ORIGINAL RESEARCH published: 24 June 2021 doi: 10.3389/fpubh.2021.671961 The Current Situation Regarding Long-Acting Insulin Analogues Including Biosimilars Among African, Asian, European, and South American Countries; Findings and Implications for the Future Brian Godman 1,2,3*† , Mainul Haque 4† , Trudy Leong 5† , Eleonora Allocati 6 , Santosh Kumar 7† , Salequl Islam 8† , Jaykaran Charan 9† , Farhana Akter 10† , Amanj Kurdi 1,2,11† , Carlos Vassalo 12 , Muhammed Abu Bakar 13† , Sagir Abdur Rahim 14† , Nusrat Sultana 15† , Farzana Deeba 16† , M. A. Halim Khan 17† , A. B. M. Muksudul Alam 17† , Iffat Jahan 18† , Zubair Mahmood Kamal 19† , Humaira Hasin 20† , Munzur-E-Murshid 21† , Shamsun Nahar 8† , Monami Haque 22† , Edited by: Siddhartha Dutta 9† , Jha Pallavi Abhayanand 9† , Rimple Jeet Kaur 9† , Roza Adany, Godfrey Mutashambara Rwegerera 23,24† , University of Debrecen, Hungary Renata Cristina Rezende Macedo do Nascimento 25† , Isabella Piassi Dias Godói 26,27† , Reviewed by: Mohammed Irfan 28† , Adefolarin A. Amu 29† , Patrick Matowa 29 , Joseph Acolatse 30† , Mohamed Izham Mohamed Ibrahim, Robert Incoom 30 , Israel Abebrese Sefah 31,32† , Jitendra Acharya 33 , Sylvia Opanga 34 , Qatar University, Qatar Lisper Wangeci Njeri 35† , David Kimonge 34 , Hye-Young Kwon 36† , SeungJin Bae 37† , Piotr Romaniuk, Karen Koh Pek Khuan 38† , Abdullahi Rabiu Abubakar 39† , Ibrahim Haruna Sani 40† , Medical University of Silesia, Poland Tanveer Ahmed Khan 41 , Shahzad Hussain 41 , Zikria Saleem 42† , Oliver Ombeva Malande 43,44 , Michael Ekubu Otim, Thereza Piloya-Were 45† , Rosana Gambogi 46† , Carla Hernandez Ortiz 46 , Luke Alutuli 47 , University of Sharjah, Aubrey Chichonyi Kalungia 48† , Iris Hoxha 49 , Vanda Marković-Peković 50† , Biljana Tubic 51,52 , United Arab Emirates Guenka Petrova 53 , Konstantin Tachkov 53 , Ott Laius 54 , András Harsanyi 55 , András Inotai 56,57 , *Correspondence: Arianit Jakupi 58† , Svens Henkuzens 59 , Kristina Garuoliene 60 , Jolanta Gulbinovič 61† , Brian Godman Magdalene Wladysiuk 62,63 , Jakub Rutkowski 63 , Ileana Mardare 64† , Jurij Fürst 65 , brian.godman@strath.ac.uk Stuart McTaggart 66 , Sean MacBride-Stewart 67† , Caridad Pontes 68,69† , Corinne Zara 68† , Received: 24 February 2021 Eunice Twumwaa Tagoe 70† , Rita Banzi 6† , Janney Wale 71 and Mihajlo Jakovljevic 72,73† Accepted: 29 April 2021 1 Published: 24 June 2021 Department of Pharmacoepidemiology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom, 2 Division of Public Health Pharmacy and Management, School of Pharmacy, Sefako † ORCID: Makgatho Health Sciences University, Pretoria, South Africa, 3 School of Pharmaceutical Sciences, Universiti Sains Malaysia, Brian Godman George Town, Malaysia, 4 Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional orcid.org/0000-0001-6539-6972 Malaysia (National Defence University of Malaysia), Kuala Lumpur, Malaysia, 5 Essential Drugs Programme, South African Mainul Haque National Department of Health, Pretoria, South Africa, 6 Center for Health Regulatory Policies, Istituto di Ricerche orcid.org/0000-0002-6124-7993 Farmacologiche “Mario Negri” IRCCS, Milan, Italy, 7 Department of Periodontology and Implantology, Karnavati University, Trudy Leong Gandhinagar, India, 8 Department of Microbiology, Jahangirnagar University, Dhaka, Bangladesh, 9 Department of orcid.org/0000-0003-2687-7751 Pharmacology, All India Institute of Medical Sciences, Jodhpur, India, 10 Department of Endocrinology, Chittagong Medical Santosh Kumar College, Chittagong, Bangladesh, 11 Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, orcid.org/0000-0002-5117-7872 Iraq, 12 Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina, 13 Department of Endocrinology Salequl Islam and Metabolism, Chattogram Maa-O-Shishu Hospital Medical College, Chattogram, Bangladesh, 14 Bangladesh Institute of orcid.org/0000-0001-6131-4132 Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders General Hospital, Dhaka, Bangladesh, 15 Jaykaran Charan Department of Endocrinology and Metabolism, Bangabandhu Sheik Mujib Medical University Hospital, Dhaka, Bangladesh, 16 orcid.org/0000-0002-4857-6725 Department of Obstetrics and Gynaecology, Bangabandhu Sheik Mujib Medical University, Dhaka, Bangladesh, 17 Shaheed Farhana Akter Suhrawardy Medical College Hospital, Dhaka, Bangladesh, 18 Department of Physiology, Eastern Medical College, Cumilla, orcid.org/0000-0002-4488-9388 Bangladesh, 19 National Institute of Mental Health (NIMH), Dhaka, Bangladesh, 20 Clinical Fellow, Epsom and St Helier Amanj Kurdi University Hospitals NHS Trust, Surrey, United Kingdom, 21 Women’s Integrated Sexual Health (WISH) 2 Access Choice orcid.org/0000-0001-5036-1988 Together Innovate Ownership Now (ACTION) Project, Handicap International, Kurigram, Bangladesh, 22 Human Resource Muhammed Abu Bakar Department, Square Toiletries Limited, Rupayan Center, Dhaka, Bangladesh, 23 Department of Medicine, Sir Ketumile Masire orcid.org/0000-0003-3127-3522 Teaching Hospital, Gaborone, Botswana, 24 Faculty of Medicine, University of Botswana, Gaborone, Botswana Frontiers in Public Health | www.frontiersin.org 1 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries 25 Department of Pharmacy, Postgraduate Program in Pharmaceutical Sciences (CiPharma), School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Brazil, 26 Institute of Health and Biological Studies, Universidade Federal do Sul e Sudeste do Pará, Cidade Universitária, Marabá, Brazil, 27 Group (CNPq) for Epidemiological, Economic and Pharmacological Sagir Abdur Rahim Studies of Arboviruses (EEPIFARBO), Universidade Federal do Sul e Sudeste do Pará, Marabá, Brazil, 28 Faculdade de orcid.org/0000-0002-4601-6417 Odontologia, Universidade Federal de Pelotas, Pelotas, Brazil, 29 Pharmacy Department, Eswatini Medical Christian Nusrat Sultana University, Mbabane, Eswatini, 30 Cape Coast Teaching Hospital (CCTH), Cape Coast, Ghana, 31 Pharmacy Department, Keta orcid.org/0000-0002-6858-2110 Municipal Hospital, Ghana Health Service, Keta-Dzelukope, Ghana, 32 Pharmacy Practise Department of Pharmacy Practise, Farzana Deeba School of Pharmacy, University of Health and Allied Sciences, Volta Region, Ghana, 33 Department of Dentistry, SP Medical orcid.org/0000-0001-8434-6292 College, Bikaner, India, 34 Department of Pharmaceutics and Pharmacy Practise, School of Pharmacy, University of Nairobi, M. A. Halim Khan Nairobi, Kenya, 35 Department of Pharmacy, Kenyatta National Hospital, Nairobi, Kenya, 36 Division of Biology and Public orcid.org/0000-0002-3459-270 Health, Mokwon University, Daejeon, South Korea, 37 College of Pharmacy, Ewha Woman’s University, Seoul, South Korea, A. B. M. Muksudul Alam 38 Friends’ Pharmacy Pekan Sg Besi 42G, Kuala Lumpur, Malaysia, 39 Department of Pharmacology and Therapeutics, orcid.org/0000-0002-7309-8382 Faculty of Pharmaceutical Sciences, Bayero University, Kano, Nigeria, 40 Unit of Pharmacology, College of Health Sciences, Iffat Jahan Yusuf Maitama Sule University (YUMSUK), Kano, Nigeria, 41 National Institute of Health, Islamabad, Pakistan, 42 Department of orcid.org/0000-0003-0551-3609 Pharmacy Practise, Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan, 43 Department of Child Health and Zubair Mahmood Kamal Paediatrics, Egerton University, Nakuru, Kenya, 44 East Africa Centre for Vaccines and Immunisation (ECAVI), Kampala, orcid.org/0000-0001-9659-2925 Uganda, 45 Paediatric Endocrinologist, School of Medicine, College of Health Sciences, Makerere University, Kampala, Humaira Hasin Uganda, 46 National Resources Fund (FNR), Montevideo, Uruguay, 47 University Teaching Hospital Group, Department of orcid.org/0000-0002-7736-3315 Pharmacy, Lusaka, Zambia, 48 Department of Pharmacy, School of Health Sciences, University of Zambia, Lusaka, Zambia, Munzur-E-Murshid 49 Department of Pharmacy, Faculty of Medicine, University of Medicine, Tirana, Albania, 50 Department of Social Pharmacy, orcid.org/0000-0001-5503-7757 Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina, 51 Agency for Medicinal Products and Shamsun Nahar Medical Devices of Bosnia and Herzegovina, Banja Luka, Bosnia and Herzegovina, 52 Department of Medicinal Chemistry, orcid.org/0000-0002-3580-5576 Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina, 53 Department of Social Pharmacy and Monami Haque Pharmacoeconomics, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria, 54 State Agency of Medicines, Tartu, orcid.org/0000-0002-7970-6094 Estonia, 55 Department of Health Policy and Health Economics, Eotvos Lorand University, Budapest, Hungary, 56 Syreon Siddhartha Dutta Research Institute, Budapest, Hungary, 57 Center of Health Technology Assessment, Semmelweis University, Budapest, orcid.org/0000-0001-6525-5950 Hungary, 58 Faculty of Pharmacy, UBT Higher Education Institute, Pristina, Kosovo, 59 Independent Researcher, Riga, Latvia, Jha Pallavi Abhayanand 60 Department of Pharmacy, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania, orcid.org/0000-0002-6936-3315 61 Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Rimple Jeet Kaur Vilnius University, Vilnius, Lithuania, 62 Chair of Epidemiology and Preventive Medicine Jagiellonian University, Medical College, orcid.org/0000-0003-4478-1411 Kraków, Poland, 63 HTA Consulting, Kraków, Poland, 64 Faculty of Medicine, Public Health and Management Department, Godfrey Mutashambara Rwegerera “Carol Davila” University of Medicine and Pharmacy Bucharest, Bucharest, Romania, 65 Health Insurance Institute, Ljubljana, orcid.org/0000-0002-5896-6065 Slovenia, 66 Public Health Scotland, Edinburgh, United Kingdom, 67 Pharmacy Services, Greater Glasgow and Clyde (NHS Renata Cristina Rezende Macedo do GGC), Glasgow, United Kingdom, 68 Drug Department, Catalan Health Service, Barcelona, Spain, 69 Department of Nascimento Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain, 70 Department of orcid.org/0000-0001-7756-2157 Management Science, Business School, University of Strathclyde, Glasgow, United Kingdom, 71 Independent Consumer Isabella Piassi Dias-Godói Advocate, Brunswick, VIC, Australia, 72 Department of Global Health Economics and Policy, University of Kragujevac, orcid.org/0000-0002-0568-6625 Kragujevac, Serbia, 73 Faculty of Economics, Institute of Comparative Economic Studies, Hosei University Tokyo, Mohammed Irfan Tokyo, Japan orcid.org/0000-0003-0683-106X Adefolarin A. Amu orcid.org/0000-0003-3212-2283 Background: Diabetes mellitus rates continue to rise, which coupled with increasing Joseph Acolatse orcid.org/0000-0001-6556-3208 costs of associated complications has appreciably increased global expenditure in recent Israel Abebrese Sefah years. The risk of complications are enhanced by poor glycaemic control including orcid.org/0000-0001-6963-0519 hypoglycaemia. Long-acting insulin analogues were developed to reduce hypoglycaemia Lisper Wangeci Njeri orcid.org/0000-0002-1559-2788 and improve adherence. Their considerably higher costs though have impacted their Hye-Young Kwon funding and use. Biosimilars can help reduce medicine costs. However, their introduction orcid.org/0000-0001-9772-1354 SeungJin Bae has been affected by a number of factors. These include the originator company dropping orcid.org/0000-0002-8993-8884 its price as well as promoting patented higher