Recommendations and feedback from the European Bioanalysis Forum Workshop: 1 year into ICH M10 - keeping our finger on the pulse.

The ICH M10 guideline on bioanalytical method validation and sample analysis is being adopted since 2023. However, and inevitably, some paragraphs or requirements remain ambiguous and are open for different interpretations. In support of a harmonized interpretation by the industry and health authorities, the European Bioanalysis Forum organized a workshop on 14 November 2023 in Barcelona, Spain, to discuss unclear and/or ambiguous paragraphs which were identified by the European Bioanalysis Forum community and delegates of the workshop prior to the workshop. This manuscript reports back from the workshop with recommendations and aims at continuing an open scientific discussion within the industry and with regulators in support of a science-driven guideline for the bioanalytical community and in line with the ICH mission - that is, achieve greater harmonization worldwide to ensure that safe, effective and high-quality medicines are developed and registered in the most resource-efficient manner.

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.

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.

Biosimilar Insulins and Their Impact on Prices and Utilization of Insulins in Bulgaria.

The aim was to explore the availability of biosimilar insulins on the national market in Bulgaria and their impact on prices and utilization. This was a retrospective, quantitative, longitudinal study during the period 2014-2020. Authorized-for-sale, biosimilar insulins at the European level were compared with those on the national market. Prices and utilization were compared in value, number of defined daily dose (DDD), and DDD/1000 inh/day. Almost all types of insulins possessed biosimilars, and even more than one on the European market, but only two were found to be available and reimbursed on the national market. The total number of reimbursed INNs was 11, and for seven of them, changes in reference price per DDD were found. The highest price decrease was observed for insulin (price per DDD decline from 2.77 to 2.22 Bulgarian Leva (BGN)). The total expenditure for insulin increased from 68 to approximately 72.8 mil BGN (34 to approximately 37 mil Euro). The utilization in DDD/1000/inh/day decreased from 16.12 to 15.31. Only two biosimilar insulins were found to be available on the national market, with a slow decrease in prices and stable utilization. Other regulatory and financial measures are probably necessary to foster the insulins' competition at the biosimilar level.

Availability and reimbursement of biological products for severe asthma in Bulgaria.

OBJECTIVES: This study aims to analyze the reimbursement and cost of biological therapy for severe asthma in Bulgaria during 2014-2019 from the perspective of the National Health Insurance Fund. METHODS: It is a retrospective, Marco-costing, top-down study of the expenditures for biological products for severe asthma. The changes in the cost paid by the National Health Insurance Fund per year, per product, and per patient during 2015-2020 were systematized and calculated. The utilization of biologicals was analyzed by calculating the defined daily dose/1000inh/day. Three databases were searched-the European Medicines Agency for the date of marketing authorization of biological products, National Council of Prices and Reimbursement for the date of their respective inclusion in the positive drug list, and National Health Insurance Fund about the number of patients with asthma, reimbursed sum for all asthma patients, and number of packages sold of biological products. RESULTS: At the end of 2019, five international non-proprietary names of biologicals with indication for severe asthma had received European marketing authorization, and three of them were included in the Bulgarian positive drug list-omalizumab, mepolizumab, and benralizumab with a 75% reimbursement. Upon their introduction into the positive drug list, the reimbursed expenditures for asthma therapy started to increase from 27 million in 2014 to 33 million BGN in 2019 (€13.5-€16.5 million). The cost of therapy with biologicals rose from 16% to 24% of all anti-asthmatic medicines budget. The National Health Insurance Fund database reported that between 47,000 and 52,000 of patients with asthma, 466 are on biological therapy. The yearly cost of one asthma patient ranges between 512 and 615 BGN (€258-€307), and the yearly per-patient cost of severe asthma is 16,666 BGN (appr. €8333). Total utilization in defined daily dose/1000inh/day increases from 0.0199 to 0.0383 from 2015 to 2019. CONCLUSION: The access to biological therapy through the reimbursement system has improved during the last 3 years. The cost of therapy is posing a high burden on the National Health Insurance Fund and on the patients and is expected to increase due to the small number of patients on biological therapy currently in comparison to all reimbursed asthmatics.