healthcare challenges: high prevalence of hypertension; overconsumption of cardiovascular medicines; low adherence to medication treatment; and resulting uncontrolled blood pressure. The results may identify new possibilities and capacities in healthcare with low additional costs and high value to patients. Trial registration ClinicalTrials.gov, NCT03105687 . Registered on 07 March 2017.

Objectives: The aim of this study was to review the impact of new reimbursement requirements for medicines in the Slovak Republic based on legislation that came into force in January 2018.Methods: The new legislation was reviewed. The reimbursement dossiers for medicines and health technology assessments and appraisals, justifications for reimbursement decisions, final reimbursement decisions, and all aspects of the appeal mechanisms have been transparently published on the website of the Slovak Ministry of Health and were used for this analysis.Results: Based on the new legislation, there was no need to submit information about relative effectiveness and cost-effectiveness of medicines with less than 1:50,000 eligible patients prior to reimbursement decisions, and the cost-effectiveness threshold has been increased for all other medicines. The estimated impact of the 2-year budget for the 59 medicines submitted for reimbursement without relative effectiveness and cost-effectiveness analysis was €181,273,698, based on the published submission dossiers. The estimated impact of the 2-year budget for the 45 medicines with evidence of relative effectiveness and cost-effectiveness was €178,566,634. In contrast to the easier market access criteria for new original medicines, the new legislation enforces stricter price erosion criteria for generic and biosimilar medicines. Consequently, the number of generic and biosimilar entries was reduced from 242 in 2017 to 224 in 2018.Conclusions: Although some of the new reimbursement applications were not approved by the Ministry of Health, many new medicines were added to the Slovak pharmaceutical reimbursement list based on “balanced assessment” requirements; hence, the system became financially unsustainable. It was necessary to change the legislation from January 2019.

BackgroundReimbursement policies influence access of patients to orphan drugs in the European countries.ObjectivesTo provide a comprehensive description of orphan drug reimbursement policies and to assess reimbursement decision-making process in the EU-CEE countries as well as the impact of the type of approval and disease on reimbursement decisions.MethodsFor each drug, the information regarding conditional approval or approval under exceptional circumstances was obtained from the EMA website. The reimbursement status for analyzed drugs was collected in a questionnaire survey performed in a group of experts in reimbursement policy. The agreement between countries was assessed using the κ coefficient, nominal variables tests were compared using the χ2 test or the Fisher exact test. The impact of the EMA’s conditional approval and approval under exceptional circumstances was assessed using logistic regression and presented as an odds ratio (OR).ResultsThe analysis revealed that most orphan drugs were authorized for the treatment of oncological or metabolic diseases [36 drugs (38%) and 22 drugs (23%), respectively]. The shares of reimbursed orphan drugs varied significantly (p = 0.0031) from 6.3% in Latvia to 27.4% in Poland. No correlation (r = 0.02; p = 0.9583) with GDP per capita was observed. The highest agreement in reimbursement decisions was observed between Estonia and Lithuania, and the lowest – between Estonia and Latvia, with kappa of 0.69 and 0.11, respectively. Significant impact of the type of approval and reimbursement status was observed for Czechia, Lithuania and Slovakia where conditional approval and exceptional circumstances negatively influenced reimbursement decision. Type of disease has significant influence on reimbursement decision in 4 out of 10 analyzed countries with significant outweigh of positive decisions for oncological diseases.ConclusionIn considered countries specific regulations on reimbursement of orphan drugs are valid but in Lithuania and Romania no formal HTA process was employed; in case of some countries higher ICER values for orphans are used. The share of reimbursed orphan drugs varied significantly across the countries, but it was not associated with GDP per capita.

The effectiveness of statins in secondary prevention of peripheral arterial disease (PAD) largely depends on patients’ adherence to treatment. The aims of our study were: (a) to analyze non-adherence during the whole follow-up in persistent patients, and only during persistence for non-persistent patients; (b) to identify factors associated with non-adherence separately among persistent and non-persistent patients. A cohort of 8330 statin users aged ≥65 years, in whom PAD was newly diagnosed between January 2012–December 2012, included 5353 patients persistent with statin treatment, and 2977 subjects who became non-persistent during the 5-year follow-up. Non-adherence was defined using the proportion of days covered p < 0.001). Associated with non-adherence in both persistent and non-persistent patients was high intensity statin treatment, while in non-persistent patients, it was employment and increasing number of medications. In patients with a poor adherence during their persistent period, an increased risk for discontinuation may be expected. However, there is also non-adherence among persistent patients. There are differences in factors associated with non-adherence depending on patients’ persistence.

