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.

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.

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.

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.

Comparison of Cardiovascular Medicines Prices in Four European Countries.

The aim of the current study was to compare pricing methodologies at the manufacturer, wholesale, and retail levels, and to estimate the price differences of AT1-receptor blockers (sartans), Angiotensin-converting enzyme (ACE)-inhibitors, and their fixed-dose combinations (FDCs) in four countries using similar methodologies: Slovakia, Greece, Bulgaria, and Romania (SK, GR, BG, and RO, respectively). The methodologies for manufacturer, wholesale, and retail price establishment have been compared using nationally implemented rules. Overlapping trademarks were established retrospectively on the manufacturer and retail levels in November 2017. The average price per tablet, percentage of price deviation, and statistically significant differences were calculated. The selected countries apply external reference pricing at the manufacturer level. A wide variation in the number of referent countries was observed (from 12 to 27). Despite the use of a regressive scale for price calculation, large variations between margins and value-added tax (VAT) are established, thus leading to different final medicine prices. This study found that medicine prices were lower in RO than in other selected countries. It was caused by the fact that 15 products had the lowest manufacturer price and 14 products had the lowest retail price in RO. Results of Kruskal-Wallis test showed that there were no significant differences between prices per tablet on the manufacturer and retail levels. In the group of fixed-dose combinations, ramipril/hydrochlorothiazide, and irbesartan/hydrochlorothiazide showed more than 100% deviation. The prices of cardiovascular medicines differed within the observed countries. The differences in pricing methodologies (e.g., margins, VAT) at the national level did not significantly affect retail prices, as a low manufacturer price usually leads to a low retail price.

Cost-effectiveness of insulin degludec versus insulin glargine U100 in adults with type 1 and type 2 diabetes mellitus in Bulgaria.

BACKGROUND: This analysis evaluates the cost-effectiveness of insulin degludec (degludec) versus biosimilar insulin glargine U100 (glargine U100) in patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) in Bulgaria. METHODS: A simple, short-term model was used to compare the treatment costs and outcomes associated with hypoglycaemic events with degludec versus glargine U100 in patients with T1DM and T2DM from the perspective of the Bulgarian National Health Insurance Fund. Cost-effectiveness was analysed over a 1-year time horizon using data from clinical trials. The incremental cost-effectiveness ratio (ICER) was the main outcome measure. RESULTS: In Bulgaria, degludec was highly cost-effective versus glargine U100 in people with T1DM and T2DM. The ICERs were estimated to be 4493.68 BGN/quality-adjusted life year (QALY) in T1DM, 399.11 BGN/QALY in T2DM on basal oral therapy (T2DMBOT) and 7365.22 BGN/QALY in T2DM on basal bolus therapy (T2DMB/B), which are below the cost-effectiveness threshold of 39,619 BGN in Bulgaria. Degludec was associated with higher insulin costs in all three patient groups; however, savings from a reduction in hypoglycaemic events with degludec versus glargine U100 partially offset these costs. Sensitivity analysis demonstrated that the results were robust and largely insensitive to variations in input parameters. At a willingness-to-pay threshold of 39,619 BGN/QALY, the probability of degludec being cost-effective versus glargine U100 was 60.0% in T1DM, 99.4% in T2DMBOT and 91.3% in T2DMB/B. CONCLUSION: Degludec is a cost-effective alternative to biosimilar glargine U100 for patients with T1DM and T2DM in Bulgaria. Degludec could be of particular benefit to those patients suffering recurrent hypoglycaemia and those who require additional flexibility in the dosing of insulin.

Аn affordability of statins therapy - comparative analysis between Ukraine and Bulgaria.

BACKGROUND: The statins are а developing group of cardiovascular medicines, widely used for dyslipidemia. As a whole statins consumption leads to reduction in cardiovascular events and death, and improves the disease control. The main study issue considers the differences in an affordability to lipid lowering medicines in the countries with the highest morbidity and mortally rate within and outside EU. The affordability has been researched by exploring the price differences and average wages. METHODS: On total 7 international nonproprietary names and 19 dosage forms available on both markets are observed during 2013-2016. An average, minimum, and maximum retail prices per DDD, standard deviation (SD) has been calculated for all marketed dosage forms. A price ratio between the minimal and maximal price per DDD is estimated in order to evaluate their difference. Affordability of the treatment is determined as the number of working hours per month needed for patient to purchase medicines for a monthly therapy. RESULTS: Large variations of price per DDD, SD and the average price exist between different dosage forms in both countries. The highest value of a price ratio is observed for 5 mg rosuvastatin in Bulgaria and 10 mg rosuvastatin in Ukraine. The number of working hours needed to cover monthly therapy has increased during 2013-2016 in Ukraine. The most affordable is treatment with a generic atorvastatin in Bulgaria and generic rosuvastatin in Ukraine. The most expensive rosuvastatin in Bulgaria and atorvastatin in Ukraine are found as the least affordable for a monthly therapy. CONCLUSIONS: The decrease of prices for statins is not the only reason influencing patients' affordability to therapy for statin therapy in Ukraine and Bulgaria. The difference in affordability in Ukraine and Bulgaria is affected mainly by the economic development in the country as well as wages variation.

