BACKGROUND AND OBJECTIVES:Biopharmaceuticals add value in the treatment of many diseases but different health systems in Europe face clinical and economic challenges with introducing them. Joint efforts across Europe are therefore essential to ensure their sustainable and equitable use. However, to date few cross-national comparative studies have assessed their introduction. This study aimed to assess the availability of health authority data and variation in the early diffusion of biopharmaceuticals across Europe. METHODS:A cross-sectional study was undertaken to analyze the diffusion of 17 biopharmaceuticals, approved between 2015 and 2019, among European countries between 2015 and 2022. The study assessed data availability, diffusion rates measured as accumulated defined daily doses per 1000 inhabitants, as well as relative rankings between countries during the first 4 years following market authorization. RESULTS:Twenty countries and two regions out of 31 European countries provided data on biopharmaceutical utilization for out-of-hospital care, 15 provided wholesaler data, and 14 provided hospital data. Certain countries and regions contributed data in multiple categories, while six did not provide any data. Diffusion rates were assessed for 17 countries and two regions, which showed appreciable variation, with secukinumab and erenumab being introduced in most countries and follitropin delta and tildrakizumab in the least number of countries. Germany, Austria, and Norway demonstrated the highest early diffusion rates, while Lithuania, Romania, and Latvia had the lowest. CONCLUSIONS:This study revealed a substantial variation between European countries and regions in the early diffusion of biopharmaceuticals and the availability of data to monitor their use. The reasons behind these patterns require further investigation to support European countries in optimizing the use of biopharmaceuticals to reach an equitable and cost-effective use of medicines across Europe.

Background The European cross-border electronic prescription (CBeP) was first introduced in Estonia and Finland. The CBeP service is gradually being implemented across Europe, prompting a need for practical studies to assess its benefits and potential shortcomings. Objective This study aimed to investigate Estonian and Finnish pharmacists’ experiences with patient identification, personal data protection and safe use of medications with CBeP, as well as main advantages and areas of development of CBeP. Methods An online survey was conducted among Estonian and Finnish pharmacists in Spring 2021. The survey was distributed to 664 community pharmacies (289 Estonian and 375 Finnish pharmacies) where CBePs had been dispensed in 2020. The data were analysed using frequencies and a chi-square test. Answers to open-ended questions were categorized using content analysis and quantifying. Results In total, 84 responses from Estonia and 154 responses from Finland were included in the study. Majority of the respondents had never or had rarely encountered problems with identifying the patient with CBeP. Nearly all respondents rated the CBeP system to be safe from the standpoint of personal data protection. Approximately 70% of the respondents in both countries agreed that it is difficult to counsel the patient with CBeP due to language barrier. More than half of the respondents reported that it is not easy to monitor drug interactions with CBeP. The most often mentioned benefit of CBeP was an improved medication availability and the main problem the CBeP dispensing software rigidity. Conclusions Estonian and Finnish pharmacists recognize the positive impact of CBeP on medication availability. Variations in providing patient counselling due to language barriers highlight the need for improved communication tools. Addressing concerns about drug interaction monitoring and technical rigidity is essential for seamless cross-border adoption of CBeP in Europe.

To determine possible changes in prescribing of fluoroquinolones in relation to the European Medicines Agency's (EMA) recommendation in October 2018.

BACKGROUND:The European cross-border electronic prescription (CBeP) and cross-border electronic dispensing system was first implemented in January 2019 when it became possible to purchase medications from community pharmacies in Estonia using a Finnish ePrescription. In 2020, Estonian ePrescriptions became available to be dispensed in Finnish pharmacies. The CBeP is an important milestone in increasing access to medicines across the European Union, and it has been unstudied to date.OBJECTIVE:This study aimed to investigate Estonian and Finnish pharmacists' experiences of factors influencing access to, and dispensing of, CBePs.METHODS:A web-based survey was conducted among Estonian and Finnish pharmacists between April and May 2021. The survey was distributed to all 664 community pharmacies (n=289, 43.5% in Estonia and n=375, 56.5% in Finland) where CBePs had been dispensed in 2020. The data were analyzed using frequencies and a chi-square test. Answers to open-ended questions were categorized using content analysis and then analyzed by frequency.RESULTS:In total, 66.7% (84/126) of the responses from Estonia and 76.6% (154/201) of the responses from Finland were included in the study. The majority of Estonian (74/84, 88%) and Finnish (126/154, 81.8%) respondents agreed that CBePs have improved patients' access to medications. Problems with the availability of medications when dispensing CBePs were reported by 76% (64/84) of the Estonian respondents and 35.1% (54/154) of the Finnish respondents. In Estonia, the most commonly reported availability problem concerned the same active ingredient (49/84, 58%) of the medication not being available in the market, whereas in Finland, the most common issue was the unavailability of equivalent package size in the market (30/154, 19.5%). Encountering ambiguities or errors in the CBePs was reported by 61% (51/84) of the Estonian respondents and 42.8% (66/154) of the Finnish respondents. Mostly, the availability issues and ambiguities or errors were encountered rarely. The most commonly encountered ambiguities or errors were incorrect pharmaceutical form (23/84, 27%) in Estonia and incorrect total amount of medication (21/154, 13.6%) in Finland. Technical problems with using the CBeP system were reported by 57% (48/84) of the Estonian respondents and 40.2% (62/154) of the Finnish respondents. Most of the Estonian and Finnish respondents (53/84, 63%, and 133/154, 86.4%, respectively) had access to guidelines for dispensing CBePs. More than half of the Estonian (52/84, 62%) and Finnish (95/154, 61.7%) respondents felt that they had received sufficient training on dispensing CBePs.CONCLUSIONS:Pharmacists in both Estonia and Finland agreed that CBePs improve access to medications. However, interfering factors, such as ambiguities or errors in CBePs and technical problems in the CBeP system, can reduce access to medications. The respondents had received sufficient training and were informed of the guidelines; however, they felt that the content of the guidelines could be improved.

