The role of insurance policies in the drug pricing landscape.

INTRODUCTION: This overview paper aims at summarizing and analyzing the available literature on healthcare system organization and pricing policies of 11 European countries, comparing them to the Bulgarian pharmaceutical system. The countries were selected based on the reference basket for the pricing of pharmaceuticals in Bulgaria - Belgium, Greece, Spain, Italy, Latvia, Lithuania, Romania, Slovakia, Slovenia, and France. AREAS COVERED: In the first part, we explore the health system models in the above-mentioned countries. In the second part we explore the pricing and reimbursement policies, and in the third part we analyze healthcare and pharmaceutical economic indicators, as well as life expectancy. The major focus of the review is the outpatient care. EXPERT OPINION: In this work, we attempted to outline differences and similarities between the countries of interest. Despite the differences in their healthcare system organization, health and pharmaceutical expenditures constantly increased during the observed 2 decades. This increase in expenditures, however, has not had a significant impact on life-expectancy. Minor increases were observed - from 2 to 4 years total. No country had an expectancy above 85 years of age. It might be said that other factors are influencing the life expectancy to a greater extent.

Therapeutic Results and Survival of Patients with Myelofibrosis Treated with Ruxolitinib-A Real-Life Longitudinal Study.

The aim of this study was to analyze the therapeutic results and survival of patients with myelofibrosis treated with ruxolitinib in comparison with a group on standard therapy. It is a cross-sectional, retrospective, non-interventional, real-life study that was performed between January 2000 and February 2023. Patients treated between 2000 and 2016, before the introduction of ruxolitinib, constituted the control group (n = 45), while those treated after May 2016, after ruxolitinib inclusion, constituted the active group (n = 66). Demographic characteristics, clinical indicators, the severity of the disease, and survival were explored using Kaplan-Meier survival analyses. Spearman's correlation, linear regression, and other statistical analyses were performed. According to the Kaplan-Meier analysis, there was a 75.33% reduction in the fatality risk in the sample. On a general-population level, the fatality risk in the group treated with ruxolitinib varied between 7.9% and 77.18% compared to that of the risk in the control group. There was a decrease in blood parameters (leukocytes, hemoglobin, and platelets) and spleen size. During the first six months, the spleen size of the patients on ruxolitinib decreased by 6%, and during the second six months, it decreased by another 9%. This study shows that patients in a real-life clinical setting treated with ruxolitinib exhibited improved clinical signs of the disease, had a lower symptom severity, and survived longer than patients on standard therapy before ruxolitinib's entrance into the national market. The improvements correlate with those reported in randomized clinical trials.

How Managed Entry Agreements Influence the Patients' Affordability to Biological Medicines-Bulgarian Example.

Managed entry agreements are applied in almost all European countries in order to improve patients' access to therapy. The current study aims to evaluate the changes in the affordability of biological medicines for patients in Bulgaria during 2019-2022. The study is a top-down macroeconomic analysis of the key economic indicators and reimbursed costs of biologic therapies. Affordability was determined as the number of working hours needed to pay for monthly therapy. The average NHIF budget for pharmaceuticals increased significantly along with inflation in the healthcare sector. Bulgarian patients had to devote a large part of their income to buying medicines if a co-payment existed. The percentage of the monthly income of pensioners needed for therapy co-payment varied between 10% and 280%. The hours of work required to purchase a package of biologicals varied between 7 and 137 working hours. The global economic crisis has affected Bulgaria and led to worsening economic parameters. There are still no well-established practices to control public spending, as the measures taken to reduce the final cost of medicines mainly affect the pharmaceutical companies. This type of cost-containment policy provides an opportunity for innovative treatment with biologicals for patients with inflammatory diseases. Most of the therapies cost more than the patients' monthly income.

Recommendations for wider adoption of clinical pharmacy in Central and Eastern Europe in order to optimise pharmacotherapy and improve patient outcomes.

