Decentralized clinical trials are a new approach in health technology research and development that take advantage of innovative digital technologies in data collection for clinical trial purposes. Decentralized clinical trials achieve shorter participant recruitment periods, better adherence to assigned therapy, lower drop-out rates and shorter trial duration overall. Participants reported greater convenience compared to traditional clinical trials due to the studies being conducted at home and the removal of transport and time barriers.

Multiple Sclerosis (MS) is the most prevalent chronic inflammatory disease of the central nervous system, characterized by demyelination, axonal damage and progressive disability. This literature review aims to provide an overview of cost-effectiveness of multiple sclerosis therapies around the world. We used PubMed and PubMed filters to identify the studies published in English related to cost-effectiveness of MS treatment from January 1, 2015 until September 8, 2020. We included a total of 39 studies out of the 224 articles that met the initial search criteria. The characteristics of each study were gathered and systematized. Due to the variety of characteristics of each study it was hard to define which therapy is the most affordable one.

To analyse the differences in household and public healthcare and pharmaceutical expenditures during 2016-2019 in Bulgaria. A comparative, retrospective, observational, and macroeconomic analysis was performed. National Statistical Institute (NSI) and National Health Insurance Fund (NHIF) databases were analyzed. Household and public healthcare and pharmaceutical expenditures were systematized and statistically proceeded. Household spending is increasing more than twice in some of the observed categories. The pharmaceuticals' spending has arisen from 229 to 280, those for herbal, homeopathic medicines and food supplements - from 3.57 to 7.65, medical devices and equipment - from 14.79 - 26.52, out-patient services - from 39 to 44, dental services - from 17 to 21, laboratory analysis and x-ray examinations increase from 5 to 6 euro, and hospital services -from 24 - 66 euro average per household annually. Overall growth of healthcare services cost is about 35 %. The public expenditures for reimbursed medicines, food supplements, and medical devices increased - from 365 in 2016 to 420 mln euro in 2019 with rate almost 15 %. All changes were found statistically significant. The households and public healthcare and pharmaceutical expenditures are progressively increasing with higher rate for public ones but still the burden on families is heavy. The introduction of cost containment measures could ensure more affordable medical services as well as better clinical Results:

Glaucoma is a chronic ophthalmic disease related to significant clinical, social and economic burden for the patients and society as a whole. The study assessed the cost-effectiveness of therapies included in therapeutic guidelines for glaucoma patients in the Republic of North Macedonia. Cost-utility analysis was performed from the healthcare perspective. The analysis was based on real-world data for 236 glaucoma patients in 2020. The costs within a year for each alternative (laser, surgical or pharmacotherapy) were evaluated on the basis of top-down approach. Costs for laser and surgical procedure were paid only once per patient and no subsequent pharmacotherapy was needed. Data for quality of life came from EQ-5D-5L questionnaire as Quality-adjusted life years (QALYs) were calculated for 1-year. Cost–utility was expressed in incremental cost-effectiveness ratio. Cost-effectiveness planes and Tornado diagrams were generated to illustrate the cost-effectiveness of treating glaucoma with the available approaches. Mean annual cost per patient and QALYs values in the group on medication therapy were 239.11 € (SD = 4.54) and 0.77 (SD = 0.14), 22.50 € and 0.52 (SD = 0.11) for laser therapy and 562.50 € and 0.55 (SD = 0.06) for surgery, respectively. Pharmacotherapy (beta-blockers, carbonic anhydrase inhibitors) was dominant over surgical therapy as it was associated with lower costs and a higher value for QALYs (Ϫc = - 323.39 € and ϪQALY = 0.22). Surgical therapy compared to laser therapy led to higher costs and greater QALYs as the incremental ratio of 15,329.78 € was higher than 3-times gross domestic product per capita for the Republic of North Macedonia (14,617.95 € in 2020). One-way sensitivity analysis showed that in all cases pharmacotherapy remained dominant alternative except decreasing QALYs with 30%. This real-world evidence demonstrates the cost-effectiveness of pharmacotherapy for glaucoma in the Republic of North Macedonia.

The National Centre for Pharmacoeconomics (NCPE) assesses all new drugs approved by the European Medicines Agency. Based on these assessments to the NCPE we investigated the characteristics of all oncology drugs since 2009 with a focus on precision oncology drugs, which benefit a subset of patients whose cancer displays specific molecular signatures.