Incretins and SGLT-2i Therapy of Type 2 Diabetes - Real Life Study of Their Therapeutic and Economic Effects.

AIM: Incretins [dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide 1 RA (GLP-1 RA)] and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) groups are now routinely used for type 2 diabetes therapy and comprise a large number of medicinal products. The long term therapeutic and economic effect of the incretins' and SGLT-2i in real life setting is not well documented. The goal of the current study is to analyze the cost and results of incretins and SGLT-2i based therapy for type 2 diabetes in Bulgaria. METHODS: The study uses information about the changes in glycated hemoglobin (HbA1c) level from the National diabetes register for 6122 patients and cost paid by the National Health Insurance Fund (NHIF) for diabetes complications, and medicine prices. RESULTS: The results show that after the therapy patients achieved excellent diabetes control. There were no HbA1c values less than 6% before treatment. After the therapy, 3356 people showed values less than 7% HbA1c. It is considered very good diabetic control. The number of people with HbA1c above 8% is decreasing significantly. The number of people with values above 9% is decreasing by almost four times. HbA1c level decreases with the highest percentage for the patients treated with GLP-1 RA, followed by those treated with DPP-4i and SGLT-2i. For a year NHIF reimbursed 5.25 million BGN for incretins and SGLT-2i therapy. NHIF can save between 306 and 510 thousand BGN from incidents that have not occurred as a result of 5 years of therapy. CONCLUSION: Incretins [dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA)] and sodium-glucose linked transporter-2 inhibitors (SGLT-2i) therapy steadily decreases the HbA1c level, and risk of developing diabetic incidents is reduced to between 333 and 465 cases among 6122 treated patients. Avoided cost for therapy of diabetes incidents account for between 305 and 510 thousand BGN.

Historical overview of regulatory framework development on pricing and reimbursement of medicines in Bulgaria.

Objectives: The current study aims to analyze, from a historical perspective, the regulatory framework of prices and reimbursement in Bulgaria with emphasis on the introduction of economic evaluation.Methods: The study explores all regulatory changes during the period 1995-2016 combining the macroeconomic and regulatory analysis on medicines pricing and reimbursement. A roadmap summarizing the current regulatory requirements for the medicinal product entrance on national market and access to public funding was elaborated.Results: Demographic processes in the country have been negative for the past decade. On the other hand, health care and pharmaceutical expenditures experienced a growth up to 8.6% and 3% of total GDP, respectively. The total pharmaceutical market permanently grew from 309 to 1409 million of Euro. During the last 20 years, the pricing and reimbursement legislation of medicines in Bulgaria was changed extensively.Conclusion: Pricing policy remains oriented toward the lowest European prices and reimbursement policy impose cost containment measures. Appraisal of the obligatory Health Technology Assessment Dossiers and pharmacoeconomic analysis is in accordance with world recommendations. Main regulatory issues that still remain to be tackled are the slower entrance of medicines on the national market and lower national prices that often lead to parallel import.

Comparative Price Analysis of Biological Products for Treatment of Rheumatoid Arthritis.

Biological products for treatment of rheumatoid arthritis usually are cost effective for healthcare systems in Europe, but they are huge financial burden due to the high number of patients and the significant budget impact. The expected saving from introduction on the market of biosimilars are significant and are linked to better access and affordability. The aim of this study was to conduct comparative price analysis of biological products for rheumatoid arthritis therapy among seventeen EU countries. The point of view is that of the Bulgarian pricing and reimbursement system and the chosen countries are those from external reference basket for prices comparison at manufacturing level. All authorized biological products by EMA with therapeutic indication rheumatoid arthritis were selected. The access for treatment is evaluated as the availability of the product on the market and the prices level. We assessed the availability of all trade names in the price lists of the observed countries. The prices data was obtained from the official web pages of the responsible institutions up to date December 2017. The results show that four out of all six INNs have authorized biosimilars in EMA. Despite its earlier authorization biosimilar adalimumab is not present in any of the price lists of countries. From all eighteen countries only in Lithuania and Estonia there were no published prices of any of the selected medicinal products. Countries with higher number of biosimilar prices are Spain and France. Differences in manufacturers' prices of reference biological products in selected countries in comparison with the lowest manufacturer price are higher with 22 to 69% while the retail prices between 62 and 95%. Differences are mostly notable for rituximab, and less notable for tocilizumab. Manufacturers' and retail prices of biosimilar products were established only for three INNs (etanercept, rituximab, and infliximab). Manufacturers' prices differ between 26 and 75%, while retail prices differ between 40 and 92% for biosimilars. Comparison of the differences between manufacturer prices of reference biological product and biosimilars shows 36% difference for etanercept, 39% for rituximab, and 31% for infliximab, while at retail level the differences are 11, 86, and 143%, respectively. The limitation of the study is that the prices are the official ones without discounts due to confidentiality and the real prices may be lower. The second limitation is that the methodology for pricing differs in the countries and this could also influence the prices on both levels (manufacturer and retail). Introduction of biosimilars on the national markets led to significant decrease in reimbursed prices paid by public funds and thus might benefit the patients' access to biological therapy. The decrease of prices after biosimilars entrance on the market is not as notable as for commodity generics.

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.