Clinical pharmacy as an area of practice, education and research started developing around the 1960s when pharmacists across the globe gradually identified the need to focus more on ensuring the appropriate use of medicines to improve patient outcomes rather than being engaged in manufacturing and supply. Since that time numerous studies have shown the positive impact of clinical pharmacy services (CPS). The need for wider adoption of CPS worldwide becomes urgent, as the global population ages, and the prevalence of polypharmacy as well as shortage of healthcare professionals is rising. At the same time, there is great pressure to provide both high-quality and cost-effective health services. All these challenges urgently require the adoption of a new paradigm of healthcare system architecture. One of the most appropriate answers to these challenges is to increase the utilization of the potential of highly educated and skilled professionals widely available in these countries, i.e., pharmacists, who are well positioned to prevent and manage drug-related problems together with ensuring safe and effective use of medications with further care relating to medication adherence. Unfortunately, CPS are still underdeveloped and underutilized in some parts of Europe, namely, in most of the Central and Eastern European (CEE) countries. This paper reviews current situation of CPS development in CEE countries and the prospects for the future of CPS in that region.

Study of Symptom Severity and Adherence to Therapy of Myelofibrosis Patients Treated with Ruxolitinib.

We aimed to explore symptom severity and adherence to therapy for patients with myelofibrosis treated with ruxolitinib in Bulgaria. It is a prospective, non-interventional study performed at the specialized hospital for active treatment of hematological diseases in Sofia during 2022-2023. Date of diagnosis, demographic characteristics, clinical indicators, ruxolitinib dose, and other data points were collected. Clinical indicators were assessed at baseline, in the middle, and at the end of observation. Severity of symptoms was measured with MPN-SAF TSS and adherence to therapy with the Morisky 4 questionnaire six times during the observation. The mean age of diagnosis was 58.5 years, with the average duration of disease of 3 years. Patients' laboratory results were within physiological ranges, with spleen size experiencing a constant decrease. The average value for the severity of the symptoms per MPN-SAF TSS results decreased significantly, indicating better disease control. The average adherence to therapy did not change and remained high at around 9 points, except for one patient. In conclusion the treatment of myelofibrosis patients with ruxolitinib decreased symptom severity and spleen size. Patients were adherent to the therapy over the observed period, but as treatment duration increases, the risk of adherence decreases.

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.

Corrigendum to "Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications".

[This corrects the article DOI: 10.1155/2021/9996193.].

Tackling reimbursement challenges to fair access to medicines - introduction to the topic.

INTRODUCTION: Ensuring both financial and physical access to medicines is a challenge for the reimbursement system. How countries are currently tackling this challenge is an issue worth exploring in this review paper. AREAS COVERED: The review covered three areas of studies such as pricing, reimbursement, and patient access measures. We compared the use and shortcomings of all measures influencing patients' access to medicines. EXPERT OPINION: In this work, we tried attempted to outline fair access policies toward reimbursed medicines in a historical manner by researching the measures accepted during different time periods by governments that affect patient access. From the review, it is evident that the countries are following similar models with a focus on pricing measures, reimbursement measures, and measures directly affecting the patients. It is our opinion that most of the measures are focused on ensuring the sustainability of the payer's funds and less are those that stimulate faster access. Even worse, we found that studies that are measuring the real patients access, and affordability are scarce.

Guidance on using real-world evidence from Western Europe in Central and Eastern European health policy decision making.

Aim: Real-world data and real-world evidence (RWE) are becoming more important for healthcare decision making and health technology assessment. We aimed to propose solutions to overcome barriers preventing Central and Eastern European (CEE) countries from using RWE generated in Western Europe. Materials & methods: To achieve this, following a scoping review and a webinar, the most important barriers were selected through a survey. A workshop was held with CEE experts to discuss proposed solutions. Results: Based on survey results, we selected the nine most important barriers. Multiple solutions were proposed, for example, the need for a European consensus, and building trust in using RWE. Conclusion: Through collaboration with regional stakeholders, we proposed a list of solutions to overcome barriers on transferring RWE from Western Europe to CEE countries.

Budget cap and pay-back model to control spending on medicines: A case study of Bulgaria.

