Clinical aspects of reimbursement policies for orphan drugs in Central and Eastern European countries.

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.

Recommendations for patient involvement in health technology assessment in Central and Eastern European countries.

Introduction: Meaningful 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. Methods: Built 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. Results: A 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. Conclusion: In 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.

Recommendations to overcome barriers to the use of artificial intelligence-driven evidence in health technology assessment.

Background: Artificial 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. Methods: We 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. Results: Recommendations 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. Conclusion: In 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.

Implementation of coverage with evidence development schemes for medical devices: A decision tool for late technology adopter countries.

Experiences with coverage with evidence development (CED) schemes are fairly limited in Central and Eastern European (CEE) countries, which are usually late adopters of new health technologies. Our aim was to put forward recommendations on how CEE health technology assessment bodies and payer organizations can apply CED to reduce decision uncertainty on reimbursement of medical devices, with a particular focus on transferring the structure and data from CED schemes in early technology adopter countries in Western Europe. Structured interviews on the practices and feasibility of transferring CED schemes were conducted and subsequently, a draft tool for the systematic classification of decision alternatives and recommendations was developed. The decision tool was reviewed in a focus group discussion and validated within a wider group of CEE experts in a virtual workshop. Transferability assessment is needed in case of (1) joint implementation of a CED scheme; (2) transferring the structure of an existing CED scheme to a CEE country; (3) reimbursement decisions that are linked to outcomes of an ongoing CED scheme in another country and (4) real-world evidence transferred from completed CED schemes. Efficient use of available resources may be improved by adequately transferring evidence and policy tools from early technology adopter countries.

Health technology assessment and reimbursement policy for oncology orphan drugs in Central and Eastern Europe.

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.

Potential Cost-Savings From the Use of the Biosimilars in Slovakia.

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.

Development of transferability guidance for integrated care models with special focus on Central and Eastern European countries.

AIM: To develop pragmatic recommendations for Central and Eastern European (CEE) policymakers about transferability assessment of integrated care models established in higher income European Union (EU) countries. METHODS: Draft recommendations were developed based on Horizon 2020-funded SELFIE project deliverables related to 17 promising integrated care models for multimorbid patients throughout Europe, as well as on an online survey among CEE stakeholders on the relevance of implementation barriers. Draft recommendations were discussed at the SELFIE transferability workshop and finalized together with 22 experts from 12 CEE countries. RESULTS: Thirteen transferability recommendations are provided in three areas. Feasibility of local implementation covers the identification and prioritization of implementation barriers and proposals for potential solutions. Performance measurement of potentially transferable models focuses on the selection of models with proven benefits and assurance of performance monitoring. Transferability of financing methods for integrated care explores the relevance of financing methodologies and planning of adequate initial and long-term financing. CONCLUSIONS: Implementation of international integrated care models cannot be recommended without evidence on its local feasibility or scientifically sound and locally relevant performance assessment in the country of origin. However, if the original financing method is not transferable to the target region, development of a locally relevant alternative financing method can be considered.

The transferability of health technology assessment: the European perspective with focus on central and Eastern European countries.

INTRODUCTION: Lower-income European countries have a worse health status and less funds for health care compared to Western Europe. Despite their limited human and financial capacities for conducting Health Technology Assessment (HTA), the need for evidence-based decision-making is growing. Two main approaches emerged as potential solutions: joint clinical assessments on the European level, and simplified procedures relying on the judgments of well-established HTA agencies of Western countries. AREAS COVERED: Based on considerations of transferability, the European Network for Health Technology Assessment (EUnetHTA) was built up to harmonize HTA methodologies across the European Union, and to develop an HTA Core Model by focusing on joint production of relative effectiveness assessment, which can be used as a basis for national value assessments. The second approach has been suggested in various forms without considering transferability issues. EXPERT OPINION: Joint clinical assessments reduce duplication of efforts based on appropriate scientific rationale. On the other hand, recent examples show that relying on judgments of HTA agencies from wealthier countries with potentially different health-care priorities can lead to suboptimal allocation decisions. In the short term, some stakeholders may benefit from ignoring transferability, but it will ultimately lead to limited access in other disease areas.

How Changes in Reimbursement Practices Influence the Financial Sustainability of Medicine Policy: Lessons Learned from Slovakia.

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.

The effectiveness of daily SMS reminders in pharmaceutical care of older adults on improving patients' adherence to antihypertensive medication (SPPA): study protocol for a randomized controlled trial.

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.

Pricing and Reimbursement of Biosimilars in Central and Eastern European Countries.

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.

INTRODUCTION OF HEALTH TECHNOLOGY ASSESSMENT FOR MEDICINES IN SLOVAKIA.

OBJECTIVES: The aim of our study was to describe approaches to health technology assessment (HTA) for medicines in the Slovak healthcare system and the related decision-making processes concerning reimbursement for medicines. METHODS: Analysis of the Slovak legislative framework related to HTA and the reimbursement process for medicines was performed. Additionally, current practices of the Working Group for Pharmacoeconomics, Clinical Outcomes and Health Technology Assessment of the Slovak Ministry of Health were evaluated. RESULTS: In Slovakia, there is always at least one treatment available in each determined therapeutic class with no co-payment. HTA is becoming an established method for the evaluation of cost-effectiveness of medicines in Slovak healthcare policy. The majority of decision makers within Slovakia support the idea of increased use of and the quality and efficiency of HTA methods. However, it is crucial to overcome several practical barriers to facilitate progress in the field of HTA in the Slovak Republic. CONCLUSIONS: It can be seen that participation within the European Network for Health Technology Assessment (EUnetHTA JA 2 and EUnetHTA JA 3 projects) has significantly improved the quality of the process of HTA in Slovakia. Further legislative activities in this field are required due to the approved strategy for European Union cooperation on HTA.

Cost-Utility Analysis of Heberprot-P as an Add-on Therapy to Good Wound Care for Patients in Slovakia with Advanced Diabetic Foot Ulcer.

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 <€273, its ICER would be <€30,030.

Pharmaceutical Regulation in Central and Eastern European Countries: A Current Review.

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.