Medication non-adherence is prevalent across all clinical conditions and causes major medical and economic challenges. While medication adherence enhancing interventions (MAEIs) have demonstrated proven benefits in improving outcomes, to date there is no comprehensive overview on the assessment of these interventions. This study aimed to fill this gap by systematically collect outcome measures used for the value assessment of MAEIs.

For more than three decades the world has been facing the global challenge of tackling the HIV epidemic. The objective of this study was to conduct comparative analysis of different therapeutic groups of drugs intended for treatment of HIV / AIDS, according to the recommendations of the European AIDS Clinical Society (EACS) and their availability in the United Kingdom, Germany, France, Italy, Spain and Bulgaria, to compare the levels of these indicators in Bulgaria and to make a reasonable assumption about the degree of coverage of the needs of Bulgarian patients for innovative treatment, guaranteeing survival and good quality of life. Comparison of the pricing and reimbursement policies, the role of the health technology assessment (HTA) and measurement of the compliance and availability indexes of all considered markets. Access to Antiretroviral treatment across Europe's Big 5 and Bulgaria was generally provided to a high standard, although time to initiation may vary. HTA was mandatory in Bulgaria, while in the other considered markets HTA requirements differed or were not compulsory due to major influence of the local HIV societies. Compliance and availability indexes' value revealed Bulgarian patients were treated with novel therapies in line with the recommendations of the EACS guidelines, however the country fell in the middle of the range with reimbursed HIV medicines authorized by EMA. CONCLUSION: In the beginning of 2021, Bulgaria was the only country without a national program for prevention and control of HIV infections and the only one where pre-exposure prophylaxis (PrEP) was not introduced. Testing rate, percentage of diagnosed people treated with ARTs and share of viral suppression among treated people were areas for improvement where execution level was far behind Europe's Big 5 and a lot more efforts need to be invested to put the country on an equal footing.

There is a global call for action for Cervical Cancer elimination as a public health problem – WHO Strategy 90-70-90. One of the strategic pillars, alongside with vaccination, is cervical cancer screening. The aim of the current study is to assess the economic consequences and cost-effectiveness of HPV screening in Bulgaria.

European medicines agency (EMA) supports early patient access to innovative therapies, especially in areas with unmet medical needs or high social burden (oncology, rare diseases, chronic diseases, etc) with the introduction of several specific procedures - conditional approval, accelerated assessment, approval under exceptional circumstances and compassionate use. The objective of the study is to evaluate time to market access since marketing authorization of new direct acting antivirals (DAA) for HCV. First, we analysed the EMA database for type of specific procedure and the Bulgarian Positive drug list (PDL) for time of inclusion of the new DAAs. Time to market access is evaluated as the elapsed time from EMA's marketing authorization to inclusion in Bulgaria's Positive Drug List as well as to the actual time of reimbursement by the National Health Insurance Fund Second (NHIF). EMA introduced the specific procedures for early access in 2002 and since then has issued 29 conditional approvals, 34 exceptional circumstances and 39 accelerated assessments. 7 out 8 authorized DAAs for chronic HCV infection are authorized with accelerated assessment. All of the medicines are included in PDL as time inclusion in PDL in Bulgaria since marketing authorization in the EU is 1-1.5 years on average in 2014-2016 and 2 years in 2017-2019. Time to reimbursement varies from 6 months to 1 to year since inclusion in PDL. The difference in time to market access between the two observed periods may be attributed to the dynamic pharmaceutical legislation in 2016-2019 which experienced a lot of changes in the health technology assessment domain. Nevertheless there are mechanisms in place to foster patient access of innovative medicines for unmet medical needs and diseases with high social burden, there are still some barriers to earlier market access attributed to nationally specific pricing and reimbursement practices.