Central and Eastern European countries (CEEC) have among the highest rates of increase in healthcare expenditure. External reference pricing, generics and biologics price capping, regressive scale for price setting, health technology assessment (HTA), and positive drug lists for reimbursed medicines are among the variety of implemented cost-containment measures aimed at reducing and controlling the rising cost for pharmaceuticals. The aim of our study was to analyze the influence of a recently introduced measure in Bulgaria-budget capping in terms of overall budget expenditure. A secondary goal was to analyze current and extrapolate future trends in the healthcare and pharmaceutical budget based on data from 2016 to 2021. The study is a retrospective, observational and prognostic, macroeconomic analysis of the National Health Insurance Fund's (NHIF) budget before (2016-2018) and after (2019-2021) the introduction of the new budget cap model. Subgroups analysis for each of the three new budget groups of medicines (group A: medicines for outpatient treatment, prescribed after approval by a committee of 3 specialists; group B: all other medicines out of group A; and group C: oncology and life-saving medicines out of group A) was also performed, and the data were extrapolated for the next 3 years. The Kruskal-Wallis test was applied to establish statistically significant differences between the groups. During 2016-2021, healthcare services and pharmaceutical spending increased permanently, observing a growth of 82 and 80%, respectively. The overall healthcare budget increased from European €1.8 billion to 3.3 billion. The subgroup analysis showed a similar trend for all three groups, with similar growth between them. The highest spending was observed in group C, which outpaced the others mainly due to the particular antineoplastic (chemotherapy) medicines included in it. The rising overall healthcare cost in Bulgaria (from European €1.8 billion to 3.3 billion) reveals that implementation of a mechanism for budget predictability and sustainability is needed. The introduced budget cap is a relatively effective measure, but the high level of overspending and pay-back amount (from European €34 billion to 59 billion during 2019-2021) reveals that the market environmental risk factors are not well foreseen and practically implemented.

Prevalence of potentially inappropriate prescribing in older adults in Central and Eastern Europe: a systematic review and synthesis without meta-analysis.

We aimed to systematically review the prevalence of potentially inappropriate prescribing (PIP) in older adults in Central and Eastern Europe (CEE) in all care settings. We searched Embase and MEDLINE (up to June 2019) and checked the reference lists of the included studies and relevant reviews. Eligible studies used validated explicit or implicit tools to assess the PIP prevalence in older adults in CEE. All study designs were considered, except case‒control studies and case series. We assessed the risk of bias using the Joanna Briggs Institute Prevalence Critical Appraisal Tool and the certainty of evidence using the GRADE approach. Meta-analysis was inappropriate due to heterogeneity in the outcome measurements. Therefore, we used the synthesis without meta-analysis approach-summarizing effect estimates method. This review included twenty-seven studies with 139,693 participants. Most studies were cross-sectional and conducted in high-income countries. The data synthesis across 26 studies revealed the PIP prevalence: the median was 34.6%, the interquartile range was 25.9-63.2%, and the range was 6.5-95.8%. The certainty of this evidence was very low due to the risk of bias, imprecision, and inconsistency. These findings show that PIP is a prevalent issue in the CEE region. Further well-designed studies conducted across countries are needed to strengthen the existing evidence and increase the generalizability of findings.

Barriers to Use Artificial Intelligence Methodologies in Health Technology Assessment in Central and East European Countries.

The aim of this paper is to identify the barriers that are specifically relevant to the use of Artificial Intelligence (AI)-based evidence in Central and Eastern European (CEE) Health Technology Assessment (HTA) systems. The study relied on two main parallel sources to identify barriers to use AI methodologies in HTA in CEE, including a scoping literature review and iterative focus group meetings with HTx team members. Most of the other selected articles discussed AI from a clinical perspective (n = 25), and the rest are from regulatory perspective (n = 13), and transfer of knowledge point of view (n = 3). Clinical areas studied are quite diverse-from pediatric, diabetes, diagnostic radiology, gynecology, oncology, surgery, psychiatry, cardiology, infection diseases, and oncology. Out of all 38 articles, 25 (66%) describe the AI method and the rest are more focused on the utilization barriers of different health care services and programs. The potential barriers could be classified as data related, methodological, technological, regulatory and policy related, and human factor related. Some of the barriers are quite similar, especially concerning the technologies. Studies focusing on the AI usage for HTA decision making are scarce. AI and augmented decision making tools are a novel science, and we are in the process of adapting it to existing needs. HTA as a process requires multiple steps, multiple evaluations which rely on heterogenous data. Therefore, the observed range of barriers come as a no surprise, and experts in the field need to give their opinion on the most important barriers in order to develop recommendations to overcome them and to disseminate the practical application of these tools.

Potential Barriers of Patient Involvement in Health Technology Assessment in Central and Eastern European Countries.