Objectives: The aim of the study was to compare the access of patients with rare diseases (RDs) to biotechnological drugs in several Central and Eastern European countries (CEECs). We focused on the legislative pricing and reimbursement requirements, availability of biotechnological orphan medicinal products (BOMPs) for RDs, and reimbursement expenditures.Methods: A questionnaire-based survey was conducted among experts from 10 CEECs: Bulgaria, Croatia, Estonia, Greece, Hungary, Poland, Romania, Slovakia, Serbia, and Macedonia. The legal requirements for reimbursement and pricing of BOMPs were collected. All BOMPs and medicines without prior orphan designations were extracted from the European list of orphan medicinal products, 2017. The reimbursement status of these medicinal products in 2017 in the public coverage of the included CEECs as well as the share of their costs in relation to the total public pharmaceutical spending for the period from 2014 to 2016 were defined.Results: Our survey revealed that some differences in the legal requirements for pricing and reimbursement of BOMPs amongst the countries included in the study. All European Union countries have developed and implemented pharmacoeconomic guidelines with or without some specific reimbursement requirements for orphan medicinal products. Cost-effectiveness analysis, cost-utility analysis, Markov models, meta-analysis, and discount levels of costs and results were required only in Bulgaria, Poland and Hungary. The number of reimbursed BOMPs and biotechnological medicinal products for RDs without prior orphan designation was the highest in Hungary (17 and 40, respectively). Patient-based reimbursement schemes were available only in Hungary for 11 out of 17 BOMPs. Poland and Greece have the highest pharmaceutical expenditure of reimbursed BOMPs with are ~214 million and 180 million EUR, respectively in the observed period from 2014 to 2016. High proportion of the pharmaceutical expenditure on the reimbursed biotechnological medicinal products for RDs for the observed period 2014–2016 is presented in Bulgaria and Slovakia.Conclusions: The non-European Union CEECs face a significant delay in the legal implementation of pharmacoeconomic guideline for assessment of BOMPs. The access to BOMPs is similar among the observed CEECs and the countries with the best access are Hungary and Greece. The influence of BOMP expenditures on the budget in the individual countries is significant.

Drug shortages have been identified as a public health problem in an increasing number of countries. This can negatively impact on the quality and efficiency of patient care, as well as contribute to increases in the cost of treatment and the workload of health care providers. Shortages also raise ethical and political issues. The scientific evidence on drug shortages is still scarce, but many lessons can be drawn from cross-country analyses. The objective of this study was to characterize, compare, and evaluate the current systemic measures and legislative and organizational frameworks aimed at preventing or mitigating drug shortages within health care systems across a range of European and Western Asian countries. The study design was retrospective, cross-sectional, descriptive, and observational. Information was gathered through a survey distributed among senior personnel from ministries of health, state medicines agencies, local health authorities, other health or pharmaceutical pricing and reimbursement authorities, health insurance companies and academic institutions, with knowledge of the pharmaceutical markets in the 28 countries studied. Our study found that formal definitions of drug shortages currently exist in only a few countries. The characteristics of drug shortages, including their assortment, duration, frequency, and dynamics, were found to be variable and sometimes difficult to assess. Numerous information hubs were identified. Providing public access to information on drug shortages to the maximum possible extent is a prerequisite for performing more advanced studies on the problem and identifying solutions. Imposing public service obligations, providing the formal possibility to prescribe unlicensed medicines, and temporary bans on parallel exports are widespread measures. A positive finding of our study was the identification of numerous bottom-up initiatives and organizational frameworks aimed at preventing or mitigating drug shortages. The experiences and lessons drawn from these initiatives should be carefully evaluated, monitored, and presented to a wider international audience for careful appraisal. To be able to find solutions to the problem of drug shortages, there is an urgent need to develop a set of agreed definitions for drug shortages, as well as methodologies for their evaluation and monitoring. This is being progressed.