strength 300 IU/ml insulin glargine. There Karen Koh Pek Khuan can also be concerns with different devices between the manufacturers. orcid.org/0000-0002-3634-2083 Abdullahi Rabiu Abubakar Objective: To assess current utilisation rates for insulins, especially long-acting insulin orcid.org/0000-0002-9740-7856 Ibrahim Haruna Sani analogues, and the rationale for patterns seen, across multiple countries to inform orcid.org/0000-0003-1153-5900 strategies to enhance future utilisation of long-acting insulin analogue biosimilars to Zikria Saleem benefit all key stakeholders. orcid.org/0000-0003-3202-6347 Thereza Piloya-Were Our approach: Multiple approaches including assessing the utilisation, expenditure orcid.org/0000-0002-9818-093X Rosana Gambogi and prices of insulins, including biosimilar insulin glargine, across multiple continents orcid.org/0000-0003-0781-7745 and countries. Frontiers in Public Health | www.frontiersin.org 2 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries Results: There was considerable variation in the use of long-acting insulin analogues as Aubrey Chichonyi Kalungia a percentage of all insulins prescribed and dispensed across countries and continents. orcid.org/0000-0003-2554-1236 Vanda Marković-Peković This ranged from limited use of long-acting insulin analogues among African countries orcid.org/0000-0001-8963-5720 compared to routine funding and use across Europe in view of their perceived benefits. Arianit Jakupi orcid.org/0000-0002-7719-9690 Increasing use was also seen among Asian countries including Bangladesh and India for Jolanta Gulbinovič similar reasons. However, concerns with costs and value limited their use across Africa, orcid.org/0000-0003-3776-6934 Brazil and Pakistan. There was though limited use of biosimilar insulin glargine 100 IU/ml Ileana Mardare orcid.org/0000-0002-4725-9808 compared with other recent biosimilars especially among European countries and Korea. Sean MacBride-Stewart This was principally driven by small price differences in reality between the originator orcid.org/0000-0002-2553-5939 Caridad Pontes and biosimilars coupled with increasing use of the patented 300 IU/ml formulation. A orcid.org/0000-0002-3274-6048 number of activities were identified to enhance future biosimilar use. These included only Corrine Zara reimbursing biosimilar long-acting insulin analogues, introducing prescribing targets and orcid.org/0000-0002-6831-2233 Eunice Twumwaa Tagoe increasing competition among manufacturers including stimulating local production. orcid.org/0000-0002-2198-4980 Rita Banzi Conclusions: There are concerns with the availability and use of insulin glargine orcid.org/0000-0002-2211-3300 biosimilars despite lower costs. This can be addressed by multiple activities. Mihajlo Jakovljevic orcid.org/0000-0002-9160-6846 Keywords: Africa, biosimilars, cross-national study, drug utilisation, Europe, health policy, insulin glargine, prices INTRODUCTION 100 IU/ml insulin glargine (22). Global sales of insulin detemir were US$2.7 billion in 2015 and growing at 7.5% per year (23), Prevalence rates for diabetes mellitus continue to rise across and annual sales of insulin degludec are also growing. Sales of countries and continents (1–7). This has been exacerbated by insulin degludec grew 1.8-fold in 2017 vs. 2016, rising to US$1.11 over 100% increases in incident cases of diabetes mellitus from billion in 2017 (24). This increase has been supported by studies 1990, rising to 22.936 million in 2017 (8), which has resulted demonstrating the cost-effectiveness of degludec compared with in an estimated 463 million people worldwide with diabetes other long-acting insulin analogues (25–28). mellitus in 2019 (8, 9). These prevalence rates are expected to However, there are concerns in some countries regarding grow unless addressed. The costs of medicines to treat patients the additional costs of long-acting insulin analogues vs. Neutral with diabetes, coupled with the cost of associated complications, Protamine Hagedorn (NPH) and other insulins, and whether has increased the global economic burden of diabetes, including these additional costs represent value (29, 30). These concerns both direct and indirect costs, from US$1.3 trillion in 2015 to and issues are reflected by long-acting insulin analogues currently an estimated US$2.1 to US$2.5 trillion by 2030, equating to not being included in the World Health Organization Essential 2.2% of Gross Domestic Product (GDP), with most costs as Medicines List (WHO EML) (31). In addition, long-acting indirect costs (10, 11). The high economic burden of diabetes insulin analogues have not been funded in the public healthcare is amplified by diabetes currently among the leading causes system in Brazil following advice from the National Health of non-traumatic lower-extremity amputation and blindness Technology Agency (CONITEC) as the considerably higher price worldwide, with patients also at greater risk of cardiovascular could not be justified by only modest additional patient benefits disease (9). In view of this, patients with diabetes should be (32, 33). Consequently, patients in Brazil have been required to carefully managed. This increasingly includes greater use of long- fund the costs of long-acting insulin analogues themselves unless acting insulin analogues, which were developed to reduce the there is a successful court case (29). Alongside this, there have risk of hypoglycaemia, especially nocturnal hypoglycaemia, and been calls for disinvestment in insulin glargine (29); however, this provide greater convenience for patients with a reduced number is changing (34). The same situation persists in Bangladesh where of injections (9, 12–17). the Government only funds NPH and other insulins in public As a result, we are now seeing usage of long-acting hospitals until funds run out, and in parts of India (18, 35). insulins exceed human insulins in upper-middle and high- Similarly, long-acting insulin analogues are currently not income countries (18–20). This increase, combined with growing funded within the public healthcare systems in South Africa and prevalence rates, has resulted in the global insulin market valued Zambia due again to concerns with higher costs than basal/ at US$24 billion in 2018 and envisaged to grow at a compounded NPH insulins and no perceived clinical advantage (20, 36), rate of 4.9% (8, 21). Expenditure on long-acting insulin glargine with limited funding and use generally of long-acting insulin is also growing and envisaged to reach up to US$9.26 billion analogues across Africa (37). This mirrors the findings of Ewen by 2025 (22), assisted by increasing sales of patented 300 IU/ml et al. (18), who showed considerable price differences between insulin glargine (Toujeo R —Gla-300). Increasing use of Gla-300 human insulins (US$5 per 10 mL of 100 IU/mL) and long- has helped offset losses from the increasing sales of biosimilar acting insulin analogues among a range of lower- and middle- Frontiers in Public Health | www.frontiersin.org 3 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries income countries (LMICs) (US$33), which limited their funding IU/ml formulation. In addition, improving patient comfort and and use. The situation is exacerbated across Africa and other convenience (62). Published studies have shown that Gla-300 LMICs by concerns with access and availability of insulins does improve glycaemic control alongside reducing the incidence including NPH and short-acting insulins in the first place as of nocturnal hypoglycaemia vs. the 100 IU/ml formulation (25, well as limited facilities and equipment to diagnose diabetes 62–65). However, some authors and health authorities are not and enable patients to regularly monitor their insulin levels to convinced of the benefits of Gla-300 (66), and have restricted its reduce hypoglycaemia (18, 36, 38–41). However, some studies prescribing vs. the 100 IU/ml formulation (67). Overall, these have shown that the higher acquisition costs of long-acting combined factors appear to have reduced the attractiveness of insulin analogues can potentially be offset by savings from the 100 IU/ml market to biosimilar manufacturers as well as averted costs of hypoglycaemia and other diabetes-associated reduced potential savings from the availability of biosimilar complications (42–45). insulin glargine 100 IU/ml. However, this is not universal with Biosimilars are a potential way forward to reduce the costs some commissioning groups in England in December 2018 of long-acting insulin analogues, similar to other situations already achieving utilisation rates of 53.3% for biosimilar insulin (46–48), thereby potentially enhancing their reimbursement glargine vs. total insulin glargine (68). In the US, usage of the and funding. As an example, among hospitals in Denmark, biosimilar insulin glargine reached over 40% of the total insulin expenditure on adalimumab decreased by 82.8% from September glargine public market by 2018 (54). 2018 to December 2018 with a switch to adalimumab biosimilars The first priority within a country should be to ensure that at considerably lower prices (46). In England, the uptake of NPH insulin and other standard insulins, along with other biosimilars has appreciably increased with multiple activities essential medicines listed in the WHO EML to treat patients with among health authorities and other key stakeholder groups, diabetes and associated co-morbidities, are readily accessible and which include education and prescribing targets for biosimilars available to all citizens. This is not always the case as seen among (49). These multiple activities enhancing biosimilar use resulted several African countries unless there are access programmes in estimated savings from infliximab, etanercept and rituximab in (69–72). In addition, there is the necessary equipment and England at GB£99.4, GB£60.3, and GB£50.4 million, respectively, facilities to rapidly diagnosis diabetes, especially given levels in 2017 (48). Expenditure on adalimumab is also envisaged to of misdiagnosis among a number of LMICs (73, 74), as well fall by 75% in England following the availability of biosimilars as enable patients to routinely monitor their insulin levels at combined with multiple demand-side measures to encourage home to prevent complications (37). This is before considering their prescribing (48). In the USA, Claytor and Gellad recently funding more expensive long-acting insulin analogues given the calculated that greater use of biosimilars could save up to US$54 morbidity and mortality associated with diabetes (75). However, billion over the next 10 years (50, 51). Realising these savings the situation can be very different among a number of Asian and though includes addressing any concerns with biosimilars European countries. including any misinformation and its impact on any nocebo Consequently, in view of the many issues and challenges effect (52). identified, we believe there is a need to assess current utilisation However, we have seen in practise that potential savings and expenditure patterns for long-acting insulin analogues across from biosimilar insulin glargine can be limited. In their countries and continents, including biosimilars, and the rationale study, Ewen