Patients' perspectives are important to identify preferences, estimate values and appreciate unmet medical needs in the process of research and development and subsequent assessment of new health technologies. Patient and public involvement in health technology assessment (HTA) is essential in understanding and assessing wider implications of coverage and reimbursement decisions for patients, their relatives, caregivers, and the general population. There are two approaches to incorporating the patients' voice in HTA, preferably used in a mix. In the first one, patients, caregivers and/or their representatives directly participate at discussions in different stages of the HTA process, often at the same table with other stakeholders. Secondly, patient involvement activities can be supported by evidence on patient value and experience collected directly from patients, caregivers and/or their representatives often by patient groups Patient involvement practices, however, are limited in Central and Eastern European (CEE) countries without clear methodology or regulatory mechanisms to guide patient involvement in the HTA process. This poses the question of transferability of practices used in other countries, and might call for the development of new CEE-specific guidelines and methods. In this study we aim to map potential barriers of patient involvement in HTA in countries of the CEE region.

Quality of life and disease activity of patients with rheumatoid arthritis on tofacitinib and biologic disease-modifying antirheumatic drug therapies.

The aim of this study was to analyze the therapeutic results of rheumatoid arthritis (RA) therapy with different biologic disease-modifying antirheumatic drugs (bDMARDs) and the first Janus-activated kinase (JAK) inhibitor in real-life clinical settings. This is a prospective, observational, longitudinal study at the largest rheumatology clinic in Bulgaria conducted during the period 2012-2020. One hundred seventy-four patients were followed up for a period of one year. Patients naïve to biological therapy were consecutively assigned on the available at the time bDMARDs (infliximab, etanercept, adalimumab, rituximab, golimumab, cetrolizumab, tocilizumab) or tofacitinib. We evaluated the disease activity score (DAS28-CRP), Health assessment questionnaires (HAQ) and short form 36 (SF-36) were applied at the initiation of biological therapy, after 6, and 12 months of follow-up. We analyze the changes in the two major subgroups of SF36-physical (MCS) and mental health (PCS). The age and gender distribution were similar between the groups on bDMARDs and tsDMARD. All observed indicators for disease control and QoL improve after the initiation of the biological or JAK inhibitor therapy. We also analyze the effect of therapies on DAS28-CRP, HAQ, SF-36 (PCS, MCS). Dispersion analysis for the effect of therapy measured through DAS28 between 1st and 3rd measurement shows a statically significant difference in between the average effect of therapies (p = 0.005). According to the average change in DAS28 between the first and third measurement the most effective is the golimumab (Median difference = 2.745), followed by rituximab (median = 2.305) and etanercept (median = 2.070). According to the average change in HAQ between first and third the most effective is tofacitinib (median 0.563), followed rituximab and infliximab (median 0.500 for both). Less effective in term of HAQ changes between the first and third measurement appears to be etanercept (median difference 0.250). All differences are statistically significant (p < 0.05). Regarding the changes in the QoL measured with SF-36 MCS and PCS there is no statistically significant differences in the average effect of different therapeutic agents. Tofacitinib is non-inferior in comparison to bDMARDs and improve both-disease activity and QoL in patients with RA.

Using real-world evidence in healthcare from Western to Central and Eastern Europe: a review of existing barriers.

As part of the HTx (Next Generation Health Technology Assessment) project, this study was aimed at identifying the main barriers for application of real-world evidence (RWE) for the purposes of health technology assessment in the Central and Eastern European countries. A mixed methods approach was employed to identify the main barriers: a scoping review of the literature and a series of discussions with stakeholders. Based on the applied approaches, we attempted to summarize the main barriers and challenges related to transferability of RWE in five main groups: technical, regulatory, clinical, scientific and perceptional barriers. Further research should pursue the development of detailed, consensus-based guidelines to improve the harmonization and standardization of RWE.

Impact of Polypharmacy, Drug-Related Problems, and Potentially Inappropriate Medications in Geriatric Patients and Its Implications for Bulgaria-Narrative Review and Meta-Analysis.

Objective: Polypharmacy and inappropriate prescribing are overlooked issues in Bulgaria. We aimed at collecting and analyzing global literature on the most prevalent risk factors and investigating what they could reveal about current practice. Materials and Methods: A systematic narrative review and meta-analysis was conducted on the topic, investigating the prevalence of polypharmacy, odds of potentially inappropriate medications (PIMs) due to polypharmacy, and the likelihood of developing a drug-related problem (DRP) due to PIMs. The results were then related to current demographic statistics to estimate the potential impact on Bulgarian elderly patients. Results: The prevalence of polypharmacy was estimated at 41% in elderly populations. The odds of a potentially inappropriate medication being prescribed were 2.095, with an expected 30.84% of those leading to a DRP. These numbers indicated that the expected Bulgarian elderly with polypharmacy should be 709,676 with 212,903 cases of DRPs. Conclusion: Global polypharmacy rates seem to be on the rise, with an expected increase in DRPs.