Isotretinoin, indicated for severe acne, is a potent teratogen and therefore contraindicated in pregnancy. Thus, the pregnancy prevention program (PPP) for isotretinoin has been introduced. The aim of this study was to assess the concomitant use of isotretinoin and effective contraception and the rate of potential isotretinoin-exposed pregnancies in females of childbearing age in 2017–2020 in Estonia. In addition, we aimed to evaluate whether compliance with the PPP has improved compared with the previous study conducted in Estonia covering the period of 2012–2016. This retrospective, nationwide study using prescription and healthcare claims data included 2575 females aged 15–45 years who started using isotretinoin between 2017 and 2020. For 64.7

Early detection and timely resolution of potentially inappropriate prescribing (PIP) prevents adverse outcomes and improves patient care. An explicit tool specifically designed to detect PIP among people with Type 2 Diabetes Mellitus (T2DM) has not been published.This study aims to develop and validate the Inappropriate Medication Prescribing Assessment Criteria for Type 2 Diabetes Mellitus (IMPACT2DM); an explicit tool that can be used to identify PIP for adults with T2DM.Current national and international guidelines for the management of T2DM and drug information software programs were used to generate potential items. The content of the IMPACT2DM was validated by 2 consecutive rounds of Delphi method. Physicians and clinical pharmacists experienced in providing care for people with diabetes and authors of selected diabetes guidelines were invited to participate in the Delphi panel. Consensus was assumed if 90% (first round) and 85% (second round) of expert panelists showed agreement to include or exclude an item.A total of 95 potential items were generated from selected diabetes guidelines and drug information software programs. After the first Delphi round 27 items had ≥90% agreement and were included in the tool; 19 items were considered not PIP and were excluded from the tool. The second round contained 49 items; of these 43 were included and 6 were excluded from the tool. The final IMPACT2DM contains 70 items categorized by type of PIP and arranged in terms of medical conditions and medication classes. IMPACT2DM can be applied using information on medical charts and requires minimal or no clinical knowledge to assess quality of diabetes care and improve medication selection.IMPACT2DM has been developed from current quality evidence and undergone content validation. It is the first explicit tool specifically designed to identify PIP for adults with T2DM.

An evidence-based randomized controlled trial for a novel Pharmacy Asthma Service was tested in 3 Australian states. Positive asthma outcomes were achieved after the 12-month intervention, albeit in both the intervention and comparator arms. The current investigation uses a mixed methods approach to 1) qualitatively explore how comparator arm pharmacists implemented the trial protocol and 2) quantitatively examine how this may have impacted patient outcomes in this trial.Post-intervention semi-structured qualitative interviews were conducted with 20 pharmacists, representing 21 of 37 (57%) comparator arm pharmacies that completed the trial. Based on these interviews, pharmacies were classified as 'adherent' to the trial protocol (reporting no interventions other than general practitioner referral) or 'non-adherent' (reporting at least one extra intervention to the trial protocol), or 'inconclusive'. These subgroups were compared descriptively in relation to patient outcomes.Overall, 33% (n = 8/24) of the comparator pharmacies who were interviewed (n = 21) or determined to have monitoring by a project officer to ensure adherence to the protocol (n = 3) were classified as adherent), 58% (n = 14/24) as non-adherent, 8% inconclusive (n = 2/24). While all patients commenced with uncontrolled asthma (Asthma Control Questionnaire score (ACQ) > 1.5), after 12 months the mean ACQ score for patients from adherent comparator pharmacies ('true control') was 1.8 (still uncontrolled asthma) compared to a score of 1.4 (controlled asthma) in the non-adherent comparator group. Quality of life significantly improved in the non-adherent comparator group over the 12 months of the trial.The majority of pharmacists in the comparator arm who were interviewed, introduced their own interventions, which may have influenced the outcomes of the trial. The naturalistic setting of the study was not protective against these confounders. These findings question the feasibility of comparator arms within primary care settings and that alternative study designs should be considered when designing future intervention studies in pharmacy practice.