et al. (18) found among a range of LMICs that for the patterns seen. This includes their funding and use in median biosimilar prices for insulin glargine in the public multiple LMICs building on the studies of Ewen et al. (18). sector ranged from only 2–25% lower than the originator Subsequently, investigate the extent of current price reductions depending on the presentation, with sometimes higher prices and other activities among originator and biosimilar companies for biosimilars in private pharmacies. This matches limited price to enhance the affordability and use of long-acting insulin reductions for biosimilar insulin glargine seen in other markets, analogues. The objective being to suggest potential activities that which are easily matched by the originator company reducing could be introduced among all key stakeholder groups to enhance their attractiveness (53). Besides, there can be concerns with future availability and use of biosimilar long-acting insulin switching patients between originators and biosimilars due to analogues across countries to the benefit of all key stakeholder different devices and the potential for hypoglycaemia in some groups. This includes potential strategies to enhance funding and countries (53–56); however, this is not universal (35). Concerns use of lower cost biosimilars, which will likely vary by country regarding the different devices resulted in, for instance, low and considerations including those countries where affordability use of insulin glargine biosimilars (9%) among diabetologists is a key consideration. in the UK in 2017 (57). Consequently, some European health authorities have advised against switching between METHODOLOGY originator and biosimilar insulin glargine despite publications demonstrating similar effectiveness and safety between We adopted a mixed approach to collect utilisation and them (58–61). expenditure data for insulins in general, and long-acting We are also aware that the parent company has launched insulin analogues in particular, across a range of countries and a patented 300 IU/ml formulation of insulin glargine (Gla- continents, and the subsequent rationale for the patterns seen. 300) to further reduce the risk of hypoglycaemia given its We focused on insulin glargine among the long-acting insulin longer half-life and more stable bioavailability vs. the 100 analogues as there are biosimilars currently available across Frontiers in Public Health | www.frontiersin.org 4 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries countries. There has also been calls for insulin glargine to be as well as financial consequences when family members become disinvested in view of appreciably increased costs vs. NPH and ill (97–99). other insulins and limited perceived additional value (29). Pricing and utilisation data were also included from a range The European regions selected included both Western of South American and African countries since long-acting European and Central and Eastern European (CEE) countries insulin analogues are not routinely listed or reimbursed within as they constitute a range of countries with different economic the public healthcare systems in a number of these countries powers, geographies and populations (76) to robustly compare or recommended in national treatment guidelines (20, 37, 100, and contrast the different approaches to long-acting insulin 101), although this is changing. Since originator or biosimilar analogues and biosimilar insulin glargine preparations. long-acting insulin analogues in these countries are typically However, the principal focus was on CEE countries as dispensed in private community pharmacies or drugs stores, there has been appreciably lower utilisation of originator or in private hospitals, feedback from physicians, pharmacists biologic medicines among these countries vs. Western and key personnel working within pharmacies, combined with European countries given their high costs and associated local knowledge, has been used to provide information on high patient co-payments (77–79). Consequently, there utilisation and prices of the different long-acting insulin analogue should be greater potential for long-acting insulin biosimilar preparations together with changes in recent years and any analogues among CEE countries. The limited number of rationale. We have used this approach before when national Western European countries and regions for comparative datasets are not routinely available (97–99, 102). Similar to purposes included Italy, Spain (Catalonia) and the UK previous projects, impressions were provided from physicians (Scotland). These countries and regions were chosen as and pharmacists when no Ministry of Health or other robust data they have instigated multiple activities to enhance biosimilar use sets were available to document changes in utilisation and prices (54, 80–83). of insulin glargine as well as other insulin preparations in recent The data collection approach was opportunistic and adapted years. That is, if other information sources were unavailable due depending on the availability and access of pertinent data to issues of confidentiality and local culture since we were not across countries, as well as the situation within countries. paying physicians or pharmacy personnel for their time (35, 97– Among the European countries, the principal focus was on 99). The data from community pharmacies and drug stores have reimbursed utilisation and expenditure data. Utilisation and been supplemented with utilisation and expenditure data from expenditure data was based on health authority and health hospitals where available. The hospitals were typically selected insurance company data. We have extensively used these to provide a representation of the situation within a country. In databases in the past as they provide robust data sets which Brazil, Korea and Pakistan, data was extracted from the MIDAS- are regularly audited (76, 84, 85). Consequently, these databases IQVIA International database as well as government sources to are seen as a reliable source for comparing utilisation and provide current data on utilisation and expenditure patterns. In expenditure data across countries (84). The only exception in the case of Korea, this builds on a recent study with infliximab Europe was Kosovo where the data was based on imports. biosimilar (103). This is because formal reimbursement of medicines has not Feedback from the senior-level co-authors and some of the yet started in Kosovo; hopefully, by the end of 2021 or community pharmacists involved in the study will be also used the first quarter of 2022. We have used this approach in to suggest potential ways to enhance future listing, funding Kosovo in previous studies (86, 87). Utilisation data where and use of long-acting insulin analogues including biosimilars available was broken down into Defined Daily Doses (DDDs) where currently these are not available/not routinely funded to aid comparisons between countries. DDDs are a well- and used within public healthcare systems to the benefit of all recognised measure for comparing utilisation patterns between key stakeholders. countries (88, 89). We have used DDDs before in multiple Ethical approval for this study was not required according publications when assessing utilisation and expenditure patterns to national legislation and institutional guidelines in line across disease areas and countries (76, 90–95). Expenditure with previous studies in similar circumstances (97–99, 102, and pricing data typically remained in the local currency 104, 105). However, where pertinent, all pharmacists freely across Europe without conversion to either Euros or US$ as provided the requested information having been allowed to the principal focus especially in Europe was on percentage refuse to participate if wished. This is in line with previous differences in reimbursed prices over time between the originator studies undertaken by the co-authors in this and related and the different biosimilars rather than actual price levels. areas, which include analysis of policies to enhance the Pricing data has also been collected for a number of African rationale use of medicines and biosimilars, pricing policies and Asian countries, especially where long-acting insulins and issues surrounding generics, which involved direct contact are currently not reimbursed, and converted to US$ where with health authority personnel and other key stakeholders pertinent for comparative purposes using current exchange (76, 99, 104, 106–109). rates (https://www.xe.com/currencyconverter/). The Asian countries chosen included Bangladesh, India, RESULTS Korea, Malaysia and Pakistan. These countries again provide a range of countries based on their population size, economic We will first consolidate the findings from those continents where status—-Gross Domestic Product (GDP) per capita (96), the long-acting insulin analogues are not routinely funded before extent of universal healthcare, geography, level of co-payments, discussing the situation across Europe. This reflects variable Frontiers in Public Health | www.frontiersin.org 5 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries listing and funding of long-acting insulin analogues among the (similar DDD). This is encouraging as reductions in the price countries in these continents vs. upper-middle- and high-income of insulin glargine toward soluble and isophane insulin, coupled countries. In this way, seek to develop a logical sequence of with additional education of key Government personnel, could activities to enhance future funding and use of long-acting insulin potentially enhance future EML listing and funding of biosimilar analogues starting from a situation where these are currently not insulin glargine in the public healthcare system in Eswatini. being funded within public healthcare systems. Insulin utilisation increased to 3.19 billion DDDs in the We also know in Canada that Basaglar R insulin glargine public health system in South Africa in 2019, an increase biosimilar accounted for 7.8% of all insulin glargine dispensed of 11.1% compared with 2018, reflecting increased diabetes between July 2016 and June 2018 among the Provinces in Canada prevalence rates (3). However, expenditure went down by 3.6% (110). These rates are expected to grow with the instigation of suggestive of the additional savings that can be made through further demand-side measures to enhance biosimilar prescribing economies of scale as part of procurement practises (Table 2). within the public health system in Canada (111, 112) guiding Currently, long-acting insulin analogues are not listed on the other countries. essential medicine list in the public healthcare system in South Africa due to higher costs than basal/NPH insulins and no General perceived clinical advantage (20). Cost considerations are critical Table 1 summarises listing and funding of long-acting insulin in South Africa when considering reimbursement and funding analogues among the studied countries in Africa, Asia and of treatments within the public system in view of growing South America, with long-acting insulin analogues funded prevalence rates for NCDs (including diabetes) coupled with the in all the studied European