Analysis of Healthcare Expenditures in Bulgaria.

The growth of public expenditure worldwide has set the priority on assessment of trends and establishment of factors which generate the most significant public costs. The goal of the current study is to review the tendencies in public healthcare expenditures in Bulgaria and to analyze the influence of the demographic, economic, and healthcare system capacity indicators on expenditures dynamics. A retrospective, top-down, financial analysis of the healthcare system expenditures was performed. Datasets of the National Statistical Institute (NSI), National Health Insurance Fund (NHIF), and National Center of Public Health and Analysis (NCPHA) were retrospectively reviewed from2014-2019 to collect the information in absolute units of healthcare expenditures, healthcare system performance, demographics, and economic indicators. The research showed that increasing GDP led to higher healthcare costs, and it was the main factor affecting the cost growth in Bulgaria. The number of hospitalized patients and citizens in retirement age remained constant, confirming that their impact on healthcare costs was negligible. In conclusion, the population aging, average life expectancy, patient morbidity, and hospitalization rate altogether impacted healthcare costs mainly due to the multimorbidity of older people and the rising need for outpatient hospital services and medications.

Evaluation of potentially inappropriate medication in older patients with cardiovascular diseases-STOPP/START-based study.

Objective: This study aims to evaluate the use of STOPP/START criteria in the identification of Potentially inappropriate medication and potential prescribing omissions in older patients with cardiovascular diseases in Bulgaria. Excessive morbidity and mortality has been linked to drug-related problems and increased use of healthcare services and is an understudied problem for Bulgaria. Materials and methods: A prospective, questionnaire-based study was conducted among 543 older patients across 25 pharmacies in Bulgaria. Socio-demographic characteristic, disease profile, symptoms, and medication data were collected. The questionnaire was developed for the purposes of the EUROAGEISM project. Out of all 543 patients, only those with documented cardio-vascular diseases were extracted and the medication profile per patient was evaluated for Potentially inappropriate medication (PIMs) and potentially prescribing omissions (PPOs) using STOPP/START criteria version 2. In addition, several risks for potentially inappropriate prescribing (PIPs), PPOs and PIMs were calculated with the focus being on the Odds and Risks to develop a PIP. Results: Four hundred and twenty eight from 531 patients with known therapy for cardiovascular diseases (CVDs) were included in the analysis of PIP (40.52% aged 65-69 years, 61.88% female, 64% had up to 6 comorbidities, and 21.72% presenting with polypharmacy). A total of 71 PIMs in 64 patients with polypharmacy were identified during applying STOPP criteria. 56% of patients taking above five medicines daily had PIMs. The majority of PIMs (31%) were related to CVDs treatment, followed by PIMs in the treatment of endocrine diseases (22.54%), duplication of medicines (8.46%) and prolonged treatment with benzodiazepines (8.46%). Forty four PPOs were identified with START criteria. 22.72% were related to lack of proton pump inhibitors (PPI) in the presence of gastroesophageal disorders, and the same percentage was for lack of Calcium-vitamin D supplementation in osteoporosis. Applying the methodology of risks calculation the sample risk for PPO was 2.1% and for PIM 3.4%. At sample level the relative risk for PPO was 62% out of the risk for PIM and at population level varied between 42.8 and 89.8% and it is statistically significant. The number needed to treat for the event to happen is 77.5, meaning that at every 78 prescriptions there is a chance to appear PIP. Conclusion: Application of methodologies for detection of potentially inappropriate prescribing is not part of routine clinical practice in Bulgaria. Our study demonstrates a high percentage of potentially inappropriate medication among older patients with polypharmacy. Along with the aging population in Bulgaria, economic burden of polypharmacy and the prevalence of cardiovascular diseases, it is especially important to address potentially inappropriate medication use in cardiovascular patients. There is a considerable necessity for implementation of measures for early detection of potentially inappropriate medication and potentially prescribing omission as a part of de-prescribing strategies in older patients.