Generic competition and drug prices in the Malaysian off-patent pharmaceutical marketOmotayo Fatokun, Mohamed Izham Mohamed Ibrahim, Mohamed Azmi Hassali

Background. Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction. Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel. Results. Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups. Conclusions. There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed.

Objective: For many women with epilepsy (WWE), decision making about pregnancy is difficult, due mainly to the potential teratogenic risks of anti-seizure medications (ASMs). Pre-pregnancy counseling is essential to minimize these risks. This study was conducted to assess the rate and effectiveness of pre-pregnancy counseling for women treated with valproate (VPA) in Estonia. Methods: We used outpatient prescription data from the national health insurance provider to identify all women treated with VPA during 2011-2018 in Estonia. The personal medical documentation of women who became pregnant while on VPA treatment was reviewed. Pre-pregnancy counseling history and VPA-treatment indications were analyzed. Results: Data from 141 women who became pregnant while on VPA treatment during 2011-2018 time period were analyzed. Of these patients, 77% had epilepsy and 19% psychiatric diagnoses. Pre-pregnancy counseling was recorded for 13% (n = 19) of women who later became pregnant. VPA monotherapy and the lack of VPA treatment indication were associated with the lack of counseling before pregnancy. Conclusions: This study revealed a significant deficit in pre-pregnancy counseling for WWE treated with VPA in Estonia. Awareness of the need for such counseling should be increased among medical specialists. (c) 2021 Elsevier Inc. All rights reserved.

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems.Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines.Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments.

Background: Diabetes mellitus rates continue to rise, which coupled with increasing costs of associated complications has appreciably increased global expenditure in recent years. The risk of complications are enhanced by poor glycaemic control including hypoglycaemia. Long-acting insulin analogues were developed to reduce hypoglycaemia and improve adherence. Their considerably higher costs though have impacted their funding and use. Biosimilars can help reduce medicine costs. However, their introduction has been affected by a number of factors. These include the originator company dropping its price as well as promoting patented higher strength 300 IU/ml insulin glargine. There can also be concerns with different devices between the manufacturers. Objective: To assess current utilisation rates for insulins, especially long-acting insulin analogues, and the rationale for patterns seen, across multiple countries to inform strategies to enhance future utilisation of long-acting insulin analogue biosimilars to benefit all key stakeholders. Our approach: Multiple approaches including assessing the utilisation, expenditure and prices of insulins, including biosimilar insulin glargine, across multiple continents and countries. Results: There was considerable variation in the use of long-acting insulin analogues as a percentage of all insulins prescribed and dispensed across countries and continents. This ranged from limited use of long-acting insulin analogues among African countries compared to routine funding and use across Europe in view of their perceived benefits. Increasing use was also seen among Asian countries including Bangladesh and India for similar reasons. However, concerns with costs and value limited their use across Africa, Brazil and Pakistan. There was though limited use of biosimilar insulin glargine 100 IU/ml compared with other recent biosimilars especially among European countries and Korea. This was principally driven by small price differences in reality between the originator and biosimilars coupled with increasing use of the patented 300 IU/ml formulation. A number of activities were identified to enhance future biosimilar use. These included only reimbursing biosimilar long-acting insulin analogues, introducing prescribing targets and increasing competition among manufacturers including stimulating local production. Conclusions: There are concerns with the availability and use of insulin glargine biosimilars despite lower costs. This can be addressed by multiple activities.

Purpose To describe trends in hormonal contraceptive use, incidence of thromboembolism and presence of risk factors for thromboembolism among the users in Estonia. Material and methods Data of 223 312 female patients aged 15-49 years in 2005-2019 from national health insurance databases was derived. Annual prevalence rates of hormonal contraceptive users, incidence rates of thromboembolism and prevalence rates of risk factors were calculated. Results Between 2005-2019 usage of progestogen-only contraceptives (POCs) increased steadily (from 24 to 135 users per 1000 population), whereas combined hormonal contraceptive (CHC) use declined (from 209 in 2012 to 161 users per 1000 population in 2019). During the study period, 390 cases of venous thromboembolism and 108 arterial thromboembolism coincided with hormonal contraceptive use. Incidence rate for venous thromboembolism was 5.0 (95% CI 4.5-5.5) and for arterial thromboembolism 1.4 per 10 000 person-years (95% CI 1.1-1.7) among hormonal contraceptive users. Age adjusted incidence of venous thromboembolism among CHC users was 5.8 (95% CI 4.1-8.2) times higher than in POC users. Among CHC users, 10.3% had more than one risk factor for thrombosis. Conclusions In regards to the risk of thromboembolism, wider use of POCs and declining prevalence of CHCs in Estonia is positive trend. Still, women with history of thrombosis receiving CHC is a serious concern.

