Hindawi BioMed Research International Volume 2021, Article ID 9996193, 16 pages https://doi.org/10.1155/2021/9996193 Research Article Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications Brian Godman ,1,2,3 Magdalene Wladysiuk,4,5 Stuart McTaggart,6 Amanj Kurdi ,1,2,7 Eleonora Allocati,8 Mihajlo Jakovljevic ,9,10 Francis Kalemeera ,11 Iris Hoxha,12 Anna Nachtnebel,13 Robert Sauermann,13 Manfred Hinteregger,13 Vanda Marković-Peković ,14 Biljana Tubic,15,16 Guenka Petrova,17 Konstantin Tachkov ,17 Juraj Slabý,18 Radka Nejezchlebova,18 Iva Selke Krulichová,19 Ott Laius,20 Gisbert Selke ,21 Irene Langner,21 András Harsanyi,22 András Inotai,23 Arianit Jakupi,24 Svens Henkuzens,25 Kristina Garuolienė,26 Jolanta Gulbinovič,26 Patricia Vella Bonanno,1,27 Jakub Rutkowski,5 Skule Ingeberg,28 Øyvind Melien,28 Ileana Mardare ,29 Jurij Fürst,30 Sean MacBride-Stewart ,31 Carol Holmes,32 Caridad Pontes ,33,34 Corinne Zara ,33 Marta Turu Pedrola ,33 Mikael Hoffmann,35 Vasileios Kourafalos,36 Alice Pisana,37 Rita Banzi,8 Stephen Campbell,38,39 and Bjorn Wettermark 40 1 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK 2 Division of Public Health Pharmacy and Management, School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, South Africa 3 School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia 4 Chair of Epidemiology and Preventive Medicine, Medical College, Jagiellonian University, Krakow, Poland 5 HTA Consulting, Starowiślna Str. 17/3, 31-038 Krakow, Poland 6 Public Health Scotland, Gyle Square, 1 South Gyle Crescent, Edinburgh, UK 7 Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, Iraq 8 Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Milan, Italy 9 Department of Global Health Economics and Policy, University of Kragujevac, Kragujevac, Serbia 10 Institute of Comparative Economic Studies, Faculty of Economics, Hosei University Tokyo, Tokyo, Japan 11 Department of Pharmacy Practice and Policy, Faculty of Health Sciences, University of Namibia, Windhoek, Namibia 12 Department of Pharmacy, Faculty of Medicine, University of Medicine, Tirana, Albania 13 Dachverband der Österreichischen Sozialversicherungen, Kundmanngasse 21, AT-1030 Vienna, Austria 14 Faculty of Medicine, Department of Social Pharmacy, University of Banja Luka, Banja Luka, Bosnia and Herzegovina 15 Faculty of Medicine, Department of Medicinal Chemistry, University of Banja Luka, Banja Luka, Bosnia and Herzegovina 16 Agency for Medicinal Product and Medical Devices of Bosnia and Herzegovina, 78000 Banja Luka, Bosnia and Herzegovina 17 Faculty of Pharmacy, Department of Social Pharmacy and Pharmacoeconomics, Medical University of Sofia, Sofia, Bulgaria 18 State Institute for Drug Control, Prague, Czech Republic 19 Department of Medical Biophysics, Faculty of Medicine in Hradec Králové, Charles University, Simkova 870, 500 03 Hradec Králové, Czech Republic 20 State Agency of Medicines, Nooruse 1, 50411 Tartu, Estonia 21 Wissenschaftliches Institut der AOK (WIdO), Rosenthaler Straße 31, 10178 Berlin, Germany 22 Department of Health Policy and Health Economics, Eotvos Lorand University, Budapest, Hungary 23 Syreon Research Institute and Semmelweis University, Center of Health Technology Assessment, Budapest, Hungary 24 Faculty of Pharmacy, UBT Higher Education Institute, Pristina, Kosovo 25 Independent Consultant, Riga, Latvia 26 Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania 27 Department of Health Services Management, University of Malta, Valletta, Malta 2 BioMed Research International 28 Medicines Committee, Oslo University Hospitals, Oslo, Norway 29 Faculty of Medicine, Public Health and Management Department, “Carol Davila” University of Medicine and Pharmacy Bucharest, 050463 Bucharest, Romania 30 Health Insurance Institute, Miklosiceva 24, SI-1507 Ljubljana, Slovenia 31 Pharmacy Services, Greater Glasgow and Clyde (NHS GGC), Glasgow, UK 32 NHS Lothian, Edinburgh, UK 33 Drug Department, Catalan Health Service, Gran Via de les Corts Catalanes, 08007 Barcelona, Spain 34 Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain 35 NEPI-Nätverk för läkemedelsepidemiologi, Stockholm, Sweden 36 National Organization for the Provision of Healthcare Services (EOPYY), Athens, Greece 37 Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden 38 Centre for Primary Care and Health Services Research, School of Health Sciences, University of Manchester, Manchester M13 9PL, UK 39 NIHR Greater Manchester Patient Safety Translational Research Centre, School of Health Sciences, University of Manchester, Manchester, UK 40 Department of Pharmacy, Disciplinary Domain of Medicine and Pharmacy, Uppsala University, Uppsala, Sweden Correspondence should be addressed to Brian Godman; brian.godman@strath.ac.uk Received 26 March 2021; Accepted 6 August 2021; Published 11 October 2021 Academic Editor: Kumud Kafle Copyright © 2021 Brian Godman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction predicted to rise to 68 million by 2045 [9]. Whilst the major- ity of these patients will have type 2 diabetes (T2DM), up to Global expenditure on medicines is envisaged to reach 30% or more of patients with diabetes require insulin to help US$1.5 trillion by 2023 enhanced by growing prevalence control HbA1c levels [10–13]. rates for noncommunicable diseases (NCDs) [1, 2]. This is As a result of growing prevalence rates, the global eco- a concern among European countries given their desire to nomic burden of diabetes is envisaged to be as high as 2.2% retain universal healthcare as a core principle as well as limit of Gross Domestic Product (GDP) by 2030 [14], supported out-of-pocket expenditures especially among citizens with by GDP growth rates worldwide across many countries low income [3–6]. Currently across Europe, approximately including developing countries [15, 16]. The economic one-fifth of health spending is paid for out of pocket, with a impact of diabetes is enhanced by the cost of the complica- higher proportion among those with low income potentially tions including complications arising from hypoglycaemia leading to catastrophic consequences [4]. [9, 13, 17, 18]. This is important with estimated rates of One NCD of increasing priority is diabetes mellitus, hypoglycaemia up to 3.5–3.6 events/month among patients where prevalence rates grew to 463 million people worldwide with type 1 diabetes (T1DM) and 2.2–3.7 among those with in 2019 [7, 8]. In Europe, approximately 59 million people type 2 diabetes (T2DM) [19–23], with some authors finding are currently estimated to have diabetes, with this number that rates of hypoglycaemia may be similar for T2DM BioMed Research International 3 patients taking insulins for >5years [13]. In addition, the seri- insulin glargine) [62]. Alongside this, there are concerns with ous consequences of hypoglycaemia may turn out to be increased rates of hypoglycaemia if patients are switched greater in T2DM patients, particularly regarding the effects between different formulations of insulin glargine 100 IU/ml on the cardiovascular system [13]. Overall, diabetes is among with different devices without full patient education [63–65]. the leading causes of nontraumatic lower extremity amputa- These limited price differences were also seen in a recent tion and blindness worldwide, with patients with diabetes study by Ewen et al. where median biosimilar prices for also at greater risk of cardiovascular disease [7, 24–26]. In insulin glargine across lower- and middle-income (LMIC) view of this, it is important that patients with diabetes should countries ranged from 2% to 25% below originator prices, be carefully managed, which includes reducing the risk of and sometimes biosimilar prices were higher in private phar- hypoglycaemia [13]. macies [35]. However, this was not the case in a recent study Long-acting insulin analogues were specifically devel- in Bangladesh with appreciable price reductions for biosimi- oped to lower the risk of hypoglycaemia in patients with dia- lar insulin glargine enhanced by competition between manu- betes requiring insulin, especially nocturnal hypoglycaemia, facturers [37]. WHO prequalification should also enhance as well as improve patient convenience through reducing competition leading to lower prices for biosimilar long- the number of injections thereby enhancing adherence rates, acting insulin analogues [66]. This is welcomed since limited which is a continuing concern with insulin [7, 9, 27–30]. price reductions for the biosimilar analogues can easily be There is still controversy though regarding the level of benefit matched by the originator company to protect its market seen with long-acting insulin analogues versus NPH and given envisaged low cost of goods apart from insulin detemir other insulins [31–33]. However, a recent systematic review [46, 67]. As a result, the attractiveness of the European long- and network meta-analysis suggests that long-acting insulin acting insulin analogue market for biosimilar manufacturers analogues were superior to intermediate-acting insulins in could be potentially reduced, and thereby, possible competi- key areas including major, serious, and nocturnal hypogly- tion leading to lower prices. caemia [34]. Having said this, the perceived patient benefits Concerns regarding the different devices between the of long-acting insulin analogues are potentially reflected by originator and biosimilars may well have resulted in the low their usage now typically exceeding that of human insulins use of insulin glargine biosimilars (9%) among diabetologists in upper-middle and high-income countries as well as grow- in the UK in 2017 further limiting the attractiveness of the ing in lower middle-income countries including Bangladesh long-acting insulin biosimilar market [68]. However, this is [35–37]. In addition, global expenditure on insulin glargine not universal with some commissioning groups in England was already US$3.88 billion in 2018 out of a total market of achieving utilisation rates of 53.3% for biosimilar insulin US$24million and envisaged to potentially reach as high as glargine in December 2018 versus total insulin glargine [69]. US$9.26 billion by 2025 helped by growing sales of Toujeo® Other activities to reduce the attractiveness of the long- 300 IU/ml [38, 39]. Expenditure on insulin detemir was acting insulin analogue market for biosimilar manufacturers US$2.7 billion in 2015, growing at 7.5% per year [40], with include the originator company launching more concen- sales of insulin degludec also growing with studies demon- trated patented formulations to enhance patient convenience strating their improved effectiveness and cost-effectiveness and potentially further reduce rates of hypoglycaemia, i.e., a versus other long-acting insulin analogues [41–45]. 