Objectives: The aim of this study was to review reimbursement environment as well as pricing and reimbursement requirements for drugs in selected Central and Eastern Europe (CEE) countries.Methods: A questionnaire-based survey was performed in the period from November 2016 to March 2017 among experts involved in reimbursement matters from CEE countries: Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Romania. A review of requirements for reimbursement and implications of Health Technology Assessment (HTA) was performed to compare the issues in above-mentioned countries. For each specified country, data for reimbursement costs, total pharmaceutical budget, and total public health care budget in the years 2014 and 2015 were also collected. Questionnaires were distributed via emails and feedback data were obtained in the same way. Additional questions, if any, were also submitted to respondents by email. Pricing and reimbursement data were valid for March 2017.Results: The survey revealed that the relation of drug reimbursement costs to total public healthcare spending ranged from 0.12 to 0.21 in the year 2014 and 2015 (median value). It also revealed that pricing criteria for drugs, employed in the CEE countries, were quite similar. External reference pricing as well as internal reference pricing were common in mentioned countries. Positive reimbursement lists were valid in all countries of the CEE region, negative ones were rarely used; reimbursement decisions were regularly revised and updated in the majority of countries. Copayment was common and available levels of reimbursement differed within and between the countries and ranged from 20 to 100%. Risk-sharing schemes were often in use, especially in the case of innovative, expensive drugs. Generic substitution was also possible in all analyzed CEE countries, while some made it mandatory. HTA was carried out in almost all of the considered CEE countries and HTA dossier was obligatory for submitting a pricing and reimbursement application.Conclusions: Pricing and reimbursement requirements are quite similar in the CEE region although some differences were identified. HTA evaluations are commonly used in considered countries.

Objectives: To explore whether Heberprot-P (an epidermal growth factor) is a cost-effective option for the treatment of advanced diabetic foot ulcer as an add-on therapy to good wound care (GWC) in Slovakia from the perspective of health care payers.Methods: A Markov model was constructed to compare the costs and effects of Heberprot-P plus GWC to those of GWC alone from the perspective of health care payers. The 52-week clinical trial period was extended to 5- and 10-year time horizons. Transition probabilities were calculated based on a previous clinical trial of Heberprot, utility values were derived from the scientific literature, and cost vectors were collected from the General Health Insurance Fund database in Slovakia. A one-way deterministic sensitivity analysis was employed to explore the influence of uncertainty for each input parameter on the incremental cost-effectiveness ratio (ICER).Results: Based on the ICER threshold of €30,030 per quality-adjusted life year (QALY) recommended by the Slovak Ministry of Health, Heberprot-P therapy plus GWC is not a cost-effective alternative to GWC alone over a 10-year time horizon. The ICER increases if a longer time horizon is applied, as the incremental costs are similar, but the aggregated utility gain from avoided amputation is lower. Based on the sensitivity analysis, the utility multiplier for the health state “no ulcer after small amputation” had the most impact on the ICER; however, the model was robust to changes in all input parameters.Conclusions: Heberprot-P, as an add-on therapy to GWC in the treatment of advanced diabetic foot ulcer, is not a cost-effective alternative to GWC alone. However, if the unit cost of Heberprot-P were to be reduced to

Objectives: The aim of this study was to review the requirements for the reimbursement of biosimilars and to compare the reimbursement status, market share, and reimbursement costs of biosimilars in selected Central and Eastern European (CEE) countries.Methods: A questionnaire-based survey was conducted between November 2016 and January 2017 among experts from the following CEE countries: Bulgaria, Czech Republic, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Romania. The requirements for the pricing and reimbursement of biosimilars were reviewed for each country. Data on the extent of reimbursement of biologic drugs (separately for original products and biosimilars) in the years 2014 and 2015 were also collected for each country, along with data on the total pharmaceutical and total public health care budgets.Results: Our survey revealed that no specific criteria were applied for the pricing and reimbursement of biosimilars in the selected CEE countries; the price of biosimilars was usually reduced compared with original drugs and specific price discounts were common. Substitution and interchangeability were generally allowed, although in most countries they were at the discretion of the physician after a clinical assessment. Original biologic drugs and the corresponding biosimilars were usually in the same homogeneous group, and internal reference pricing was usually employed. The reimbursement rate of biosimilars in the majority of the countries was the same and amounted to 100%. Generally, the higher shares of expenditures were shown for the reimbursement of original drugs than for biosimilars, except for filgrastim, somatropin, and epoetin (alfa and zeta). The shares of expenditures on the reimbursement of biosimilar products ranged from 8.0% in Estonia in 2014 to 32.4% in Lithuania in 2015, and generally increased in 2015. The share of expenditures on reimbursement of biosimilars in the total pharmaceutical budget differed between the countries, with the highest observed value for Slovakia and Hungary and the lowest—for Croatia.Conclusions: The requirements for the pricing and reimbursement of biosimilar products as well as the access of patients to biologic treatment do not differ significantly between the considered CEE countries. Biosimilar drugs significantly influence the reimbursement systems of these countries, and the expenditure on the reimbursement of biosimilars is increasing as they are becoming more accessible to patients.