countries. Whilst there was ongoing implementation of universal healthcare (3, 37, 114). typically a greater likelihood of funding of the long-acting Despite prices of long-acting insulin analogues falling through insulin analogues among the higher income countries, and increasing competition (Table 2); the current 2.8-fold difference a lack of listing among the lower-income countries, this in price between intermediate-acting insulins and the lowest was not universal. price insulin glargine (DDD basis for 5 pens) is still cost- prohibitive for consideration for EML listing in South Africa. Africa The ministerially appointed South African National Essential Generally among the studied African countries, there is limited Medicines List Committee recently reviewed long-acting insulin utilisation of long-acting insulin analogues in the public analogues; however, they did not recommend their use at healthcare system due to cost differences with human insulins tertiary and quaternary level of cares due to continued cost and issues of affordability (Table 1). In addition, many African differences (20). Consideration of therapeutic grouping of countries currently struggle with early diagnosis of diabetes intermediate-acting and long-acting insulin analogues is ongoing due to a lack of facilities and personnel with patients also and could assist with pooled procurement/tendering and possibly struggling to routinely monitor their insulin levels (37, 41). enabling access to long-acting insulin analogues from primary In view of concerns with costs and affordability, there is to quaternary level of care in the future. However, this must be variable listing of long-acting insulin analogues within the EML at more affordable prices. Currently there is only a 22.6% price of the studied African countries (Table 1), which limits the difference between the different insulin glargine preparations (5 potential market for biosimilar insulin analogues in practise by 3 ml pen sets) available on the public sector contract on a DDD (20, 38). basis and considerable price differences still exist between the lowest priced insulin glargine and intermediate-acting insulins African Countries Where Long-Acting Analogues Are (Table 2). Not Funded in the Public Healthcare System In Uganda, long-acting insulin analogues including insulin Currently, long-acting insulin analogues (detemir) are registered glargine are currently not listed in the Ugandan EML (Table 1). in Botswana but not currently available within the public This is a concern in view of the high rates of hypoglycaemia healthcare system in Botswana. This is different to short, currently seen; however, reflects issues of affordability in Uganda, intermediate-acting and pre-mixed insulins (37). Lowering the which is a major issue (115). Currently, prices for insulin prices of long-acting insulin analogues considerably through glargine within the healthcare system in Uganda vary between biosimilars would appreciably enhance their listing in the EML US$15–$35/pen depending on whether this is a biosimilar and use within the public health system in Botswana, similar to or originator, and whether hospital or community pharmacy. other African countries. Typically, adolescents with diabetes require 2 pens/month, with In Eswatini, only standard insulins including soluble insulins, overall costs considerable higher than US$8–10 for soluble isophane, and pre-mixed insulins (30/70), are currently available insulin, NPH insulin at $9–10, with premixed insulins at $10– in the public healthcare system (113). In addition, whilst insulin 15 all at 1,000 IU (i.e., 10 ml of 100 IU/ml) with each 10 ml protaphane is not listed in the current EML, it is stocked in some vial lasting ∼25–30 days. It is believed that prices of biosimilar government hospitals and Army clinics to enhance patient care. insulin glargine will need to fall appreciably for listing of long- Insulin glargine though is available within private hospitals in acting insulin analogues in the National EML and encourage Eswatini. Current wholesale prices for insulin protaphane 5 × appreciably greater use. 3 ml pensets is ZAR 633.00 (US$42.80), with insulin glargine 100 In Zambia, stock-outs of insulins listed in the EML among IU/ml 17% higher at ZAR727 (US$49.16) for a 5 × 3 ml penset public facilities are a concern with patients having to principally Frontiers in Public Health | www.frontiersin.org 6 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries TABLE 1 | Current GDP/capita and listing of long-acting insulins in country EMLs/funding among the studied countries across Africa, Asia, and South America. Country GDP/capita (US$)* Current funding/listing in EMLs Listed in the EML/funded in the Not listed/funded in the public public healthcare system healthcare system √ Uganda 794.3 √ Pakistan 1248.7 √ Zambia 1305.1 √ Kenya 1816.5 √ Bangladesh 1855.7 √ India 2099.6 √ Ghana 2202.1 √ Nigeria 2229.9 √ Eswatini 3894.7 √** South Africa 6001.4 √ Botswana 7961.3 √** Brazil (national) 8717.2 √ Argentina 9912.3 √ Malaysia 11,414.2 √ Uruguay 16,190.1 √ Korea 31,846.2 *GDP/capita based on the latest World Bank data (96); **will change depending on appreciable price reductions. TABLE 2 | Current contract prices for different insulin preparations among public hospitals in South Africa. Insulin type Trade name EML status* Price** Intermediate-acting (human) and Protaphane® HM, 100 iu/ml, disposable EML ZAR164.10 (US$11.11) Intermediate-acting combined with pen (5 × 3 ml) and Actraphane® HM fast-acting 30/70, 100 iu/ml, disposable pen (5 × 3 ml) Glargine, long-acting insulin analogue Optisulin® 100 iu/ml cartridges (5 × 3 ml); NON-EML ZAR460.40 (US$31.41) pens provided free of charge Glargine, long-acting insulin analogue Lantus® 100 iu/ml, vial (1 × 10 ml) NON-EML ZAR534.57 (US$36.25) (originator) Detemir, long-acting insulin analogue Levemir® 100 iu/ml, disposable pen NON-EML ZAR639.20 (US$43.61) (originator) (5 × 3 ml) NB: *EML. Essential medicine list; **Contract price in South African Rand (ZAR) listed on contract circular RT297–2019 (accessed 7 February 2021 and subsequently converted to US$)—available online at: http://www.treasury.gov.za/divisions/ocpo/ostb/bidders/CMD%2024%20RT297-2019.pdf. purchase their insulin from private pharmacies subject to 100% African Countries Where Long-Acting Analogues Are out-of-pocket payments (36). To address this, the Government Funded in the Public Healthcare System in the Republic of Zambia has been routinely purchasing insulins Whilst long-acting insulin analogues, insulin glargine and listed in the Zambian EML, which includes protaphane as its determir, are currently listed in the Ghanaian EML (18, longer-acting insulin with no long-acting insulin analogues, 116), they are currently not mentioned in the Ghanaian including biosimilar insulin glargine, currently listed in the Standard Treatment Guidelines (STGs) nor reimbursed within Zambian EML due to issues of affordability and value (36, 38). the National Health Insurance Scheme in Ghana (101). This Usage of insulin protaphane has increased within the University is reflected by increased dispensing of soluble, premixed and Teaching Hospitals in Lusaka in recent years reflecting increasing isophane insulins (1,000 IU) to 9,872 units in Cape Coast prevalence rates, with this growth rate likely to continue. It is Teaching Hospital in 2019 and 7,468 units by mid 2020, up from believed that prices of long-acting insulin analogues, including 8,883 in 2018, with only very limited use of insulin glargine (3 ml biosimilar insulin glargine, would need to fall substantially to 100 IU/ml) at just 4 packs in early 2020. nearer insulin protaphane on a monthly basis for insulin glargine A similar increase in the use of premixed 30/70 insulin was to be prescribed and funded within the public healthcare system seen within Keta Hospital, in Ghana, rising from 580 packs in Zambia. in 2015 to 802 in 2019 (38.3%), with this increase expected Frontiers in Public Health | www.frontiersin.org 7 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries to continue. However, currently in Keta Hospital, there is potentially reflecting concerns with the quality of non-originator no prescribing of long-acting insulin analogues due to price medicines in Nigeria (123) as well as limited price differences in differences and issues of affordability between the various insulin reality between originators and biosimilars, e.g., currently only types. Issues of affordability generally with insulins in Ghana 4% between the biosimilar and the cheapest originator. are reflected by Novo Nordisk offering insulin free to children to improve their care under its CDiC initiative in Africa (117). South America Similar to Botswana and other African countries, prices of long- Insulins in Argentina are currently bought by the various acting insulin glargine will have to fall considerably via lower Provinces, e.g., PRODIABA in the province of Buenos Aires, cost biosimilars to enhance their availability and usage within the to help with their costs for patients as membership can lead to public health system in Ghana. additional discounts. Biosimilar insulin glargine is available in The management of NCDs, including diabetes, is a growing Argentina; however, there is currently limited price differences priority in Kenya with NCDs now accounting for an appreciable with the originator, up to a maximum of 3%, which has impacted number of in-patient beds and growing mortality (118, 119). on their use in clinical practise. Key concerns and challenges include a lack of diagnosis, issues In their recent study, Dias et al. (32) noted that the utilisation of management exacerbated by affordability problems as well as of insulins in Brazil obtained via public tendering increased from control of symptoms. These issues and concerns have resulted 5.61DDDs/1000 inhabitants/day (DIDs) in 2009 to 9.04 DIDs in a number of initiatives in recent years (69, 70, 120). These in 2017, with recent figures showing this growth is continuing include the Base of Pyramid (BoP) project, with a ceiling (124). Overall insulin utilisation rose from 687.51 million price of KSh 500–600 (US$5-6) for insulin Mixtard R insulin DDDs in 2014 to 875.64 million DDDs in 2019 (27.4%), with to help address affordability concerns. This equates up to a expenditure also rising 85.1% during this period. These figures two-thirds price reduction from the regular price of 1,800 KSh did not include long-acting insulin analogues with the National (41, 70). Consequently, there has been very variable availability Health Technology Agency (CONITEC) recommending that and use of long-acting insulin analogues in Kenya in recent they should not be reimbursed within the Brazilian NHS due years. This includes the leading tertiary hospital in Kenya— to appreciably higher prices and uncertain benefits vs. NPH and Kenyatta National Hospital (KNH), a level six hospital (120)— other insulins, with subsequent calls for disinvestment (29). This where there has been an increasing use of long-acting insulin especially given concerns with rising prevalence rates for diabetes analogues in recent years; however from a low base. Utilisation in Brazil, with Brazil already having the fourth highest number