To assess the Bulgarian health-insured patients’ access to medicines for MS, examine the trend in public expenditures for reimbursed medicines for multiple sclerosis (MS) in Bulgaria from 2016 to 2019 and predict the future costs. Data on the cost of reimbursed medicines for MS were collected retrospectively from the National Health Insurance Fund (NHIF) for the period 2016-2019. MS medicines were systematized according to ATC code and INN. Reimbursed pharmacotherapy costs were analyzed per year. The expenditures were extrapolated using TREND function for the next 3-year period 2020-2022. Patients access was assessed through analysis of the available medicines for MS in the Positive Drug List (PDL) and officially published pharmacotherapeutic guidelines. Most of the approved medicines for MS in the European Union are included in the Bulgarian PDL: interferons (interferon beta 1a, interferon beta 1b, peginterferon beta-1a), selective immunosupressants (teriflunomide, fingolimod, natalizumab, alemtuzumab, ocrelizumab, cladribine), other immunostimulants (glatiramer acetate), other immunosuppressants (dimethyl fumarate). Ocrelizumab and alemtuzumab being fully reimbursed from 2019 and 2018, respectively. The total reimbursed pharmacotherapy cost showed an increasing tendency from € 19 369 695.45 in 2016 to € 22 140 640.21 in 2019, respectively. Interferons (53% in 2016 to 37% in 2019) and immunostimulants (22% to 14%) relative share decreases, while immunosupressants increases (25% to 49%). Bulgarian patients access to medicines for MS is ensured through adequate financial measures. The pharmacotherapy cost for MS increased in 2016-2019 as the trend is predicted to be the same for the next 3 years.

NGS technologies may improve decision making in oncology, especially in enabling personalized approach based on systematic examination of the cancer genome. Knowing the tumor genetic profile and certain biomarkers, could improve risk-based stratification of patients and therapy outcomes. Oncologists are now able to use data from tumour molecular profiling and MGTO to enhance patients’ management. The current study explores the opportunities for implementation of NGS and MGTOs into routine oncology practice in Bulgaria and its economic consequences. We performed two-step study evaluating the opportunities and possible barriers for implementation of NGS and MGTO in Bulgaria. First, we studied the current health care background in terms of diagnostics and therapy resource allocation and possible ways to use NGS and MGTO. Second, based on experience in other countries, to create a list with recommendations for gradual economic implementation of NGS and MGTO in Bulgaria. Currently most drug regimes in oncology require results of different validated biomarker tests, hence NGS can be an alternative to multiple tests by simultaneously examine broad spectrum of genes. This could reduce depletion of scarce materials and decrease cost and time for result. Recommended therapeutic regimes are included in the reimbursement lists and recently suggested legislation changes could provide possibilities for off-label use in certain cases, which could be a possible pathway to introduce MGTOs. Based on Belgian experience we created a recommendation list that could serve as a guidance for economic implementation of NGS and MGTO in Bulgaria. The list includes changes in legislation, creation of genomic database/registry, update of clinical guidelines, etc. NGS and MGTO facilitate treatment choice and could improve clinical and policy decision making, especially in terms of health care resources allocation and optimization of costs. Further analyses are necessary to evaluate funding options, data management and other important implications.

At the end of 2015, 426 patients from Bulgaria were recruited by pneumologists across the country to participate in a prospective cohort study of Chronic Obstructive Pulmonary Disease (COPD) and were followed for 3 year period. Here we report data for patient status, pharmacotherapy changes, mortality, as well as costs. This is a prospective, multi-center, observational, randomized, representative, and comparative real-life study of previously diagnosed patients with COPD from 5 main regions - North-east Bulgaria [NEB], North-West Bulgaria [NWB], South-east Bulgaria [SEB]. South-west Bulgaria [SWB] including Sofia city. Patient characteristics, therapy costs and outcomes were analyzed and compared to results from 2016-2017. Statistics was done through MedCalc software version 14.8.1 At the end of year three, 406 patients remained in the study. Patients distribution according to severity of COPD are: GOLD A – 31 (7.38%); GOLD B – 145 (34.76%); GOLD C – 63 (15.24%); GOLD D – 161 (42.62%) for 2018, vs 30,149,65, and 182 in 2015, respectively. 22 patients had died, with 20 of them being in GOLD D. Median age was 66 years (65-68 years 95%CI) with 132 patients (31.36%) experiencing a change to pharmacotherapy compared to previous years, with 35 recorded instances of improvement and 44 instances of worsening of COPD symptoms. Average number of exacerbations was 2.10 (1.94-2.27 95%CI) with no significant change. Median monthly costs of pharmacotherapy were: 59.63 BGN paid by the NHIF (43.41-59.63 96%CI) and 13.08 per patient as co-pay. The cost of group C decreased due to deceased patients, cost in group A and B remain constant, and cost in group C increased. The main cost driver appears to be the severity and mortality of patients with insignificant changes in other health care resources used and significant changes in pharmacotherapy.