300 IU/ml formulation of insulin glargine (Gla-300) [41, However, there are concerns with the high costs of long- 70–75]. Having said this, other researchers have found no acting insulin analogues compared to Neutral Protamine difference in effectiveness between the different strengths of Hagedorn (NPH) and other insulins [31, 35, 46]. This is insulin glargine and concerns with possible underdosing with not universal though with published studies showing that the 300 IU/ml formulation [76]. These “evergreening” activi- the higher acquisition costs of long-acting insulin analogues ties by the originator company to preserve its market share in can be fully or partially offset by savings from averted costs the face of potential competition are similar to the launch of of hypoglycaemia and other diabetes-associated complica- different devices for the treatment of asthma to try and tions [47–51]. improve adherence rates and protect sales as well as the Biosimilars are a potential way forward to reduce the cost development of longer-acting oral formulations and intra- of long-acting insulin analogues building on the appreciable muscular formulations of atypical antipsychotics to improve price reductions seen with biosimilars to treat rheumatoid compliance and reduce recurrences [77–80]. Such company arthritis [52–56]. In addition, a number of published studies activities are also seen in other disease areas. These include have now demonstrated similar effectiveness and safety the launch of esomeprazole versus omeprazole, escitalo- between the originator and biosimilar long-acting insulin pram versus citalopram, and pregabalin versus gabapentin analogues [57–61]. However, potential savings from biosimi- [81–85]. We are aware of prescribing restrictions for Gla- lar insulin glargine can be limited in practice, potentially 300 in some of the European countries [86]; however, this accentuated by the dominance of three companies currently is not universal, and sales are growing especially with controlling 96% of the global insulin market by volume and publications suggesting improved cost-effectiveness versus 99% by value discouraging competition [36, 46]. We have 100 IU/ml formulations [41]. seen this in the United Kingdom with limited price differ- Consequently, in view of the current controversies and ences with Semglee® (biosimilar insulin glargine 100 IU/ml) issues surrounding the use of long-acting insulin analogues currently priced only 20% below the originator price and as well as the biosimilars, we believe that there is a need to only 15% below the price of Abasaglar® (another biosimilar assess current utilisation and expenditure patterns for the 4 BioMed Research International long-acting insulin analogues including biosimilars across principally interested in percentage differences in costs over Europe and the rationale for any patterns seen. The findings time between the originator and biosimilars, as well as price can be used by health authorities across Europe to enhance reductions over time, rather than absolute levels and without the use of biosimilar long-acting insulin analogues where any influence from currency fluctuations. pertinent to limit the budget impact of increasing the number Utilisation and expenditure data on insulin glargine was of patients with diabetes across Europe including those further broken down into the different formulations, e.g., dif- requiring insulins. This will be important to preserve univer- ferent 100 IU/ml formulations, as well as for the 300 IU/ml sal access especially post-COVID-19 with its resultant impact formulation (Gla-300) since, as mentioned, we were aware on available resources coupled with increases in patients with that the parent company had been switching its promotional NCDs and their complications as a result of lockdown and activities towards the patented 300 IU/ml formulation in other measures [87, 88]. recent years to protect its market and help deter biosimilar manufacturers. 2. Materials and Methods We combined the information from over 20 European countries and regions to provide the following datasets for We included a range of European countries incorporating comparisons: both Western as well as Central and Eastern European (CEE) countries covering a range of geographies, epidemiol- (i) Utilisation of long-acting insulin analogues as a per- ogy, and economic power in terms of GDP per population. centage of total insulin utilisation based on DDDs This is similar to other studies conducted across Europe (ii) Expenditure on long-acting insulin analogues as a [89–91]. We particularly wanted to include CEE countries percentage of total insulin expenditure based on since there has been appreciably lower use of biologicals in local currencies these countries versus Western European countries due to issues of cost and affordability [92–96]. (iii) Utilisation of biosimilar insulin glargine (100 IU/ml) We typically used reimbursed data from heath authority as a percentage of total insulin glargine (100 IU/ml) and health insurance company databases from 2014 or later again based on DDDs until 2020 when assessing utilisation and pricing patterns for the different insulin preparations. These were supplied (iv) Utilisation of insulin glargine 300 IU/ml as a per- by coauthors in each country since the content of these data- centage of total insulin glargine again based on bases are typically not publicly available. This is different to DDDs studies by Beran et al. and Ewen and colleagues who use a (v) Cost/DDD for both originator and biosimilar insulin wide variety of sources when computing cost data [35, 46, glargine (100 IU/ml) over time with the data subse- 97]. This is because the perspective of this paper is a health quently used to track price changes over time authority one; consequently, we concentrated on their data- bases. These databases are also seen as robust, and they are The information on utilisation and expenditure patterns regularly audited [89, 98, 99]. Consequently, health authority was supplemented by feedback from the coauthors regarding data is seen as a reliable source for comparing and contrast- the patterns seen in their countries to provide future guid- ing utilisation and expenditure patterns across countries ance. The senior-level coauthors also contributed to discus- [98]. We principally centred on insulin glargine as this is sions regarding potential next steps to enhance future the only biosimilar insulin currently available across Europe savings from increased utilisation of biosimilars based on at the time of the study. their considerable experience in this area. We have adopted Utilisation data was broken down into Defined Daily similar approaches before to provide future guidance in this Doses (DDDs). This is because DDDs are seen as a key stan- and other areas [55, 89, 104, 109–113]. dard for comparing utilisation patterns across countries We did not seek ethical approval as we were not dealing especially if there are different pack sizes and strengths with patients. This is in line with national legislation and between countries [100–102]. We acknowledge that some institutional guidelines as well as multiple previous papers published studies have suggested that DDDs may understate conducted by the coauthors in other disease areas and the amount of insulin that patients prescribed 300 IU/ml situations [89, 104, 105, 114–116]. insulin glargine receive versus those prescribed 100 IU/ml formulation; however, others have not seen this [74, 103]. 3. Results We have used this approach before in multiple publications when assessing utilisation and expenditure patterns across 3.1. Utilisation for the Different Insulin Preparations Over disease areas and countries [89–91, 104–107]. Time. There has been growing utilisation for long-acting Expenditure data was principally reimbursed data since, insulin analogues over time among both Western and CEE as mentioned, the perspective of this paper is a health author- countries, with no obvious difference in the rates of utilisa- ity one. In a minority of situations, we also used total expen- tion and increase between Western and CEE countries diture where it proved difficult to break expenditures down (Figure 1). This reflects the growing recognition of the role into the individual components. This again is in line with and value of long-acting insulin analogues in the manage- previous publications [89–91, 104–108]. Expenditure data ment of patients with diabetes mellitus across Europe remained where relevant in the local currency as we were coupled with their increasing promotion. BioMed Research International 5 60 % Long-acting insulin analogues 50 40 30 20 10 0 2014 2015 2016 2017 2018 2019 2020 Year Austria Bosnia and herzegovina Hungary Czech republic Estonia Norway Latvia Malta Slovenia Poland Scotland Sweden Bulgaria Figure 1: Utilisation of long-acting insulin analogues as a percentage of total insulins over time across Europe (DDD based). The greatest utilisation of long-acting insulin analogues in similar changes in their expenditure