of of insulin glargine rose from 0.51% of total insulins (DDD basis) patients with diabetes worldwide (32, 33). in 2015 to currently 3.4–3.6% of total insulin use (DDD basis). However, these recommendations have recently changed for Further use of long-acting insulin analogues is hampered though patients with Type 1 diabetes (T1DM) (32, 100). According to by considerably higher costs compared with standard insulins. the Ordinance of March 19, 2019, long-acting insulin analogues Affordability concerns are also reflected in limited or no use of have now been incorporated into the public healthcare system in long-acting insulin analogues, including potentially biosimilars, Brazil. However, this is conditional on the costs of the analogues outside of KNH, with patients struggling to fund even basic being equal to or less than the NPH insulin pens, and prescribed insulins despite access programmes (41, 70). Consequently, according to the guideline established by the Ministry of Health similar to other African countries, prices of long-acting insulin (125), which builds on current activities in the State of Minas analogues through biosimilars will need to appreciably fall before Gerais (34). This has limited their use in practise in the public there is increased use. health system. However, patients can still obtain long-acting Among three hospitals surveyed in the Northern part of insulin analogues via private pharmacies in Brazil but subject Nigeria, there was also low utilisation of insulin glargine vs. short, to 100% co-payment unless there has been a successful law suit medium- and longer-acting human insulins. In 2019, utilisation (29, 126). of insulin glargine ranged from 50 to 100 packs of 5 × 3 ml The maximum consumer prices (PMC) for insulin glargine 100 IU/ml, with prices per pack ranging from N3600 (US$9.47) biosimilar preparations (Basaglar R 100 IU/ml 3 ml single pen to N4300 ($11.42). There were similar utilisation patterns in refill) in Brazil is currently 51.5% cheaper than the originator. the first half of 2020; however, prices rose from for instance However, this price difference is being eroded with additional N4000 (US$10.53) to N4500 (US$11.84). This low utilisation discounts from the originator company limiting uptake of the of insulin glargine may again reflect cost considerations among biosimilar in practise. This is a concern as this may dissuade physicians and patients, with currently high levels of patient co- biosimilar manufacturers from launching additional biosimilars payments in Nigeria. This is important as high co-payments can in the future. be catastrophic for families in Nigeria when members become ill; Uruguay contrasts with Brazil as there has been considerable however, this is not universal (121, 122). growth in the utilisation of long-acting insulin analogues in The low use of insulin glargine in Nigeria was also reflected recent years, but from a low base, with this trend continuing. in a survey involving 11 community pharmacies. The average Utilisation of insulin glargine and detemir rose by 345.8% number of packs of insulin glargine dispensed ranged from between 2014 and 2019 DDDs in the public system (FNR—Fondo 35 to 110 during 2019, with an average of 75, with similar Nacional de Recursos), overall rising from a total of 4,912 DDDs patterns in the first half of 2020. Biosimilar Glaritus R typically on 2014 to 21,900 DDDs in 2019. However, the share of insulin only accounted for a small proportion of this at under 10%, glargine has gradually decreased from 77.9% of total long-acting Frontiers in Public Health | www.frontiersin.org 8 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries insulin analogues in 2014 to 71.6% (June 2020) due to increased biosimilars subsequently launched in 2010 (Table 4). There is prescribing of insulin detemir. Expenditure/DDD for insulin though growing prescribing and dispensing of insulin detemir glargine though has remained constant at 51.84 Uruguayan and insulin degludec in recent years. Peso (US$1.21)/DDD over the years with no competition from Overall, 167 pharmacies from across Bangladesh in four biosimilars. This may change as the long-acting insulin market groups provided data on dispensing and pricing patterns, giving becomes more attractive to biosimilar manufacturers, helping all a response rate of 66.8%. This wide range of prescribing patterns key stakeholder groups with lower prices. for the different insulins (Table 3) is reflected in the dispensing patterns among 76 out of 82 pharmacies contacted (first group Asia of pharmacies) (Table 4). Overall, insulin analogues were the There is typically growing use of long-acting insulin analogues principal insulin dispensed in over 40% of the community among the Asian countries studied except for Pakistan. The pharmacies surveyed in 2020, which was principally insulin increased use has been facilitated by the availability of biosimilars glargine. The biosimilars were the principal insulin glargine promoted by local companies. This is expected to continue. dispensed in over 50% of these pharmacies surveyed, reaching over 80% in 13% of those surveyed. However, again considerable Bangladesh variation depending on a number of issues including affordability Among the five surveyed public and private hospitals and and trust. institutions in Bangladesh, there was considerable variability in Table 5 contains the consolidate data on the prices seen for a the prescribing of long-acting insulin analogues as a percentage range of insulin glargine preparations among the 167 pharmacies of total insulins (Table 3). These prescribing patterns reflect and drug stores surveyed. Overall, price rises were seen in a the fact that among public hospitals in Bangladesh standard minority of pharmacies (10.8%) in 2020 vs. 2019, with the greatest insulins such as regular, intermediate and premix insulins are price increases seen for the biosimilars (11.3 vs. 10.3%). Typically typically provided free-of-charge until monies and supplies run though, there were no change in the prices of the different insulin out; however, this is not universal (35). Following this, insulins glargine preparations in the majority of pharmacies and drug are generally purchased from pharmacies and drug stores with stores surveyed (79.3%), with reductions seen 9.8% of surveyed 100% co-payment. Having said this, there are hardship funds pharmacies and drug stores, greatest for the originator (13.8%). available among some hospitals in Bangladesh to help cover Taken together, the findings from the different hospital the costs of insulin for the very poor given concerns with the personnel and the wide range of pharmacies and drugs stores potential catastrophic impact on the family if members have surveyed suggests that the usage of long-acting insulin analogues diabetes (35, 127, 128). is increasing in Bangladesh, which is principally insulin glargine, Long-acting insulins are currently subject to 100% co- reflecting their perceived patient benefits. This is increasingly the payment in all circumstances in Bangladesh. Typically, patients biosimilar reflecting issues of affordability. with diabetes being treated in private hospitals necessarily Biosimilars were also the principal preparations of insulin purchase their insulins from community pharmacies and drug glargine dispensed in a further set of 15 pharmacies, which stores with no purchasing of medicines by the hospital. accounted for just under 90% of all insulin glargine dispensed High levels of prescribing of long-acting insulin analogues (89.4% in 2019 and 88.9% in 2020). There was a 16.7% increase in some of the surveyed hospitals (Table 3) is principally in the number of insulin glargine packs dispensed in these 15 driven by endocrinologists in view of their perceived improved pharmacies between 2019 and 2020. effectiveness as well as patient convenience compared with standard insulins. Standard insulins such as premixed insulins are typically prescribed by non-endocrinologists especially as India they are provided free-of-charge until funds run out (35). Biosimilar insulin glargine Glaritus R is typically the only insulin However, their prescribing is decreasing among this group of glargine 100 IU/ml dispensed among five purposely selected physicians in favour of long-acting insulin analogues, with this government hospitals in India. There has been an increase in trend likely to continue. the prescribing of insulin glargine among these five hospitals Affordability can be an issue with the higher priced long- from 2014 to 2019 (Table 6); however, falling in 2020 with acting insulin analogues in Bangladesh, with Shariful Islam procurement changes. et al. (129) documenting that patients with diabetes paid an This is different to the findings of Ewen et al. (18) who average of 35,385 BDT (US$454) per year for their medicines found no insulin, including human insulin, was available in their vs. only 1609 BDT (US$21) for those patients without diabetes. surveyed provincial and district public hospitals in India and only Consequently, patients with diabetes and physicians should short-acting insulin was in stock in the one teaching hospital be cost-conscious; however, this is not always the case with in the state capital. The increasing use of long-acting insulin high rates of the prescribing of originator glargine among analogues (insulin glargine) may reflect a growing awareness of some hospital physicians despite higher prices (Tables 3, 4). the patient benefits with long-acting insulin analogues. Encouragingly, insulin glargine accounts for an appreciable Prices (expenditure/DDD) were generally stable in the proportion of the long-acting insulin analogues prescribed surveyed Government Hospitals over the years for insulin among the surveyed hospitals (Table 3) as this was the first glargine at 60 INR (US$0.83)/DDD between 2014 to 2016, long-acting insulin analogue launched (2005), with lower cost rising to 70.0 INR (US$0.97)/DDD in 2017 before falling to Frontiers in Public Health | www.frontiersin.org 9 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries TABLE 3 | Range of insulin prescribing patterns among the surveyed hospitals in Bangladesh [adapted from (35)]. % long-acting insulins vs. % insulin glargine vs. % insulin glargine among different presentations other insulins other total long-acting insulin analogues Biosimilar (various) Originator Public hospital (Medical university) 10–15% 20–30% 30–40% 60–70% Public hospital (Medical college) 20–30% 70–80% 70% 30% Public hospital (Medical college) 45–50% 70–80% 40–50% 50–60% Private hospital (Medical college) 15–20% 70–90% 98% 2% Private teaching hospital 20–25% 50–60% 40% 60% TABLE 4 | Dispensing patterns of different insulin preparations among 76 pharmacies and drug stores in Bangladesh (group one). 2019 2020 % Dispensed Other insulins (%) Analogues (%) Other insulins (%) Analogues (%) 0–10% 2.6 11.8 2.6 7.9 21–30% 11.8 18.4 13.2 18.4 31–40% 19/7 15.8 26.3 9.2 41–50% 18.4 15.8 15.8 18.4 51–60% 15.8 19.7 11.8 27.6 61–70% 17.1 14.5 21.1 14.5 71–80% 9.2 2.6 5.3 2.6 81–100% 5.3 1.3 3.9 1.3 NB: % dispensed is the % of the different insulin preparations dispensed that year. Analogues are principally long-acting insulin analogues including originators and biosimilars. 