To analyze the mortality and life expectancy among patients with Diabetes Mellitus (DM) and compare it to that of the general Bulgarian population for the period 2012-2015. A retrospective analysis of mortality data from the National diabetes register and National statistical institute for the diabetics and general population respectively was performed. All-cause mortality and deaths in the group of diabetics (E00-E90) were analyzed. Kaplan-Meier survival curves were constructed for each age group and a log-rank analysis of statistical significance was conducted. Average life expectancy in the general population was 73.78 years, patients with Type 1 DM was 70.30, and 74.64 years in patients with Type 2 DM. In the early stages of diabetes, survivability was similar to that of the general population, at around 45 years of age, when chronic conditions begin to develop in the general population, their survivability probability drops, but gets higher than that of patients with diabetes. Overall, diabetics have a 85% lower mortality risk than general population before the age of 70. Post 70 years, diabetics have a 13% higher mortality risk than the general population. Throughout the observed 5 year period, life expectancy increased significantly for patients with DM by approximately a year. Patients with type 2 DM have a longer life-expectancy than patients with type-1 DM and the general population. This might be an evidence of improved disease control in Bulgaria.

Breast cancer (BC) is the most frequently diagnosed and the leading cause of death amongst cancers in women. Understanding its burden is important in healthcare management (e.g. drug or health programs appraisals). The study assessed the burden of advanced BC (ABC) in Bulgaria, Croatia, Czechia, Estonia, Greece, Israel, Latvia, Poland, Romania, and Slovak Republic. The data were collected in individual countries with a unified questionnaire (covering epidemiology, mortality, treatment patterns, and economic aspects) based on databases/registries, published studies, or experts’ opinions. The doubts, inconsistencies and missing data were discussed and addressed. BC prevalence is highest in Czechia (1,647/100,000 women), and lowest in Romania (506/100,000 women). ABC constitutes approx. 20% of BC. The annual mortality in ABC ranges from 8.8% (Czechia) to 12.9% (Romania). The number of years of potential life lost ranges between approx. 2,000 (Estonia) and 55,000 (Poland), also leading to the productive years loss (accounting for retirement age and employment activity): between 250 (Estonia) and 7,000 (Poland) and the indirect cost of approx. 4 million EUR and 76 million EUR, respectively. The average indirect cost is estimated at approx. 600,000 EUR per 100,000 women. Although diagnostics and treatment patterns are rather similar between the countries still, some differences occur: e.g. >60% in Bulgaria and Poland use psychologist support, while only 5% in Czechia. This study represents the first attempt to assess the ABC burden in multiple countries. The burden of ABC comes from direct medical costs but also indirect cost due to mortality. Our findings may be used in decision making on healthcare resources allocation (supporting national cancer plans or as input in economic analyses), as a timely diagnosis, early treatment and access to innovative treatments hold potential to decrease burden of ABC.

To evaluate the social and economic burden of chronic myeloid leukemia (CML) in Bulgaria presented as disability adjusted life years (DALYs). A retrospective analysis was performed on the basis of officially published information in the national cancer registry and local representative studies. Data for the relevant survival and the average year of diagnosis of patients with CML in the country were gathered and analyzed. DALYs were calculated as the sum of the Years of Life Lost (YLL) and the Years Lost due to Disability (YLD). Disability weight, the average life expectancy and the median survival were assumed to be 0.049 (0,031-0,072) as it is in case of controlled phase of CML, 88 years of age as per WHO methodology and 25 years according to expert opinions, respectively. The average age of CML diagnosis for Bulgarian population is 53±16 years according to nationally representative study conducted between 2012 and 2014. DALYs were multiplied by the GDP/capita so as to find the economic burden of the disease. On average a patient with CML in controlled phase spends 10.89 years of his remaining life in disability due to the disease. Taking into account annual working income we found that the costs of lost productivity per patient are supposed to be around 66 398.5 (63 623 – 69 906) €. The current study is the first Bulgarian one which evaluates the social burden of CML after placing innovative tyrosine kinase inhibitors on the Bulgarian market. The disease appears to have high social and economic burden which is comparable with the burden of other non-communicable chronic diseases in Bulgaria.