compared with total in recent years was seen in Estonia (56.5% of total insulins), expenditure on insulins (Figure 2). Czech Republic (47.8%), and Malta (40.0%). There was also Variations ranged from a slight fall in Romania and Slo- considerable prescribing of long-acting insulin analogues in venia over time with the cost/DDD for originator insulin Catalonia in recent years reaching 55.2% of total insulins in glargine 100 IU/ml falling by 20.3% over time in Slovenia 2020 (not shown in Figure 1). However, the variable use of (Table 1) to a limited change in overall expenditure in Malta long-acting insulin analogues in Malta reflects procurement with the cost/DDD falling by 61.3% during the study period practices for that year; consequently, rates can be flexible (Table 1). This compares with an appreciable increase in between the years with implications for accuracy for any expenditure of long-acting insulin analogues in Kosovo over one year. time but from a low base. The least change in the prescribing patterns for long- Increasing expenditure on long-acting insulins in Kosovo acting insulin analogues was seen in Scotland (2.7% increase in recent years again reflects perceptions of improved patient over time), with the greatest change seen in Poland (210.6% convenience and outcomes versus standard insulins such as increase over time), but from a low base. In Poland, this NPH insulins. There is a similar situation in Hungary with may reflect a more cautious attitude towards long-acting expenditure on long-acting insulins reaching 53.7% of total insulin analogues coupled with issues of affordability. There expenditure in recent years, similar to high expenditure rates was also a more cautious approach to the prescribing of in Estonia (63% in 2020), the Czech Republic (62.4%), and long-acting insulin analogues in Slovenia, with similar pre- Latvia (45.5%). There was also appreciable expenditure on scribing rates over time (10.7% increase between 2014 and long-acting insulin analogues in Catalonia currently at 2019). This may again reflect issues of value and affordability; 63.2% of total insulin expenditure (not shown). however, more research is needed before we can say anything The relatively high expenditure on long-acting insulins in with certainty. Romania in recent years again reflects successful marketing The stable utilisation of long-acting insulin analogues in by the originator companies with insulin glargine being one Scotland in recent years (Figure 1) may well reflect adher- of the top selling medicines in Romania in recent years joined ence to the advice from NHS Scotland that patients in recently by insulin detemir. Scotland should ideally be started on human intermediate acting insulins, with long-acting insulin analogues only 3.3. Utilisation of Insulin Glargine including Biosimilar considered based on an assessment of a patient’s hypogly- 100 IU/ml and 300 IU/ml (Gla-300). There has also been con- caemic risk. Adherence to agreed guidance is enhanced by siderable variation in the use of biosimilar insulin glargine regular monitoring of physicians' prescribing of long- (100 IU/ml) versus total insulin glargine across Europe acting insulin analogues versus other insulin preparations (Figure 3). This reflects a number of differences between in Scotland [117]. We have seen monitoring of advice countries in terms of switching of prescribing of insulin glar- increase adherence rates to prescribed guidance in other gine from 100 IU/ml to patented 300 IU/ml (Gla-300) as well disease areas in Scotland [83, 84, 118]. as activities of the originator company to lower its price to make the market less attractive for biosimilars. 3.2. Expenditure for the Different Insulin Preparations Over Currently, no biosimilar insulin glargine is marketed in Time. The increasing use of long-acting insulin analogues Albania, Austria, or Latvia. This may reflect increasing utili- as a percentage of total insulins (Figure 1) was also reflected sation of Gla-300 in recent years rising to 45.3%, 47.7%, and 6 BioMed Research International 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 2014 2015 2016 2017 2018 2019 2020 Austria Bosnia and Herzegovina Bulgaria Czech Republic Estonia Hungary Kosovo Latvia Malta Poland Scotland Romania Slovenia Figure 2: Expenditure on long-acting insulin analogues as a percentage of total insulin expenditure over time among European countries. 51.4%, respectively, of total insulin glargine in these countries differences in recent years between the originator and biosi- as a result of commercial and other activities (Figure 4). This milars (2.1%-7.1%). coupled with reduced prescribing generally of insulin glar- Low and constant utilisation of biosimilar insulin glar- gine (Latvia), and price reductions of the originator over time gine in Bulgaria again reflects continued marketing activities (Albania and Latvia) (Table 1) appear to have made the by the originator company coupled with currently a lack of 100 IU/ml biosimilar market unattractive in these countries. physician incentives to preferentially prescribe biosimilars This is despite insulin glargine being the predominant long- alongside limited price difference in practice between the acting insulin analogue prescribed in Albania in recent years, originator and the biosimilar (Table 1), with both reducing rising to 81.1% of total long-acting insulin analogues (DDD their prices over time. basis) prescribed. Low utilisation of insulin glargine biosimilars in Norway There is also currently no biosimilar insulin glargine also potentially reflects limited price differences between the imported into Kosovo due to a number of issues including originator and biosimilar in recent years (Table 1) coupled concerns with their effectiveness and safety versus the origi- with growing utilisation of Gla-300 (Figure 4). This contrasts nator, and currently there is no biosimilar insulin glargine with Sweden which has the highest biosimilar use among the prescribed in Malta despite very limited use of Gla-300 studied European countries (Figure 3) despite growing use of (Figure 4). This probably reflects the considerable price Gla-300 (Figure 4). This is probably due to a tradition of pre- reduction by the originator company making this market scribing of multiple source medicines with compulsory unattractive to biosimilar manufacturers (61.3%, Table 1). generic substitution in Sweden coupled with ongoing initia- Similarly, whilst insulin glargine biosimilar has recently been tives to enhance the quality and efficiency of prescribing reimbursed in Romania (Abasaglar® 100), its uptake to date including enhancing the prescribing of biosimilars [55, 106, has been very limited (not shown) due to ongoing pricing 119, 120]. Ongoing initiatives also include devolving budgets and reimbursement policies coupled with limited physician locally to enhance the focus of ambulatory care physicians on incentives to preferentially prescribe biosimilars alongside prescribing efficiency. no copayment issues for patients. The situation in Lithuania contrasts with the other Baltic There was also very limited utilisation of insulin glargine countries as there has been growing utilisation of biosimilar biosimilars in Estonia, contrasting with their growing utilisa- insulin glargine as a percentage of all insulin glargine tion in Lithuania as another key member of the Baltic States. 100 IU/ml in recent years, reaching 26.5% of total insulin This again probably reflects the originator company switch- glargine 100 IU/ml in 2020 (Figure 3). This reflects the fact ing promotional activities to patented Gla-300 in Estonia to that all long-acting insulin analogues are in the same refer- reduce biosimilar competition, with utilisation of Gla-300 ence price group with patients covering the additional costs growing to 55.4% of total insulin glargine in 2020 themselves for a more expensive medicine [121, 122]. Having (Figure 4). In addition, the originator company dropping its said this, utilisation of the 100 IU/ml formulation has been price by 24.9% over time (Table 1) resulting in limited price moderated in recent years in Lithuania by increasing BioMed Research International 7 Table 1: Changes in differences between prices for the originator and biosimilar insulin glargine 100 IU/ml across Europe in recent years (based on local costs/DDD). (a) Albania Austria B&H Bulgaria Catalonia (Spain) % difference originator vs. biosimilar price Launch of the biosimilar Not applicable Not applicable No difference 4.7% 30.0% Latest difference Not applicable Not applicable 7.9% 5.7% Similar % price change over time (from 2014/2015 to 2020) Originator -32.0% No change -11.3% -10.8% -23.1% Biosimilar Not applicable Not applicable -17.1% -11.7% No change (b) Czech Republic Estonia Hungary Italy Latvia Lithuania % difference originator vs. biosimilar price Launch of the biosimilar 17.1% 16.4% 28.2% Not recorded Not applicable 12.3% Latest difference Similar 7.1% 1.6% 31.6% Not applicable Similar % price change over time (from 2014/2015 to 2020) Originator -25.5% -24.9% -21.2% 52.3% -14.4% -21.1% Biosimilar -7.7% Stable 1.2% Not recorded Not applicable -6.8% (c) Malta Norway Poland Scotland Slovenia Sweden % difference originator vs. biosimilar price Launch of the biosimilar Not applicable 12.1% 24.7% 18.1% 22.9% 13.6% Latest difference Not applicable 5.9% 0.2% 7.5% 9.9% 0.6% % price change over time (from 2014/2015 to 2020) Originator -61.3% -3.6% -31.1% -9.0% -20.3% -12.7% Biosimilar Not applicable 2.1% -6.5% No change No change -1.4% utilisation of Gla-300, rising to 39.0% of all insulin glargine in insulin glargine in Hungary is again adversely affected by early 2020 (Figure 4) coupled with price reductions by the the originator dropping its price over time (Table 1) coupled originator (21.1% between 2015 and 2020) to limit any with increasing use of Gla-300 reaching 58% of total