2020 is up to early December 2020. Figures represent %s dispensed. 50.93 INR (US$0.70)/DDD. Procured prices in 2020 were 61.60 (132). These limited price differences, coupled with limited INR (US$0.85)/DDD. demand-side measures generally in Korea to influence physician However, we did see differences in the prices of the different prescribing including biosimilars (103, 133), resulted in only insulin glargine preparations in India in 2020 among 207 limited utilisation of biosimilar insulin glargine in Korea (100 community pharmacies surveyed, with prices for Glaritus R IU/ml) in recent years. Usage is growing though from a low of glargine at similar prices to the Government hospitals at 382 INR 0.95% of total insulin glargine preparations in 2017 to 4.7% in (US$5.28)/3 mls (100 IU/ml). Pharmacy prices ranged from 382 2019, with further growth expected. to 650 INR/3 mls (US$ 5.28–8.99) over the years, with 382INR/3 Within the university hospitals in Malaysia, there is mls the most consistent. This compares to 722 INR (US$9.98)/3 considerable prescribing of long-acting insulin analogues at mls (100 IU/ml) as the most consistent price for the originator. between 50 and 70% of all insulins dispensed, which is typically Whilst there have also been changes in the prices for both the higher than seen among a range of hospitals in Bangladesh (35). originator and biosimilars between 2016 and 2020 among the Similar to India, biosimilars account for up to 90% of all long- community pharmacies surveyed, with a maximum of 20% in acting insulin analogues dispensed in government hospitals. any 1 year, appreciable price differences still exist between the This appreciable utilisation of biosimilar insulin glargine among originator and the biosimilars. This price difference may have public hospitals in Malaysia is facilitated by procurement facilitated the prescribing of biosimilar insulin glargine within practises which are based on International Non-Proprietary the surveyed hospitals in India in recent years where typically Names (INN), the government’s preferentially purchasing of insulins are provided free of charge until funds run out as part generics and biosimilars from Malaysian companies where of moves toward universal healthcare (18, 130, 131). possible (134), and the increasing production of biosimilar insulin glargine in Malaysia manufactured to a high standard Korea, Malaysia and Pakistan (135–137). This potentially serves as a model to other countries There are currently limited differences in the public price of seeking to enhance the use of biosimilar insulins in their country. insulin glargine 100 IU/ml between the originator and biosimilars Since insulins are available free of charge among public in Korea reflecting the situation with other biosimilars (103). hospitals in Malaysia, there is currently limited dispensing of Price differences between 2017 and 2019 ranged from a price biosimilars among the twelve community pharmacies surveyed reduction of 0.27% up to a maximum 5.0% difference between (Box 1). Most pharmacies typically dispense the originator for the originator and the biosimilar at US$9.04 vs. US$8.59 and patients wishing to purchase insulin glargine as they are generally US$9.02 per unit depending on the preparation prescribed willing to cover the full costs themselves (Box 1). Frontiers in Public Health | www.frontiersin.org 10 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries TABLE 5 | Typical selling prices for a range of insulin glargine preparations among 58 pharmacies and drug stores in Bangladesh. Manufacturer Packs (100 IU/ml insulin glargine) Typical selling price in pharmacies and drug stores (local currency) Lantus® (Sanofi-Aventis) 100 IU/ml 3 ml Pen, 5 × 3 ml pen 1220 BDT (US$14.40), 6100 BDT (US$72.00) Abasaglar® 100 IU/ml−3 ml Pen; 100 IU/ml – 5 × 3 ml cartridges 1085 BDT (US$12.80) to 3617 BDT (US$42.68) Glarine® 100 IU/ml—Pen, 5 × 3 ml pens 950 BDT (US$11.21), 4750 BDT (US$56.05) Larsulin® 100 IU/ml−3 ml vial and pen cartridge 600 BDT (US$7.08) Vibrent® 100 IU/ml−3 ml vial and pen set 600 BDT (US$7.08) TABLE 6 | Total annual utilisation of insulin glargine (DDDs) among 5 Government pharmacies. In addition, only one biosimilar appears to be hospitals in India. available among the community pharmacies surveyed in 2014 2016 2018 2019 Pakistan vs. a greater range of biosimilars in Bangladesh and India. As a result, no real competition currently among Hospital 1 7290.0 8280.0 9022.5 12195.0 biosimilar manufacturers and the subsequent implications for Hospital 2 31522.5 34942.5 47587.5 76657.5 lower prices. Hospital 3 26055.0 29137.5 33232.5 40995.0 Hospital 4 43200.0 49972.5 55125.0 82552.5 Europe Hospital 5 2700.0 3037.5 3937.5 6975.0 There has typically been growing utilisation and expenditure on long-acting insulin analogues among European countries in recent years. This is reflected in Figure 1 where the latest utilisation of long-acting insulins as a percentage of total In Pakistan in recent years, there has also been an increase insulins is documented. The high documented rates among in insulin utilisation reflecting increased prevalence rates for European countries including Bosnia and Herzegovina, Estonia, diabetes mellitus (124, 138). There was a 69.5% increase in Latvia and Romania, reflects increased promotion and other the total utilisation of insulin in Pakistan from 8.251 million activities by the originator companies of long-acting insulin units in 2014 to 13.988 million units in 2019 and rising. analogues. In addition, endorsement of the value of long- This translated into a 152.1% increase in expenditure during acting insulin analogues among all key stakeholder groups this period, enhanced by increasing expenditure on long-acting including the health authorities, physicians and patients. This insulin analogues including insulin glargine which accounted endorses comments by Ewen et al. that the prescribing for 9.6% of total expenditure in 2020 despite only accounting of long-acting insulin analogues has been growing among for 1.97% of total utilisation. This low utilisation of insulin upper-middle and high-income countries in recent years (18, glargine as a percentage of total insulin in Pakistan vs. Bangladesh 143). and India could be due to a number of issues and activities. The greatest increase in the utilisation of long-acting insulin These include affordability and co-payment issues for insulins analogues as a percentage of total insulins (based on DDDs) was generally in Pakistan, and for long-acting insulin analogues in seen in Poland (210.6%) among the studied countries but from particular, despite good availability of the different insulins in the a low base, with the least change in Slovenia (10.7%) but from a country combined with a lack of listing of the long-acting insulin higher base. analogues within the national EML (97, 139–141). There has also been considerable variation in the use of Currently the biosimilar (Basagine R ) is 20.5% cheaper biosimilar insulin glargine vs. total insulin glargine across than the originator among community pharmacies in Pakistan Europe (Table 7). The contrasting rates across Europe reflect similar to the findings of Ewen et al. (18), i.e. originator a number of key issues and activities. These include the (3/10 ml)–−1,132 to 3,858 PKR (US$7.14–24.32), and the extent of prescribing of Gla-300 in practise, which reached a biosimilar (3 ml)–−900 PKR (US$5.67). Despite these price maximum of 58.0% of total insulin glargine (DDD basis) in differences, and issues of affordability, it appears that the Hungary, initial as well as final differences in the prices of originator (typically 10 ml vials 100 IU/ml) is typically dispensed originator vs. biosimilar insulin glargine (100 IU/ml), price among the eight community pharmacies surveyed, although reductions by the originator company over time (Table 7) as there has been an increase in the dispensing of biosimilar well as the extent, or lack of them, of ongoing demand-side Basagine R insulin glargine in recent months with shortages of measures to enhance the preferential prescribing of biosimilar the originator. insulin glargine 100 IU/ml vs. the originator within individual This limited utilisation of the biosimilars in Pakistan European countries. vs. Bangladesh, India and Malaysia may reflect greater Overall, there was growing utilisation of biosimilar insulin physician and patient confidence in the originator due to glargine in Italy, Lithuania, Hungary, Poland and Scotland over general concerns with the quality of generics in Pakistan time, greatest in Poland. In Poland, a flat reimbursement rate (142) coupled with limited price differences in some with patients paying the price difference for a more expensive Frontiers in Public Health | www.frontiersin.org 11 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries BOX 1 | Current situation regarding insulin glargine (100 IU/ml) among twelve community pharmacies in Malaysia. • Originator ◦ Available in 9 out of the 12 pharmacies surveyed ◦ Sales price ranged from 55.00–75.00 Malaysian Ringgits (US$13.61–18.55)/dispensed preparation ◦ No change in the selling price 2020 vs. 2019 in 5/9 pharmacies−0–20% higher in one, 0–20% lower in three • Biosimilar ◦ Not sold or unavailable in 11 out 12 pharmacies in 2019 and 10 out of 12 pharmacies in 2020 ◦ When sold, the sales price ranged from 50–60 (US$12.37–14.84) Malaysian Ringgits/dispensed preparation ◦ Where sold—typically only a minority of biosimilar insulin glargine dispensed (below 40% of all insulin glargine preparations) originator may explain their high use of biosimilar insulin glargine (144, 145). Alongside this, the Ministry of Health and others in Poland are seeking to grow the prescribing of biosimilars to save resources, with Poland a leading producer of biosimilars in Europe (144, 146). However, overall utilisation of the 100 IU/ml biosimilar as a percentage of total insulin glargine has been reduced by the promotion of Gla-300 with this reaching 37.1% of total insulin glargine by early 2020 aided by a price reduction of 5.8% between 2017 and 2020. In Scotland, there has been limited utilisation of Gla- 300 following prescribing restrictions, mirroring the impact of prescribing restrictions and other activities in Scotland which have been introduced to limit the prescribing of medicines where there are concerns with their role and value (67, 147–149). The situation in Italy, Lithuania, Hungary, and Poland FIGURE 1 | Current utilisation and expenditure on long-acting insulins as a contrasts with other European countries including Albania, percentage of total insulins among European countries in either 2019 or 2020. NB: B & H, Bosnia and Herzegovina; DDD based with differences in Kosovo, and Latvia, where biosimilar insulin glargine has expenditures based on local currencies. not yet been launched as well as Estonia and Romania where there is currently very limited use. However, the utilisation of biosimilar 100 IU/ml in Italy, Lithuania, and Poland is moderated by appreciable usage of Gla-300 (Table 7). Reasons for current unavailability of biosimilar insulin Suggestions for the Future to Increase the glargine in Kosovo include concerns with their