Background: From October 2018, adalimumab biosimilars could enter the European market. However, in some countries, such as Netherlands, high discounts reported for the originator product may have influenced biosimilar entry.Objectives: The aim of this paper is to provide a European overview of (list) prices of originator adalimumab, before and after loss of exclusivity; to report changes in the reimbursement status of adalimumab products; and discuss relevant policy measures.Methods: Experts in European countries received a survey consisting of three parts: 1) general financing/co-payment of medicines, 2) reimbursement status and prices of originator adalimumab, and availability of biosimilars, and 3) policy measures related to the use of adalimumab.Results: In May 2019, adalimumab biosimilars were available in 24 of the 30 countries surveyed. Following introduction of adalimumab biosimilars, a number of countries have made changes in relation to the reimbursement status of adalimumab products. Originator adalimumab list prices varied between countries by a factor of 2.8 before and 4.1 after loss of exclusivity. Overall, list prices of originator adalimumab decreased after loss of exclusivity, although for 13 countries list prices were unchanged. When reported, discounts/rebates on originator adalimumab after loss of exclusivity ranged from 0% to approximately 26% (Romania), 60% (Poland), 80% (Denmark, Italy, Norway), and 80–90% (Netherlands), leading to actual prices per pen or syringe between €412 (Finland) and €50 – €99 (Netherlands). To leverage competition following entry of biosimilar adalimumab, only a few countries adopted measures specifically for adalimumab in addition to general policies regarding biosimilars. In some countries, a strategy was implemented even before loss of exclusivity (Denmark, Scotland), while others did not report specific measures.Conclusion: Even though originator adalimumab is the highest selling product in the world, few countries have implemented specific policies and practices for (biosimilar) adalimumab. Countries with biosimilars on the market seem to have competition lowering list or actual prices. Reported discounts varied widely between countries.

Introduction/Objectives: Health authorities are facing increasing challenges to the sustainability of their healthcare systems because of the growing expenditures on medicines, including new, high-priced oncology medicines, and changes in disease prevalence in their ageing populations. Medicine prices in European countries are greatly affected by the ability to negotiate reasonable prices. Concerns have been expressed that prices of patented medicines do not fall sufficiently after the introduction of lower-cost generic oncology medicines. The objective of this study was to examine the associations over time in selected European countries between the prices of oral oncology medicines, population size, and gross domestic product (GDP) before and after the introduction of generic versions. Evidence of periodic reassessments of the price, value, and place in treatment of these medicines was also looked for. The goal of this review was to stimulate debate about possible improvements in approaches to reimbursement negotiations. Methodology: Analysis was performed of reimbursed prices of three oral oncology medicines (imatinib, erlotinib and fludarabine) between 2013 and 2017 across Europe. Correlations were explored between GDP, population size, and prices. Findings were compared with previous research regarding prices of generic oral oncology medicines. Results: The prices of imatinib, erlotinib and fludarabine varied among European countries, and there was limited price erosion over time in the absence of generics. There appeared to be no correlation between population size and price, but higher prices of on-patent oral cancer medicines were seen among countries with higher GDP per capita. Conclusion: Limited price erosion for patented medicines contributed to increases in oncology medicine budgets across the region. There was also a concerning lack of evidence re-assessments of the price, value, and place in treatment of patented oncology medicines following the loss of patent protection of standard medicines. The use of such proactive re-assessments in negotiating tactics might positively impact global expenditures for oncology medicines.

Evelien Moorkens, Brian Godman, Isabelle Huys, Iris Hoxha, Admir Malaj , Simon Keuerleber, Silvia Stockinger, Sarah Mörtenhuber, Maria Dimitrova, Konstantin Tachkov, Luka Vončina, Vera Vlahović Palčevski , Gnosia Achniotou, Juraj Slabý, Leona Popelková, Kateřina Kohoutová, Dorthe Bartels, Ott Laius, Jaana E. Martikainen, Gisbert W. Selke, Vasileios Kourafalos, Einar Magnússon, Rannveig Einarsdóttir , Roisín Adams, Roberta Joppi, Eleonora Allocati , Arianit Jakupi, Anita Viksna, Ieva Greiči utė-Kuprijanov, Patricia Vella Bonanno, Vincent Suttorp, Øyvind Melien, Robert Plisko, Ileana Mardare, Dmitry Meshkov, Tanja Novakovic, Jurij Fürst, Corinne Zara, Vanda Marković-Peković , Nataša Grubiša, Gustaf Befrits, Robert Puckett and Arnold G. Vulto*