insulin copayment differences. glargine in recent years (Figure 4). There has also been growing utilisation of insulin glar- The growth in the prescribing of biosimilar 100 IU/ml gine biosimilars in Bosnia and Herzegovina (B & H), but insulin glargine in Italy in recent years (Figure 3) probably from a low base with the state agency recently encouraging reflects ongoing regional and national demand-side measures physicians to prescribe biosimilars for new patients where to enhance the prescribing of biosimilars given some of the possible, with physicians generally following national guide- price differences seen including for biosimilar insulin glar- lines in B & H [108, 123]. Greater growth though is ham- gine (Table 1) and the need to conserve resources [127, pered by high utilisation of Gla-300, reaching 52.1% of all 128]. However, greater utilisation of biosimilar insulin insulin glargine use in 2019 (Figure 4), and the originator glargine may again be hampered by growing utilisation of dropping its price to reduce any resultant price differential Gla-300 in Italy in recent years (Figure 4). (Table 1). We are also seeing growing utilisation of biosimilar insu- The growth in the utilisation of the biosimilar in Hungary lin glargine in Scotland. However, growth is limited by con- is also welcomed as this was not the case with biosimilars for cerns with switching between the originator and biosimilar infliximab and rituximab [124, 125]. However, there are now 100 IU/ml insulin glargine, with physicians requesting to pre- ongoing reforms in Hungary to encourage physicians to start scribe by brand name [64, 65]. This works in the UK with patients on the least expensive biosimilar as well as the refer- community pharmacists not allowed to substitute an origina- ence pricing system with patients required to fund the differ- tor with a generic without physician approval [80, 129]. ence in prices between the originator and any biosimilar Having said this, there are traditionally very high rates of themselves [126]. Having said this, utilisation of biosimilar INN prescribing in Scotland [83, 84, 118]. There is currently 8 BioMed Research International 70 60 % Insulin Glargine 300IU/ml 50 40 30 20 10 0 2015 2016 2017 2018 2019 2020 Year Albania Austria Bosnia and Herzegovina Czech republic Estonia Hungary Italy Latvia Lithuania Malta Norway Poland Scotland Slovenia Spain (Catalonia) Sweden Figure 3: Utilisation of insulin glargine biosimilar (100 IU/ml) as a % of total insulin glargine 100 IU/ml (DDD based) over time across Europe. 80 70 % Insulin glangine biosimilar 60 50 40 30 20 10 0 2015 2016 2017 2018 2019 2020 Year Bosnia and herzegovina Italy Estonia Hungary Bulgaria Poland Norway Czech Republic Sweden Slovenia Lithuania Catalonia Scotland Figure 4: Utilisation of insulin glargine 300 IU/ml (Gla-300) as a % of total insulin glargine (DDD based) across Europe over time low use of Gla-300 in Scotland as a result of ongoing pre- of biosimilars to save resources especially as Poland is a lead- scribing guidance to limit its use enhanced by concerns that ing producer of biosimilars in Europe [130, 131]. However, patients may inadvertently over dose [86]. their prescribing is also hampered by growing utilisation of The appreciably higher utilisation of biosimilar insulin Gla-300 reaching 37.1% of total insulin glargine by early glargine in Poland in recent years compared with a number 2020 (Figure 4). of other CEE countries (Figure 3) may well be facilitated by Prices are also now similar between the biosimilar insulin a flat reimbursement rate with patients paying the price dif- glargine and the originator in the Czech Republic potentially ference for a more expensive originator [126, 130]. Alongside impacting on its use following a fall in originator prices this, the Ministry of Health and the National Health Insur- (25.5%) and also biosimilar prices (7.7%) (Table 1). As a ance Fund in Poland are both looking to encourage the use result, there is limited use of biosimilars despite growing BioMed Research International 9 Educational initiatives (i) Instigate programmes that educate patients where pertinent regarding similar effectiveness and safety between the originator and biosimilar insulin glargine. This includes actively disseminating the findings from previous and current studies including studies with real-world data (ii) Instigate/help with additional research regarding the potential savings/cost-effectiveness from increasing use of biosimilar insulin glargine—building on current studies, with potential savings used to enhance either greater availability and use of long-acting insulin analogues in suitable patients with rising prevalence rates; alternatively, increase the number of professionals available to improve the care of patients with diabetes requiring insulin with the savings made (iii) Alongside this, work with patients to ensure they are familiar with the different pens/devices where this exists in cases where switching between unfamiliar devices may cause confusion—the objective being to minimise any potential for hypoglycaemia (iv) Concurrently, work with patient organisations to facilitate greater use of biosimilar insulin glargine especially where resources/- copayments are an issue and help with patient education to enhance optimal use of available devices where pertinent [132] (v) Increased competition with greater availability of biosimilars should help to further lower prices benefitting all key stakeholder groups Other suggested activities (i) Encourage greater discounts from companies to enhance the use of biosimilar insulin glargine at lower costs—building on examples with oral generics [122, 133, 134]. This includes helping to cover the costs of any educational activities needed to enhance familiarity with different devices to minimise potential hypoglycaemia (ii) Potential activities to encourage increased prescribing of biosimilars (and hence competition) could include the following: (a) Introducing/progress annual procurement practices—with preference given to biosimilar companies (b) Consider potentially delisting originator insulin glargine 100 IU/ml from reimbursement and formulary lists and/or only author- ising reimbursement for biosimilars—building on successes in other disease areas and situations [118, 135] (c) Introduce target prescribing goals for biosimilars for both new and existing patients with diabetes requiring insulin for their management—and where necessary provide additional educational support (with the help of patient organisations and other healthcare professionals) (d) Introduce prescribing restrictions/guidance for still patented Gla-300 IU/ml to further enhance the market attractiveness for 100 IU/ml formulations—similar to the situation in Scotland [86]. This builds on the successful introduction of prescribing restrictions in other disease areas across Europe [91, 136–138] (iii) Potentially form consortia surrounding the purchasing of biosimilar insulin glargine to encourage greater competition among manufacturers to reduce the current monopoly of insulin availability from the three leading pharmaceutical companies. This can build on current Pan-European consortia activities [139–141] (iv) Look to increase European production of biosimilar insulin glargine building on current activities in countries such as Poland and Malaysia [130, 131, 142]. Lower prices for biosimilar insulin glargine should help lower- and middle-income countries struggling to fund long-acting insulin analogues due to issues of affordability [35, 143, 144] Box 1: Potential activities among health authorities to enhance the prescribing and dispensing of biosimilar insulin glargine. utilisation of long-acting insulin analogues in the Czech 4. Discussion Republic reaching 47.8% of total insulins in 2020 (Figure 1). There are current restrictions regarding the pre- We believe this is the most comprehensive study to date to scribing of long-acting insulin analogues in the Czech explore current utilisation and expenditure patterns for dif- Republic, with long-acting insulin analogues only reim- ferent insulin preparations, with a particular focus on insulin bursed if current treatment regimens fail to achieve target glargine and its biosimilars, across Europe. There has typi- HbA1c levels below 60 mmol/mol or if patients prescribed cally been increasing utilisation of long-acting insulin ana- human insulins repeatedly experience severe hypoglycaemia. logues across Europe despite their higher price (Figure 1), Concomitant with this, treatment with long-acting insulin reflecting perceived patient benefits in terms or reduced analogues should no longer be reimbursed unless there is a hypoglycaemia and greater convenience. This increased use demonstrable improvement in the patient’s HbA1c levels is seen in both Western European and CEE countries demon- within three months of initiation, i.e., a reduction by at least strating that affordability is not an issue unlike a number of 10%, or significant reduction in the incidence of hypoglycae- lower- and middle-income countries [35, 143, 145]. Similar mia. However, there is currently variable follow-up of these patterns were seen when evaluating changes in expenditure restrictions in practice. on long-acting insulin analogues as a percentage of total expenditure on insulins (Figure 2). 