effectiveness Utilisation of Insulin Glargine Biosimilars and safety vs. the originator. Reasons for no availability The first step to enhance the attractiveness of the market or limited use of biosimilar insulin glargine in Albania, for manufacturers of biosimilar long-acting insulin analogues Estonia and Latvia include limited attractiveness of the market is to reimburse them in the first place. Box 2 summarises a following multiple activities by the originator company. These number of activities that Governments and others in LMICs include the originator company continually promoting both can undertake to improve the availability and use of long-acting the originator 100 IU/ml formulation as well as Gla-300 insulin analogues principally via biosimilars. alongside reducing the prices of its 100 IU/ml formulation to Once low cost biosimilar long-acting insulin analogues are limit any price differences (Table 7). The limited uptake of routinely available, funded, and used within countries, including biosimilar insulin glargine in Romania has been influenced listing on country EMLs and addressing issues of affordability by a number of factors including ongoing pricing and including co-payments, there are a number of educational and reimbursement policies coupled with limited physician other initiatives that can subsequently be undertaken to enhance incentives or constraints to preferentially prescribing biosimilars. their use. In addition, biosimilar companies may be discouraged from Encouragingly, we are seeing growing use of long- launching their biosimilars in Romania due to current acting insulin analogues across Europe (Figure 1) international reference pricing within the country and fears as well as other countries including Bangladesh, of parallel exportation. India, Malaysia and Uruguay. This would suggest The price reductions for insulin glargine biosimilars when increasing endorsement of their value, enhanced by first launched vs. originator prices (Table 7) is similar to the price reductions. In addition, additions to EMLs as seen differences seen among LMICs in the study by Ewen et al. (18). in Ghana. Frontiers in Public Health | www.frontiersin.org 12 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries TABLE 7 | Key characteristics of the insulin glargine market (100 IU/ml) among European countries. Bio Usage (%) Price difference at Price difference Latest price % Gla-300 (latest) launch (Bio vs. originator over time difference (Bio vs. Originator) % (%) Originator—%) Albania NA NA −32.2 NA 45.3 Bosnia and Herezegovina 6.2 0.0 −11.3 −7.9 52.1 Bulgaria 11.0 −4.7 −10.8 −5.7 Catalonia 12.4 −23.1 −23.1 Similar 28.1 Estonia 0.69 −16.4 −24.9 55.4 Hungary 24.6 −28.2 −21.1 −1.6 58.0 Italy 25.0 −52.3 −24.0 30.4 Latvia NA NA −14.4 NA 51.4 Lithuania 26.5 −12.3 −21.1 0.0 39.0 Poland 44.8 −24.6 −31.1 −0.2 37.1 Scotland 19.5 −18.1 −9.0 −7.5 9.3 Slovenia 15.7 −22.9 −20.3 −9.9 NB: Bio usage, % insulin glargine biosimilar vs. total insulin glargine 100 IU/ml on a DDD basis; Orig, Originator; Gla-300, TOUJEO 300 IU/ml on a DDD basis; Blanks represent no data available; NA, Biosimilars not yet launched; Latest price difference either 2019 or 2020 depending on available data; price differences calculated on a DDD basis using local currencies. BOX 2 | Potential activities to enhance funding and availability of lower cost insulin glargine preparations within public healthcare systems. • Increased competition can potentially lower the price of insulin glargine through biosimilars, similar to the situation in Bangladesh as well as for other biosimilars (35, 46, 48). This can potentially be achieved by: ◦ By Governments/procurement agencies building on the WHO prequalification initiative to enhance imports of biosimilars from other LMICs to help break the current monopoly among three principal manufacturers of insulins (150–152) ◦ Governments/procurement agencies could potentially work with insulin manufacturers and others to make long-acting insulin analogues available through biosimilars (or originators) at lower prices. This builds on initiatives in Kenya, Nigeria, and Tanzania (70–72, 117) ◦ Governments (especially across regions) across Africa and potentially Brazil could produce biosimilar insulin glargine within their countries/Regions. For instance, Biocon already supplies insulin analogues to a number of African countries, and has instigated manufacturing capabilities in Malaysia (135, 153). Consortia such as the East African Community consortia, has already advocated increased local production of medicines to address future shortages (154, 155), Aspen in South Africa is currently producing vaccines for COVID-19 under licence (156), and Fiocruz in Brazil is already producing recombinant insulins (157) • Ideally, biosimilar long-acting insulin analogues should be no more than 30–50% above current prices of NPH and other standard insulins on a daily basis, enhanced by low production costs (158) • Governments should only list biosimilar insulins (of proven quality) on EMLs where these exist and not originators to further enhance competition among biosimilar manufacturers to help drive down prices • Parallel to this, Ministries of Health and/or physician groups should heighten local knowledge of the potential patient benefits with long-acting insulin analogues if not already seen through clinical trials and other studies including real-world evidence studies as most comparisons between long-acting insulin analogues and NPH/other standard insulins have taken place in high-income countries Once available and reimbursed, the situation with biosimilar originator company coupled with limited demand-side measures insulin glargine in Europe appears very different to that among European health authorities promoting biosimilar for biosimilars for immunological diseases and cancer. For insulin glargine. In addition, there are concerns in some instance by 2017, infliximab and etanercept biosimilars had countries that the different devices between originator and already accounted for 79 and 54% of the UK market share, biosimilar insulin glargine preparations may adversely impact respectively (159, 160) and growing. In Scotland, etanercept on rates of hypoglycaemia unless patients are educated on the and infliximab biosimilars had already reached 84 and 94% different devices. of total utilisation of these biologics by December 2017, Box 3 builds on the findings to date, coupled with input and by December 2019, biosimilars trastuzumab had already from the senior-level co-authors, to suggest potential measures accounted for 92% of all trastuzumab and biosimilar adalimumab that could be instigated among all key stakeholder groups to 87% of all adalimumab (54, 83, 161, 162). We believe the enhance the future use of biosimilar insulin glargine in the limited use of biosimilar insulin glargine among the European public healthcare systems across countries once long-acting countries surveyed apart from Poland (Table 7) is due to insulins are routinely reimbursed and funded. This is particularly a number of factors. These include promotion of Gla-300 important since encouraging greater use of biosimilar insulin alongside price reductions of the 100 IU/ml formulation by the glargine should lead to lower prices, similar to the situation with Frontiers in Public Health | www.frontiersin.org 13 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries BOX 3 | Potential activities to enhance the prescribing and dispensing of biosimilar insulin glargine within public healthcare systems. Educational initiatives • Educate all key stakeholder groups where pertinent regarding similar effectiveness and safety between originator and biosimilar long-acting insulin analogues. This includes actively disseminating the findings from current and future studies to avoid/reduce any nocebo effect (52) • Instigate/help with additional research regarding the potential savings/cost-effectiveness from biosimilar insulin glargine vs. other long-acting insulins as well as NPH and other insulins especially in LMICs—building on current studies. Lower cost biosimilars can potentially enhance access/availability/usage of long-acting insulin analogues in suitable patients where there are concerns—especially given rising rates of diabetes across countries and issues of co-payments/affordability in a number of countries • Work with patients to ensure they are familiar with the different pens/devices where this is a concern in case of switching between different insulin glargine preparations (and other long-acting insulin biosimilars when they become available) to minimise the potential for hypoglycaemia. This can include an increasing role for nurse specialists and pharmacists - building on their role with patient education in non-communicable diseases including diabetes (163–166) • Work with patient organisations to reduce any misinformation about biosimilars for long-acting insulin analogues to facilitate greater use— especially where resources/co-payments are an issue. This includes warning patients that the devices may be different between originators and biosimilars where pertinent as this may not always be an issue (35). Alongside this, stressing the importance of good injection techniques (167) Other activities • Encourage lower prices from companies to stimulate the use of biosimilar insulin glargine (100 IU/ml)—with such activities potentially necessary to (i) address financial concerns with educating patients about the different devices and (ii) reverse current trends in the preferential prescribing of 300 IU/ml insulin glargine (TOUJEO) vs. biosimilar insulin glargine (100 IU/ml). This could be achieved by: ◦ Introducing annual procurement practices for insulin glargine 100 IU/ml— with preference given to biosimilar companies coupled with appropriate demand-side measures to enhance their utilisation ◦ Seek to only list biosimilar insulin glargine (100 IU/ml) on national formulary lists/essential medicine lists when prices are favourable where currently this does not happen, with the potential for delisting insulin glargine from originator companies as familiarity with the biosimilars grows—this builds on activities with renin-angiotensin inhibitors in Denmark (168) ◦ Expanding tendering/procurement activities for 100 IU/ml insulin glargine including biosimilars as seen for instance in Denmark and Norway with the anti-TNFs for patients with immunological conditions (46, 47). This could be via tendering groups as seen across Europe with the formation of groups across countries, e.g., Beneluxa group, as well as in South America with new medicines for hepatitis C (169–172). As part of this, seek to tender with different companies to encourage greater competition in the future as seen with adalimumab in the UK (48). Greater discounts for insulin glargine biosimilar will enhance formulary listing/reimbursement where there are still concerns with the current role and value of long-acting insulin analogues vs. NPH and other insulins as seen in the current WHO EML ◦ Introduce target prescribing goals (quality indicators) for starting patients on 100 IU/ml biosimilar insulin glargine where possible when prescribing a long-acting insulin analogue. In addition, seek to introduce switching