3.4. Potential Strategies to Enhance the Prescribing of However, there are concerns with limited or no use of Biosimilar Insulin Glargine. Box 1 contains a number of biosimilar insulin glargine in a number of European coun- potential strategies to enhance the utilisation of biosimilar tries despite a number of studies showing no difference in long-acting insulin analogues in Europe. This builds on cur- effectiveness and safety between the originator and biosimi- rently variable utilisation of biosimilar insulin glargine across lars [57–60] (Section 3.3). This is due to a number of factors Europe. This is seen as essential to stimulate the market for including promotional efforts by the originator company to the benefit of key stakeholders in the future. change prescriptions to patented Gla-300 with limited 10 BioMed Research International demand-side initiatives from health authorities to discourage Data Availability this with the exception of Scotland with its prescribing sug- gestions to limit the use of Gla-300 [86]. In addition, the The content of health authority and health insurance com- company lowering the price of the originator often to near pany databases is typically confidential. However, reasonable or similar to biosimilar prices (Table 1), which coupled with requests for information will be considered and actioned concerns with different devices between the different insulin where possible. The coauthors from the various European glargine 100 IU/ml formulations in some markets, has fur- countries have been responsible for the content and accuracy ther limited biosimilar use. Alongside this, the continued of the information they have provided. domination of the insulin market by three manufacturers discourages competition [36, 46]. Disclosure These issues need to be addressed to enhance the attrac- tiveness of the biosimilar long-acting insulin analogue The authors are totally responsible for the views expressed in market, especially with the potential for low cost of goods this paper, and they do not necessarily represent the deci- [46, 67]. We have seen with biosimilars for managing sions, policy, or views of the World Health Organization. patients with inflammatory diseases such as rheumatoid arthritis that increased competition can lead to low prices Conflicts of Interest for biosimilars [52, 54, 56, 146], and this should be encour- aged for long-acting insulin analogues in Europe. Failure to The authors have no relevant conflicts of interest to declare. do so will limit the attractiveness of this market to other man- However, a number of the coauthors work for health author- ufacturers of biosimilar insulin glargine as well as potential ities or are advisers to them. manufacturers of other long-acting insulin analogues as these compounds lose their patents. This will be to the detriment of Acknowledgments key stakeholder groups especially given rising rates on diabe- The authors would like to thank Elita Poplavska with her tes across Europe [9] and growing resource issues post- help with explaining the potential rationale for the prescrib- COVID-19. Box 1 contains a number of activities that ing patterns in Latvia. This analysis was commissioned and European health authorities can instigate to increase compe- paid for by the World Health Organization. tition and subsequent prescribing of biosimilar long-acting insulin analogues, building on demand-side and other mea- sures in other disease areas, and we will be monitoring these References in the future. [1] IQVIA, The Global Use of Medicine in 2019 and Outlook to We are aware of a number of limitations with this study. 2023 - Forecasts and Areas to Watch, 2019, https://www These include the fact that we did not include all European .iqvia.com/-/media/iqvia/pdfs/institute-reports/the-global- countries. However, we do not believe that increasing the use-of-medicine-in-2019-and-outlook-to-2023.pdf. number of European countries would have appreciably [2] M. Jakovljevic, M. Jakab, U. Gerdtham et al., “Comparative altered our findings. In addition, we only used health author- financing analysis and political economy of noncommunic- ity and health insurance company databases. This was delib- able diseases,” Journal of Medical Economics, vol. 22, no. 8, erate for the reasons stated. Thirdly, we used DDDs for pp. 722–727, 2019. documenting and analysing utilisation data aware though [3] A. Odone and N. Azzopardi-Muscat, “Health and the effect of of the potential problems with Gla-300. This was again delib- universal health coverage in Italy,” The Lancet Public health., erate for the reasons stated. Finally, we did not undertake an vol. 4, no. 12, pp. e597–e598, 2019. in-depth analysis of the rationale behind the trends seen in [4] OECD, Health at a Glance: Europe 2020 State of Health in the each country. However, feedback was based on the experi- EU Cyclehttps://www.oecd-ilibrary.org/docserver/82129230- ence of senior-level coauthors in each country. Consequently, en.pdf?expires=1612384979&id=id&accname= we believe our findings and suggestions are robust providing guest&checksum=E9AD44E432E325AC9EEBEB236EAE5851. future direction. [5] European Commission, “Defining value in “value based healthcare”,” Report of the expert panel on effective ways of investing in health (EXPH), 2019, https://ec.europa.eu/ 5. Conclusion health/sites/health/files/expert_panel/docs/024_defining- value-vbhc_en.pdf. In conclusion, we have seen growing use of long-acting insu- [6] M. Jakovljevic, K. Matter-Walstra, T. Sugahara et al., “Cost- lin analogues across Europe reflecting their perceived effectiveness and resource allocation (CERA) 18 years of evo- benefits with improving compliance and reducing hypogly- lution: maturity of adulthood and promise beyond tomor- caemia. However, there are concerns with limited or no use row,” Cost effectiveness and resource allocation., vol. 18, of biosimilars of long-acting insulin analogues in a number no. 1, 2020. of European countries due to a number of factors. These [7] J. C. N. Chan, L. L. Lim, N. J. Wareham et al., “The Lancet include promotional efforts by the originator company and Commission on diabetes: using data to transform diabetes price reductions matching those of biosimilar manufacturers. care and patient lives,” Lancet, vol. 396, no. 10267, These issues need to be addressed to enhance the utilisation pp. 2019–2082, 2021. of biosimilars in the future to the benefit of all key stake- [8] J. Liu, Z.-H. Ren, H. Qiang et al., “Trends in the incidence of holder groups. diabetes mellitus: results from the Global Burden of Disease BioMed Research International 11 Study 2017 and implications for diabetes mellitus preven- Qaboos University Medical Journal [SQUMJ], vol. 18, no. 4, tion,” BMC Public Health, vol. 20, no. 1, p. 1415, 2020. pp. 447–e454, 2019. [9] A. Ceriello, H. W. deValk, B. Guerci et al., “The burden of [23] N. Munro and A. H. Barnett, “Incidence, worry and discus- type 2 diabetes in Europe: current and future aspects of insu- sion about dosing irregularities and self-treated hypoglycae- lin treatment from patient and healthcare spending perspec- mia amongst HCPs and patients with type 2 diabetes: tives,” Diabetes research and clinical practice, vol. 161, results from the UK cohort of the Global Attitudes of Patient p. 108053, 2020. and Physicians (GAPP2) survey,” International journal of [10] S. Basu, J. S. Yudkin, S. Kehlenbrink et al., “Estimation of clinical practice., vol. 68, no. 6, pp. 692–699, 2014. global insulin use for type 2 diabetes, 2018-30: a microsimu- [24] M. L. Alva, A. Gray, B. Mihaylova, J. Leal, and R. R. Holman, lation analysis,” The lancet Diabetes & endocrinology., vol. 7, “The impact of diabetes-related complications on healthcare no. 1, pp. 25–33, 2019. costs: new results from the UKPDS (UKPDS 84),” Diabetic [11] M. Sharma, I. Nazareth, and I. Petersen, “Trends in inci- medicine., vol. 32, no. 4, pp. 459–466, 2015. dence, prevalence and prescribing in type 2 diabetes melli- [25] A. Papazafiropoulou, N. Tentolouris, R. P. Soldatos et al., tus between 2000 and 2013 in primary care: a retrospective “Mortality in diabetic and nondiabetic patients after amputa- cohort study,” BMJ Open, vol. 6, no. 1, article e010210, tions performed from 1996 to 2005 in a tertiary hospital pop- 2016. ulation: a 3-year follow-up study,” Journal of Diabetes and its [12] V. A P, L. Kamath, and S. Shankar, “Knowledge, attitude and Complications, vol. 23, no. 1, pp. 7–11, 2009. practice of insulin use of diabetic patients in India,” Pharma- [26] M. Narres, T. Kvitkina, H. Claessen et al., “Incidence of lower cology and Clinical Pharmacy Research., vol. 5, no. 1, pp. 23– extremity amputations in the diabetic compared with the 32, 2020. non-diabetic population: a systematic review,” PLoS One, [13] S. R. Heller, M. Peyrot, S. K. Oates, and A. D. Taylor, “Hypo- vol. 12, no. 8, article e0182081, 2017. glycemia in patient with type 2 diabetes treated with insulin: [27] P. Rys, P. Wojciechowski, A. Rogoz-Sitek et al., “Systematic it can happen,” BMJ Open Diabetes Research & Care, vol. 8, review and meta-analysis of randomized clinical trials com- no. 1, p. e001194, 2020. paring efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin [14] C. Bommer, V. Sagalova, E. Heesemann et al., “Global eco- detemir in type 2 diabetes mellitus,” Acta diabetologica, nomic burden of diabetes in adults: projections from 2015 vol. 52, no. 4, pp. 649–662, 2015. to 2030,” Diabetes Care, vol. 41, no. 5, pp. 963–970, 2018. [28] A. McGovern, Z. Tippu, W. Hinton, N. Munro, M. Whyte, [15] M. Jakovljevic, Y. Timofeyev, C. L. Ranabhat et al., “Real GDP and S. de Lusignan, “Comparison of medication adherence growth rates and healthcare spending – comparison between and persistence in type 2 diabetes: a systematic review and the G7 and the EM7 countries,” Globalization and Health, meta-analysis,” Diabetes, obesity & metabolism., vol. 20, vol. 16, no. 1, p. 64, 2020. no. 4, pp. 1040–1043, 2018. [16] M. Jakovljevic, T. Sugahara, Y. Timofeyev, and N. Rancic, [29] U. Pedersen-Bjergaard, P. L. Kristensen, H. Beck-Nielsen “Predictors of (in)efficiencies of healthcare expenditure et al., “Effect of insulin analogues on risk of severe hypogly- among the leading Asian economies - comparison of OECD caemia in patients with type 1 diabetes prone to recurrent and non-OECD nations,” Risk management and healthcare severe hypoglycaemia (HypoAna trial): a prospective, rando- policy., vol. Volume 13, pp. 2261–2280, 2020. mised, open-label, blinded-endpoint crossover trial,” The [17] S. A. Amiel, P. Aschner, B. Childs et al., “Hypoglycaemia, car- lancet Diabetes & endocrinology., vol. 2, no. 7, pp. 553–561, diovascular disease, and mortality in diabetes: epidemiology, 2014. pathogenesis, and management,” The lancet Diabetes & endo- [30] T. Semlitsch, J. Engler, A. Siebenhofer, K. Jeitler, A. Berghold, crinology, vol. 7, no. 5, pp. 385–396, 2019. and K. Horvath, “(Ultra-)long-acting insulin analogues ver- [18] S. Kalra, “Hypoglycaemia in diabetes,” Journal Of Pakistan sus NPH insulin (human isophane insulin) for adults with Medical Association, vol. 64, no. 9, pp. 1090–1093, 2014. type 2 diabetes mellitus,” The Cochrane database of system- [19] M. F. Pathan, M. Fariduddin, K. Nazimuddin et al., “The inci- atic reviews, vol. 11, p. Cd005613, 2020. dence of hypoglycemia among insulin-treated patients with [31] P. Almeida, T. B. C. Silva, F. de Assis Acurcio et al., “Quality type 1 or type 2 diabetes: Bangladeshi cohort of international of life of patients with type 1 diabetes mellitus using insulin operations-hypoglycemia assessment tool study,” Indian analog glargine compared with NPH insulin: a systematic Journal of Endocrinology and Metabolism, vol. 22, no. 3, review and policy implications,” The patient., vol. 11, no. 4, pp. 379–386, 2018. pp. 377–389, 2018. [20] K. Khunti, S. Alsifri, R. Aronson et al., “Rates and predictors [32] B. Hemmingsen, M. I. Metzendorf, and B. Richter, “(Ultra- of hypoglycaemia in 27 585 people from 24 countries with )long-acting insulin analogues for people with type 1 diabetes insulin-treated type 1 and type 2 diabetes: the global HAT mellitus,” The Cochrane database of systematic reviews, vol. 3, study,” Diabetes, obesity & metabolism., vol. 18, no. 9, p. Cd013498, 2021. pp. 907–915, 2016. [33] A. L. Caires de Souza, F. A. Acurcio, A. A. Guerra Júnior, [21] Z. Hussein, N. A. Kamaruddin, S. P. Chan et al., “Hypoglyce- R. C. Rezende Macedo do Nascimento, B. Godman, and mia awareness among insulin-treated patients with diabetes L. M. Diniz, “Insulin glargine in a Brazilian state: should the in Malaysia: a cohort subanalysis of the HAT study,” Diabetes government disinvest? An assessment based on a systematic research and clinical practice., vol. 133, pp. 40–49, 2017. review,” Applied health economics and health policy., vol. 12, [22] S. Abusnana, S. A. Beshyah, N. al-Mutawa et al., “Hypogly- no. 1, pp. 19–32, 2014. caemia among insulin-treated patients with diabetes: evalua- [34] A. C. Tricco, H. M. Ashoor, J. Antony et al., “Comparative tion of the United Arab Emirates cohort of the International efficacy and safety of ultra-long-acting, long-acting, interme- Operations-Hypoglycaemia Assessment Tool study,” Sultan diate-acting, and biosimilar insulins for type 1 diabetes 12 BioMed Research International mellitus: a systematic review and network meta-analysis,” [48] J. Jendle, Å. Ericsson, B. Ekman et al., “Real-world cost- Journal of General Internal Medicine, vol. 36, no. 8, effectiveness of insulin degludec in type 1 and type 2 diabetes pp. 2414–2426, 2021. mellitus from a Swedish 1-year and long-term perspective,” [35] M. Ewen, H. J. Joosse, D. Beran, and R. Laing, “Insulin prices, Journal of Medical Economics, vol. 23, no. 11, pp. 1311– availability and affordability in 13 low-income and middle- 1320, 2020. income countries,” BMJ global health., vol. 4, no. 3, article [49] T. Y. Lee, S. Kuo, C. Y. Yang, and H. T. Ou, “Cost-effective- e001410, 2019. ness of long-acting insulin analoguesvsintermediate/long‐ [36] D. Beran, M. Ewen, and R. Laing, “Constraints and challenges acting human insulin for type 1 diabetes: a population- in access to insulin: a global perspective,” The lancet Diabetes based cohort followed over 10 years,” British journal of clini- & endocrinology., vol. 4, no. 3, pp. 275–285, 2016. cal pharmacology., vol. 86, no. 5, pp. 852–860, 2020. [37] M. Haque, S. Islam, Z. M. Kamal et al., “Ongoing efforts to [50] B. Alemayehu, J. Speiser, L. Bloudek, and E. Sarnes, “Costs improve the management of patients with diabetes in Bangla- associated with long-acting insulin analogues in patients with desh and the implications,” Hospital practice., pp. 1–7, 2021. diabetes,” The American journal of managed care, vol. 24, 2018. [38] Zion Market Research, Insulin glargine market: by type (pre- [51] S. Gururaj Setty, W. Crasto, J. Jarvis, K. Khunti, and M. J. filled syringe and single dose vial), by application (type 1 diabe- Davies, “New insulins and newer insulin regimens: a review tes and type 2 diabetes), by distribution channel (hospital of their role in improving glycaemic control in patients with pharmacy, online sales, retail pharmacy and other distribution diabetes,” Postgraduate Medical Journal, vol. 92, no. 1085, channels): global industry perspective, comprehensive analysis pp. 152–164, 2016. and forecast, pp. 2018–2025, 2019, https://www [52] T. B. Jensen, S. C. Kim, E. Jimenez-Solem, D. Bartels, H. R. .zionmarketresearch.com/report/insulin-glargin-market. Christensen, and J. T. Andersen, “Shift from adalimumab [39] “Research and Markets,” $24 billion insulin markets - global originator to biosimilars in Denmark,” JAMA Internal Medi- intelligence database 2012-2018 & 2019-2023, 2019, https:// cine., vol. 180, no. 6, pp. 902-903, 2020. www.globenewswire.com/news-release/2019/05/29/ [53] W. Matusewicz, B. Godman, H. B. Pedersen et al., “Improv- 1856512/0/en/ 24-Billion-Insulin-Markets-Global- ing the managed introduction of new medicines: sharing Intelligence-Database-2012-2018-2019-2023.html. experiences to aid authorities across Europe,” Expert review [40] PMLive, Levemirhttp://www.pmlive.com/top_pharma_list/ of pharmacoeconomics & outcomes research., vol. 15, no. 5, pharmaceutical_products/levemir. pp. 755–758, 2015. [41] A. Y. Y. Cheng, J. Wong, N. Freemantle, S. H. Acharya, and [54] K. Davio, After biosimilar deals, UK spending on adalimumab E. Ekinci, “The safety and efficacy of second-generation basal will drop by 75%, 2018, https://www.centerforbiosimilars insulin analogues in adults with type 2 diabetes at risk of .com/news/after-biosimilar-deals-uk-spending-on- hypoglycemia and use in other special populations: a narra- adalimumab-will-drop-by-75. tive review,” Diabetes therapy., vol. 11, no. 11, pp. 2555– [55] E. Moorkens, B. Godman, I. Huys et al., “The expiry of 2593, 2020. Humira® market exclusivity and the entry of adalimumab [42] N. Thalange, J. Gundgaard, W. Parekh, and D. Tutkunkardas, biosimilars in Europe: an overview of pricing and national “Cost analysis of insulin degludec in comparison with insulin policy measures,” Frontiers in pharmacology, vol. 11, 2021. detemir in treatment of children and adolescents with type 1 [56] B. Godman, “Biosimilars are becoming indispensable in the diabetes in the UK,” BMJ open diabetes research & care., management of multiple diseases although concerns still vol. 7, no. 1, article e000664, 2019. exist,” Bangladesh Journal of Medical Science., vol. 20, no. 1, [43] M. Evans, R. G. J. Moes, K. S. Pedersen, J. Gundgaard, and pp. 5–10, 2020. T. R. Pieber, “Cost-effectiveness of insulin degludec versus [57] T. Yamada, R. Kamata, K. Ishinohachi et al., “Biosimilar vs insulin glargine U300 in the Netherlands: evidence from a originator insulins: systematic review and meta-analysis,” randomised controlled trial,” Advances in Therapy, vol. 37, Diabetes, obesity & metabolism., vol. 20, no. 7, pp. 1787– no. 5, pp. 2413–2426, 2020. 1792, 2018. [44] M. Russel-Szymczyk, V. Valov, A. Savova, and M. Manova, [58] J. J. Altman, N. Chevalier, B. Delemer, F. Travert, and “Cost-effectiveness of insulin degludec versus insulin glargine I. Benabbad, “LY2963016 insulin glargine: the first biosimilar U100 in adults with type 1 and type 2 diabetes mellitus in insulin approved in the European Union,” Presse Médicale, Bulgaria,” BMC endocrine disorders, vol. 19, no. 1, p. 132, vol. 47, no. 10, pp. 854–866, 2018. 2019. [59] T. C. Blevins, A. Barve, B. Sun et al., “Efficacy and safety of [45] U. Permsuwan, K. Thavorn, P. Dilokthornsakul, S. Saokaew, MYL-1501D versus insulin glargine in patients with type 2 and N. Chaiyakunapruk, “Cost-effectiveness of insulin dete- diabetes after 24 weeks: results of the phase III INSTRIDE 2 mir versus insulin glargine for Thai type 2 diabetes from a study,” Diabetes, obesity & metabolism., vol. 21, no. 1, payer's perspective,” Journal of Medical Economics, vol. 20, pp. 129–135, 2019. no. 9, pp. 991–999, 2017. [60] T. C. Blevins, A. Barve, Y. Raiter et al., “Efficacy and safety of [46] D. Beran, M. Lazo-Porras, C. M. Mba, and J. C. Mbanya, “A MYL-1501D versus insulin glargine in people with type 1 dia- global perspective on the issue of access to insulin,” Diabeto- betes mellitus: results of the INSTRIDE 3 phase 3 switch logia, vol. 64, no. 5, pp. 954–962, 2021. study,” Diabetes, obesity & metabolism., vol. 22, no. 3, pp. 365–372, 2020. [47] A. A. Shafie and C. H. Ng, “Cost-effectiveness of insulin glar- gine and insulin detemir in the basal regimen for naïve insu- [61] S. M. Hoy, “MYL1501D insulin glargine: a review in diabetes lin patients with type 2 diabetes mellitus (T2DM) in mellitus,” BioDrugs, vol. 34, no. 2, pp. 245–251, 2020. Malaysia,” ClinicoEconomics and outcomes research., vol. - [62] Greater Glasgow, “Greater Glasgow and Clyde,” Clyde. Med- Volume 12, pp. 333–343, 2020. icines Update - Semglee® – preferred brand of insulin glargine, BioMed Research International 13 2020, http://ggcprescribing.org.uk/blog/alternatives-insulin- [76] H. Vargas-Uricoechea, “Efficacy and Safety of Insulin Glar- glargine-post-tc/. gine 300 U/mL versus 100 U/mL in Diabetes Mellitus: A [63] M. Greener, “Why isn’t the NHS making the most of biosimi- Comprehensive Review of the Literature,” Journal of diabetes lar insulin?,” Prescriber, vol. 30, no. 8, pp. 21–24, 2019. research., vol. 2018, article 2052101, pp. 1–28, 2018. [64] Greater Glasgow, Clyde. Medicines Update - Prescribing med- [77] K. Keramatian, T. Chakrabarty, and L. N. Yatham, “Long- icines by brand, 2020, http://www.ggcprescribing.org.uk/ acting injectable second-generation/atypical antipsychotics blog/prescribing-medicines-brand/. for the management of bipolar disorder: a systematic review,” CNS Drugs, vol. 33, no. 5, pp. 431–456, 2019. [65] Lothian Formulary, 6.1.1 Insulins, 2020, https://www.ljf.scot .nhs.uk/LothianJointFormularies/Adult/6.0/6.1/6.1.1/Pages/ [78] A. T. Olagunju, S. R. Clark, and B. T. Baune, “Long-acting default.aspx. atypical antipsychotics in schizophrenia: a systematic review and meta-analyses of effects on functional outcome,” The [66] WHO, WHO launches first-ever insulin prequalification pro- Australian and New Zealand journal of psychiatry., vol. 53, gramme to expand access to life-saving treatment for diabetes, no. 6, pp. 509–527, 2019. 