targets provided suitable educational support and funding is in place to address concerns when patients are switched between different devices alongside other demand-side measures to enhance preferential prescribing of biosimilars including financial incentives (80, 108, 173). This recognizes that any quality target introduced by health authorities must be acceptable to key stakeholder groups and measurable (174, 175). Concomitant with this, seek ways to limit the prescribing of 300 IU/ml insulin glargine whilst still patented through prescribing restrictions and other activities - building on successful activities in Scotland (Table 7). European health authorities have been successful with instigating prescribing restrictions in the past (176–178) • Expanding the remit of the Medicines Patent Pool as well as use of the flexibilities enshrined in the WHO TRIPS agreement to increase access and availability of insulin glargine at affordable prices to reduce current barriers where these exist • Alongside this, make sure that there is agreement between recommendations for long-acting insulin analogues in National EMLs and STGs—addressing concerns seen for instance in Ghana biosimilars of adalimumab and oral generics (46, 48, 179, 180), (35), reflecting their increasing role and value in managing as well as encourage companies to produce biosimilars for still patients with diabetes, this is not universal (Table 1). The patented long-acting insulin analogues. This builds on the WHO situation is changing though in a number of these countries prequalification initiatives (152, 181), and is seen as critical given with increasing recognition of the value of long-acting the envisaged increase in prevalence rates and costs of diabetes, insulin analogues, which will be helped by further price and the need to appropriately manage patients requiring insulin reductions of biosimilar insulin glargine 100 IU/ml. There to reduce hypoglycaemia and improve adherence rates to reduce are a number of activities that Governments and Pan-country future complications. consortia can undertake to enhance the availability of low cost insulin glargine including increased local production DISCUSSION (Box 2). This builds on ongoing activities with insulin manufacture in Brazil and Malaysia as well as vaccines in We believe this is the first study across multiple countries South Africa (135, 137, 156, 157). This also builds on the to assess current utilisation patterns for long-acting insulin WHO prequalification initiative to stimulate competition analogues including biosimilars and the rationale for the among potential biosimilar manufacturers to break the current patterns seen. monopoly among three principal manufacturers of insulins Whilst encouragingly we are seeing growing utilisation (150–152). We have seen that increased competition has helped of long-acting insulin analogues in a number of LMICs to lower the prices of biosimilars, building on similar activities including Bangladesh, India and Malaysia (section Asia) with oral generic medicines (35, 46, 180). As a result, enhance Frontiers in Public Health | www.frontiersin.org 14 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries the possibility that all patients with diabetes worldwide that to enhance the prescribing of biosimilar insulin glargine need insulin to control their diabetes have access to the same 100 IU/ml where there have been concerns as well as range of insulin preparations to improve the management of monitoring the impact of ongoing demand-side measures to their condition. enhance the preferential prescribing of insulin glargine 100 The situation is different for higher income LMICs (Table 1) IU/ml vs. other glargine formulations and other long-acting and Europe where long-acting insulin analogues are routinely insulin analogues. funded within the healthcare systems. In this situation, we have We are aware of a number of limitations with this study. shown that the originator company has instigated a number These include the fact that we relied on impressions of of activities to reduce the impact of biosimilars. These include changes in the utilisation and prices of different insulin switching promotional efforts toward the 300 IU/ml formulation, preparations including different insulin glargine preparations which reached as high as 58.0% of total insulin glargine on in a number of African and Asian countries for the reasons a DDD basis in Hungary (Table 7). This combined with price given. We were also not able to gain robust utilisation reductions instigated by the originator limited the availability and expenditure data in all countries apart from European and prescribing of biosimilar insulin glargine in practise in a countries and South Africa. We are also aware that there number of these countries (Figure 1, Table 7). In fact, no or can be differences in comparative utilisation rates of 100 limited use of biosimilars to date in Albania, Estonia, Kosovo, vs. 300 IU/ml insulin glargine that is not reflected in their Latvia and Romania arising from these activities, exacerbated DDDs (66). However, despite these limitations, we believe our in Romania by concerns with international reference pricing findings are informative and provide pertinent directions for and issues of parallel exportation. The limited use of biosimilar the future. insulin glargine in Korea is a direct consequence of limited In conclusion, the increasing use of low-cost biosimilars price reductions vs. the originator coupled with limited demand- is essential for countries to sustain healthcare systems given side measures enhancing their prescribing, similar to other the expected growth in expenditure on medicines to address biosimilars in Korea (103). Consequently, there is a need to unmet need including the provision of new premium-priced consolidate activities to address key concerns with biosimilars medicines. The availability of insulin glargine at low prices where these exist including addressing any nocebo effect (Box 3) through a variety of activities, which includes stimulating (52), which build on examples in Poland, Lithuania and Hungary local production of biosimilars and enhancing competition in Europe as well as Bangladesh, India and Malaysia in Asia. This between manufacturers, should enhance their use and help is important as we need to encourage biosimilar manufacturers to fund increasing use of insulins to meet rising demand. to invest efforts into developing biosimilars for other long-acting The increasing availability and use of biosimilar long-acting insulin analogues when their patents are lost given envisaged insulin analogues will also further generate confidence in increase in insulin sales over the coming years. Otherwise, the their prescribing thereby enhancing future availability, funding insulin market will continue to be dominated by the same three and prescribing, which is essential given ongoing resource manufacturers limiting potential price reductions in the future constraints. However, this will typically require multiple (150, 151). demand-side measures to stimulate their use where there are Box 3 also discusses additional activities that key stakeholder currently challenges. groups could undertake to enhance utilisation and funding This is because there are concerns and issues with biosimilar for biosimilar insulin glargine 100 IU/ml vs. other long-acting insulin glargine where available and funded vs. a number insulin analogues including the patent protected 300 IU/ml of the other biosimilars. Consequently, a number of specific formulation of insulin glargine. This builds on experiences across demand-side measures may be necessary to stimulate the countries with other biosimilars as well as other situations and prescribing of biosimilar insulin glargine. This includes disease areas. As a result, potentially encouraging more 100 potentially instigating prescribing restrictions for originator IU/ml formulations to be launched and/ or produced locally, as well as higher strength (300 IU/ml) insulin glargine along thereby leading to lower prices in the future. This though with preferential listing 100 IU/ml biosimilar insulin glargine has to be accompanied by educational and other activities on formularies and EMLs. Such activities could potentially where there are concerns to ensure all key stakeholders are overcome activities by the originator company both in terms of comfortable with the increasing use of long-acting insulin reducing prices to compete with biosimilars as well as switching analogue biosimilars. Demand-side measures could include the promotional activities to enhance the prescribing of still patented development of pertinent quality indicators among physicians to formulations. There are also concerns with different devices preferentially encourage the prescribing of biosimilars as well as in some markets, although this is not universal. Improved education among patients with the help of patient organisations patient education, familiarity and lower prices for biosimilars, and healthcare professionals including pharmacists (Box 3). coupled with introducing a number of demand-side measures Future studies should concentrate on the costs and outcomes including quality indicators and prescribing restrictions where of low cost biosimilars vs. NPH and other standard insulins pertinent and feasible, will enhance their reimbursement, among LMICs as there has been a paucity of data to funding and utilisation in the future. We will continue to date. In addition, the impact of demand-side measures monitor this. Frontiers in Public Health | www.frontiersin.org 15 June 2021 | Volume 9 | Article 671961 Godman et al. Long-Acting Insulin Analogues Across Countries DATA AVAILABILITY STATEMENT FUNDING The original contributions presented in the study are included This analysis was commissioned and paid for by the World in the article/supplementary material, further inquiries can be Health Organization. The authors though were totally directed to the corresponding author/s. responsible for the views expressed in this paper and they do not necessarily represent the decisions, policy or views of the AUTHOR CONTRIBUTIONS World Health Organization. BG, EA, and RB developed the concept of this ACKNOWLEDGMENTS paper. 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Wettermark B, Godman B, Neovius M, Hedberg N, Mellgren TO, Kahan This is an open-access article distributed under the terms of the Creative Commons T. Initial effects of a reimbursement restriction to improve the cost- Attribution License (CC BY). The use, distribution or reproduction in other forums effectiveness of antihypertensive treatment. Health Policy. (2010) 94:221– is permitted, provided the original author(s) and the copyright owner(s) are credited 9. doi: 10.1016/j.healthpol.2009.09.014 and that the original publication in this journal is cited, in accordance with accepted 177. Godman B, Sakshaug S, Berg C, Wettermark B, Haycox A. Combination academic practice. No use, distribution or reproduction is permitted which does not of prescribing restrictions and policies to engineer low prices to reduce comply with these terms. Frontiers in Public Health | www.frontiersin.org 21 June 2021 | Volume 9 | Article 671961