2019, https://www.who.int/news/item/13-11-2019-who- [79] B. Godman, M. Persson, J. Miranda et al., “Can authorities launches-first-ever-insulin-prequalification-programme-to- take advantage of the availability of generic atypical antipsy- expand-access-to-life-saving-treatment-for-diabetes. chotic drugs? Findings from Sweden and potential implica- [67] D. Gotham, M. J. Barber, and A. Hill, “Production costs and tions,” Journal of Pharmaceutical Health Services Research, potential prices for biosimilars of human insulin and insulin vol. 4, no. 3, pp. 139–150, 2013. analogues,” BMJ global health., vol. 3, no. 5, article e000850, [80] H. McCabe, B. Godman, A. Kurdi et al., “Prescribing trends 2018. of inhaler treatments for asthma and chronic obstructive pul- [68] S. R. Chapman, R. W. Fitzpatrick, and M. I. Aladul, “Knowl- monary disease within a resource-constrained environment edge, attitude and practice of healthcare professionals in the Scottish national health service: findings and implica- towards infliximab and insulin glargine biosimilars: result of tions,” Expert review of respiratory medicine., vol. 13, no. 7, a UK web-based survey,” BMJ Open, vol. 7, no. 6, article pp. 679–689, 2019. e016730, 2017. [81] A. A. Alkhafaji, L. Trinquart, G. Baron, M. Desvarieux, and [69] I. Agirrezabal, E. Sánchez-Iriso, K. Mandar, and J. M. P. Ravaud, “Impact of evergreening on patients and health Cabasés, “Real-world budget impact of the adoption of insu- insurance: a meta analysis and reimbursement cost analysis lin glargine biosimilars in primary care in England (2015- of citalopram/escitalopram antidepressants,” BMC medicine, 2018),” Diabetes Care, vol. 43, no. 8, pp. 1767–1773, 2020. vol. 10, no. 1, 2012. [70] E. Standl and D. R. Owen, “New long-acting basal insulins: [82] N. Vernaz, G. Haller, F. Girardin et al., “Patented drug exten- does benefit outweigh cost?,” Diabetes Care, vol. 39, Supple- sion strategies on healthcare spending: a cost-evaluation ment 2, pp. S172–S179, 2016. analysis,” PLoS Medicine, vol. 10, no. 6, article e1001460, [71] J. Escalada, F. Bonnet, J. Wu et al., “Reduced hypoglycemia 2013. risk in type 2 diabetes patients switched to/initiating insulin [83] B. Godman, A. Kurdi, H. McCabe et al., “Ongoing initiatives glargine 300 vs 100 U/ml: a European real-world study,” within the Scottish national health service to affect the pre- Advances in Therapy, vol. 37, no. 9, pp. 3863–3877, 2020. scribing of selective serotonin reuptake inhibitors and their [72] A. Díez-Fernández, I. Cavero-Redondo, J. Moreno-Fernán- influence,” Journal of comparative effectiveness research., dez, D. P. Pozuelo-Carrascosa, M. Garrido-Miguel, and vol. 8, no. 7, pp. 535–547, 2019. V. Martínez-Vizcaíno, “Effectiveness of insulin glargine U- [84] B. Godman, A. Kurdi, H. McCabe et al., “Ongoing activities 300 versus insulin glargine U-100 on nocturnal hypoglycemia to influence the prescribing of proton pump inhibitors within and glycemic control in type 1 and type 2 diabetes: a system- the Scottish national health service: their effect and implica- atic review and meta-analysis,” Acta diabetologica., vol. 56, tions,” Generics and Biosimilars Initiative Journal., vol. 7, no. 3, pp. 355–364, 2019. no. 4, pp. 142–151, 2018. [73] G. B. Bolli, M. C. Riddle, R. M. Bergenstal et al., “New insulin [85] B. Godman, M. Wilcock, A. Martin et al., “Generic pregaba- glargine 300 U/ml compared with glargine 100 U/ml in lin; current situation and implications for health authorities, insulin-naïve people with type 2 diabetes on oral glucose- generics and biosimilars manufacturers in the future,” GaBI lowering drugs: a randomized controlled trial (EDITION Journal., vol. 4, no. 3, pp. 125–135, 2015. 3),” Diabetes, obesity & metabolism., vol. 17, no. 4, pp. 386– [86] Scottish Medicines Consortium, Insulin glargine 300 394, 2015. units/mL solution for injection in a pre-filled pen (Toujeo®), [74] A. Abitbol, R. E. Brown, D. Jiandani, L. Sauriol, and 2015, https://www.scottishmedicines.org.uk/media/1860/ R. Aronson, “Real-world health outcomes of insulin glargine insulin_glargine__toujeo_solostar__abbreviated_final_july_ 300 U/mL vs insulin glargine 100 U/mL in adults with type 1 2015_for_website.pdf. and type 2 diabetes in the Canadian LMC Diabetes Patient [87] H. H. P. Kluge, K. Wickramasinghe, H. L. Rippin et al., “Pre- Registry: the REALITY Study,” Canadian journal of diabetes, vention and control of non-communicable diseases in the vol. 43, no. 7, 2019. COVID-19 response,” Lancet, vol. 395, no. 10238, [75] R. Ritzel, R. Roussel, A. Giaccari, J. Vora, C. Brulle-Wohl- pp. 1678–1680, 2020. hueter, and H. Yki-Järvinen, “Better glycaemic control and [88] O. O. Ogunleye, D. Basu, D. Mueller et al., “Response to the less hypoglycaemia with insulin glargine 300 U/mL vs glar- novel corona virus (COVID-19) pandemic across Africa: suc- gine 100 U/mL: 1-year patient-level meta-analysis of the cesses, challenges, and implications for the future,” Frontiers EDITION clinical studies in people with type 2 diabetes,” in pharmacology, vol. 11, no. 1205, 2020. Diabetes, obesity & metabolism., vol. 20, no. 3, pp. 541– [89] B. Godman, A. Hill, S. Simoens et al., “Pricing of oral generic 548, 2018. cancer medicines in 25 European countries; findings and 14 BioMed Research International implications,” Generics and Biosimilars Initiative Journal., generics: impact and implications,” Frontiers in pharmacol- vol. 8, no. 2, pp. 49–70, 2019. ogy., vol. 5, 2014. [90] B. Godman, W. Shrank, M. Andersen et al., “Policies to [105] B. Godman, M. Petzold, K. Bennett et al., “Can authorities enhance prescribing efficiency in Europe: findings and future appreciably enhance the prescribing of oral generic risperi- implications,” Frontiers in pharmacology., vol. 1, 2011. done to conserve resources? Findings from across Europe [91] L. Vončina, T. Strizrep, B. Godman et al., “Influence of and their implications,” Medicine, vol. 12, no. 1, 2014. demand-side measures to enhance renin-angiotensin pre- [106] B. Godman, W. Shrank, M. Andersen et al., “Comparing pol- scribing efficiency in Europe: implications for the future,” icies to enhance prescribing efficiency in Europe through Expert review of pharmacoeconomics & outcomes research., increasing generic utilization: changes seen and global impli- vol. 11, no. 4, pp. 469–479, 2011. cations,” Expert review of pharmacoeconomics & outcomes [92] D. C. Baumgart, L. Misery, S. Naeyaert, and P. C. Taylor, research., vol. 10, no. 6, pp. 707–722, 2010. “Biological therapies in immune-mediated inflammatory dis- [107] B. Godman, I. Bishop, A. E. Finlayson, S. Campbell, H. Y. eases: can biosimilars reduce access inequities?,” Frontiers in Kwon, and M. Bennie, “Reforms and initiatives in Scotland pharmacology., vol. 10, p. 279, 2019. in recent years to encourage the prescribing of generic drugs, [93] M. Kostic, L. Djakovic, R. Sujic, B. Godman, and S. M. Janko- their influence and implications for other countries,” Expert vic, “Inflammatory bowel diseases (Crohn´s disease and review of pharmacoeconomics & outcomes research., vol. 13, ulcerative colitis): cost of treatment in Serbia and the implica- no. 4, pp. 469–482, 2013. tions,” Applied health economics and health policy., vol. 15, [108] B. Tubic, V. Markovic-Pekovic, S. Jungić, E. Allocati, and no. 1, pp. 85–93, 2017. B. Godman, “Availability and accessibility of monoclonal [94] M. Péntek, P. L. Lakatos, T. Oorsprong et al., “Access to bio- antibodies in Bosnia and Herzegovina: findings and implica- logicals in Crohn's disease in ten European countries,” World tions,” Medicine Access@Point of Care., vol. 5, Journal of Gastroenterology, vol. 23, no. 34, pp. 6294–6305, p. 239920262110276, 2021. 2017. [109] P. Vella Bonanno, M. Ermisch, B. Godman et al., “Adaptive [95] P. Putrik, S. Ramiro, T. K. Kvien et al., “Inequities in access to pathways: possible next steps for payers in preparation for biologic and synthetic DMARDs across 46 European coun- their potential implementation,” Frontiers in pharmacology, tries,” Annals of the rheumatic diseases., vol. 73, no. 1, vol. 8, p. 497, 2017. pp. 198–206, 2014. [110] A. Ferrario, D. Arāja, T. Bochenek et al., “The implementa- [96] F. Rencz, M. Péntek, M. Bortlik et al., “Biological therapy in tion of managed entry agreements in Central and Eastern inflammatory bowel diseases: access in Central and Eastern Europe: findings and implications,” PharmacoEconomics, Europe,” World Journal of Gastroenterology, vol. 21, no. 6, vol. 35, no. 12, pp. 1271–1285, 2017. pp. 1728–1737, 2015. [111] T. Bochenek, V. Abilova, A. Alkan et al., “Systemic Measures [97] D. Beran, R. O. Laing, W. Kaplan et al., “A perspective on and Legislative and Organizational Frameworks Aimed at global access to insulin: a descriptive study of the market, Preventing or Mitigating Drug Shortages in 28 European trade flows and prices,” Diabetic medicine., vol. 36, no. 6, and Western Asian Countries,” Frontiers in pharmacology., pp. 726–733, 2019. vol. 8, 2018. [98] S. Vogler and P. Schneider, “Assessing data sources for med- [112] C. Pontes, C. Zara, J. Torrent-Farnell et al., “Time to review icine price studies,” International journal of technology assess- authorisation and funding for new cancer medicines in ment in health care., vol. 35, no. 2, pp. 106–115, 2019. Europe? Inferences from the case of olaratumab,” Applied [99] K. Garuoliene, B. Godman, J. Gulbinovic, K. Schiffers, and health economics and health policy., vol. 18, no. 1, pp. 5–16, B. Wettermark, “Differences in utilization rates between 2020. commercial and administrative databases: implications for [113] B. Godman, M. Haque, S. Kumar et al., “Current utilization future health-economic and cross-national studies,” Expert patterns for long-acting insulin analogues including biosimi- review of pharmacoeconomics & outcomes research., vol. 16, lars among selected Asian countries and the implications for no. 2, pp. 149–152, 2016. the future,” Current medical research and opinion., pp. 1–17, [100] WHO, “WHO Collaborating Centre for Drug Statistics 2021. Methodology,” ATC/ DDD Indexhttps://www.whocc.no/. [114] M. Haque, S. Kumar, J. Charan et al., “Utilisation, availability [101] WHO, “WHO Collaborating Centre for Drug Statistics and price changes of medicines and protection equipment for Methodology,” Guidelines for ATC classification and DDD COVID-19 Among Selected Regions in India: findings and assignment, 2021, https://www.whocc.no/filearchive/ implications,” Frontiers in pharmacology, vol. 11, no. 1822, publications/2021_guidelines_web.pdf. 2021. [102] H. Neville and S. C. Trenaman, “Drug utilization research: [115] B. Godman, M. Haque, S. Islam et al., “Rapid assessment of methods and applications,” The Canadian journal of hospital price instability and paucity of Medicines and protection for pharmacy, vol. 70, no. 4, p. 325, 2017. COVID-19 across Asia: findings and public health implica- [103] S. Gupta, H. Wang, N. Skolnik et al., “Treatment dosing pat- tions for the future,” Frontiers in Public Health, vol. 8, terns and clinical outcomes for patients with type 2 diabetes no. 744, 2020. starting or switching to treatment with insulin glargine (300 [116] M. Gad, A. Salem, W. Oortwijn, R. Hill, and B. Godman, units per milliliter) in a real-world setting: a retrospective “Mapping of current obstacles for rationalizing use of medi- observational study,” Advances in Therapy, vol. 35, no. 1, cines (CORUM) in Europe: current situation and potential pp. 43–55, 2018. solutions,” Frontiers in pharmacology, vol. 11, no. 144, 2020. [104] J. C. Moon, B. Godman, M. Petzold et al., “Different initia- [117] NHS Scotland, Quality Prescribing for Diabetes - A Guide for tives across Europe to enhance losartan utilization post Improvement 2018 - 2021, 2018, https://www.therapeutics BioMed Research International 15 .scot.nhs.uk/wp-content/uploads/2018/03/Strategy- .com/24011/top-biosimilar-companies-with-approved-and- Diabetes-Quality-Prescribing-for-Diabetes-2018.pdf. pipeline-products-in-the-us-and-eu/. [118] A. Leporowski, B. Godman, A. Kurdi et al., “Ongoing activi- [132] S. A. Schreiber and A. Russmann, “Long-term efficacy of ties to optimize the quality and efficiency of lipid-lowering insulin glargine therapy with an educational programme agents in the Scottish national health service: influence and in type 1 diabetes patients in clinical practice,” Current implications,” Expert review of pharmacoeconomics & out- medical research and opinion., vol. 23, no. 12, pp. 3131– comes research., vol. 18, no. 6, pp. 655–666, 2018. 3136, 2007. [119] B. Godman, M. Persson, J. Miranda et al., “Changes in the [133] M. Woerkom, H. Piepenbrink, B. Godman et al., “Ongoing utilization of venlafaxine after the introduction of generics measures to enhance the efficiency of prescribing of proton in Sweden,” Applied health economics and health policy., pump inhibitors and statins in The Netherlands: influence vol. 11, no. 4, pp. 383–393, 2013. and future implications,” Journal of comparative effectiveness [120] B. Godman, B. Wettermark, J. Miranda, M. Bennie, research., vol. 1, no. 6, pp. 527–538, 2012. A. Martin, and R. E. Malmstrom, “Influence of multiple ini- [134] P. Dylst and S. Simoens, “Does the market share of generic tiatives in Sweden to enhance ARB prescribing efficiency fol- medicines influence the price level?: a European analysis,” lowing generic losartan; findings and implications for other PharmacoEconomics, vol. 29, no. 10, pp. 875–882, 2011. countries,” International journal of clinical practice., vol. 67, [135] U. Hesse, B. Godman, M. Petzold, A. Martin, and R. E. Mal- no. 9, pp. 853–862, 2013. mstrom, “Impact of delisting ARBs, apart from losartan, on [121] K. Garuoliene, B. Godman, J. Gulbinovic, B. Wettermark, and ARB utilisation patterns in Denmark: implications for other A. Haycox, “European countries with small populations can countries,” Applied health economics and health policy., obtain low prices for drugs: Lithuania as a case history,” vol. 11, no. 6, pp. 677–685, 2013. Expert review of pharmacoeconomics & outcomes research., [136] J. Fürst, M. Čižman, J. Mrak et al., “The influence of a sus- vol. 11, no. 3, pp. 343–349, 2011. tained multifaceted approach to improve antibiotic prescrib- [122] B. Godman, B. Wettermark, M. van Woerkom et al., “Multi- ing in Slovenia during the past decade: findings and ple policies to enhance prescribing efficiency for established implications,” Expert review of anti-infective therapy., medicines in Europe with a particular focus on demand- vol. 13, no. 2, pp. 279–289, 2015. side measures: findings and future implications,” Frontiers [137] B. Godman, S. Sakshaug, C. Berg, B. Wettermark, and in pharmacology., vol. 5, 2014. A. Haycox, “Combination of prescribing restrictions and pol- [123] V. Marković-Peković, R. Škrbić, A. Petrović et al., “Polyphar- icies to engineer low prices to reduce reimbursement costs,” macy among the elderly in the Republic of Srpska: extent and Expert review of pharmacoeconomics & outcomes research., implications for the future,” Expert review of pharmacoeco- vol. 11, no. 1, pp. 121–129, 2011. nomics & outcomes research., vol. 16, no. 5, pp. 609–618, [138] B. Wettermark, B. Godman, M. Neovius, N. Hedberg, T. O. 2016. Mellgren, and T. Kahan, “Initial effects of a reimbursement [124] IQVIA, The Impact of Biosimilar Competition in Europe, restriction to improve the cost- effectiveness of antihyperten- 2019, https://ec.europa.eu/docsroom/documents/38461. sive treatment,” Health Policy, vol. 94, no. 3, pp. 221–229, [125] A. Harsanyi, M. Csanadi, K. Marky, A. Z. Vincziczki, Z. Kalo, 2010. and A. Inotai, “Influence of biosimilar infliximab launch on [139] E. Eatwell and A. Swierczyna, “Emerging voluntary coopera- the utilization pattern of biological medicines: the case of tion between European healthcare systems: are we facing a Hungary,” Expert review of pharmacoeconomics & outcomes new future?,” Medicine Access@Point of Care, vol. 3, research., vol. 20, no. 6, pp. 653–659, 2020. p. 239920261985231, 2019. [126] P. Kawalec, E. Stawowczyk, T. Tesar et al., “Pricing and [140] J. F. O’Mahony, “Beneluxa: what are the prospects for collec- Reimbursement of Biosimilars in Central and Eastern Euro- tive bargaining on pharmaceutical prices given diverse health pean Countries,” Frontiers in pharmacology., vol. 8, p. 288, technology assessment processes?,” PharmacoEconomics, 2017. vol. 37, no. 5, pp. 627–630, 2019. [127] A. Bertolani and C. Jommi, “Local policies on biosimilars: are [141] WHO, WHO Guideline on Country Pharmaceutical Pricing they designed to optimize use of liberated resources?,” Policies, World Health Organization, Geneva, second edition, Generics and Biosimilars Journal (GaBI)., vol. 9, no. 4, 2020, https://apps.who.int/iris/bitstream/handle/10665/ pp. 163–170, 2020. 335692/9789240011878-eng.pdf. [128] B. Godman, E. Allocati, E. Moorkens, and H.-Y. Kwon, [142] S. Singh, Biocon’s Malaysia insulin glargine manufacturing “Can local policies on biosimilars optimize the use of freed facility receives EU GMP certification, 2019, https:// resources – experiences from Italy,” Generics and Biosimi- indiamedtoday.com/biocons-malaysia-insulin-glargine- lars Initiative Journal (GABI)., vol. 9, no. 4, pp. 183–187, manufacturing-facility-receives-eu-gmp-certification/. 2020. [143] S. Opanga, L. W. Njeri, D. Kimonge, B. Godman, and [129] R. E. Ferner, W. Lenney, and J. F. Marriott, “Controversy over M. Oluka, “Assessing utilisation and expenditure on long- generic substitution,” BMJ, vol. 340, no. jun01 1, p. c2548, acting insulin analogues in Kenya; findings and implications 2010. for the future,” Scholars Academic Journal of Pharmacy, [130] IQVIA, Country Scorecards for Biosimilar Sustainability, vol. 10, no. 4, pp. 63–70, 2021. 2020, https://www.iqvia.com/-/media/iqvia/pdfs/institute- [144] Department of Health Republic of South Africa, National reports/country-scorecards-for-biosimilar-sustainability/ Essential Medicines List Committee (NEMLC) - Tertiary and iqvia-institute-scorecards-appendix-orb2520.pdf?la=en. Quaternary Level Essential Medicines List Reviewed Items, [131] V. Singh, Top biosimilar companies with approved and pipe- 2021, https://www.knowledgehub.org.za/system/files/ line products in the US and EU, 2019, https://pharmashots elibdownloads/2021-04/Tertiary%20and%20Quaternary% 16 BioMed Research International 20Level%20Essential%20Medicine%20Recommendations_ April%202021.pdf. [145] D. Beran, M. Ewen, K. Lipska, I. B. Hirsch, and J. S. Yudkin, “Availability and affordability of essential medicines: implica- tions for global diabetes treatment,” Current diabetes reports., vol. 18, no. 8, 2018. [146] B. Godman, J. Fadare, H. Y. Kwon et al., “Evidence-based public policy making for medicines across countries: findings and implications for the future,” Journal of comparative effec- tiveness research., vol. 10, no. 12, pp. 1019–1052, 2021.