ABSTRACT:

Background:

From 2006 to 2017, the Brazilian federal government provided free of charge traditional insulins for diabetes treatment. This involved public tendering by the Department of Health Logistics of the Ministry of Health (DLOG-MOH) and the reimbursement after direct contracting for supply with commercial private retailers (Brazilian Popular Pharmacy Program - PFPB).

Objective:

We aim to describe the budget of the Brazilian federal government committed to for the acquisition of insulin, as well as corresponding prices and treatment availability from 2009 to 2017.

Methods:

Insulin volume and expenditure data were obtained in official administrative databases and in the Electronic System of the Information Service to Citizens. Data were analyzed according to the total provision by the federal government, DLOG-MOH and PFPB. Moreover, data were presented according to insulin type. Volumes were calculated in number of defined daily doses (DDD)/1,000 inhabitants/day.

Results:

Budgetary commitments due to insulin over nine years amounted to U$1,027 billion in 2017, with an approximate average of U$114.1 million per year. DLOG-MOH was the main insulin provider, despite the increase in PFPB provision along period. DLOG-MOH and PFBP together provided an average of 6.08 DDD/1000 inhabitants/day for nine years. Average prices in PFPB were higher than those in the DLOG series, with a downward trend over the years, narrowing to 2.7 times in 2017, when compared to 2009.

Conclusions:

Brazil evidenced a moderately sustainable and effective, albeit imperfect, policy for public provision of traditional insulins in the period preceding mandatory free supply of insulin analogues. Future studies must address treatment availability and financial sustainability in the new scenario.

Keywords:
Diabetes mellitus; Insulin; Healthcare financing; Supply; Drug price

RESUMO:

Introdução:

Entre 2006 e 2017, o governo federal forneceu gratuitamente insulinas tradicionais para o tratamento de diabetes por meio de licitação pública pelo Departamento de Logística em Saúde do Ministério da Saúde (DLOG-MOH) e reembolso a drogarias privadas credenciadas pelo Programa Farmácia Popular do Brasil (PFPB) após contratação direta para fornecimento.

Objetivo:

Descrever o orçamento federal brasileiro empenhado pela aquisição de insulinas, bem como preços e disponibilidade de tratamento correspondentes entre 2009 e 2017.

Métodos:

Dados de despesas e volume de insulina foram obtidos em registros administrativos oficiais e mediante solicitação ao Sistema Eletrônico do Serviço de Informações ao Cidadão. Os dados foram analisados de acordo com a provisão total do governo federal e segundo aquisições via DLOG-MOH e PFPB e tipo de insulina. Os volumes de insulina foram calculados em número de doses diárias definidas (DDD)/1.000 habitantes/dia.

Resultados:

Em nove anos, o orçamento empenhado com a insulina totalizou US$ 1.027 bilhões em 2017, média de US$ 114,1 milhões/ano. O DLOG-MOH foi o principal fornecedor de insulina apesar do crescimento do PFPB durante o período. O DLOG-MOH e o PFPB disponibilizaram em média 6,08 DDD/1.000 habitantes/dia durante o período analisado. Os preços médios no PFPB foram maiores que os do DOG-MOH ao longo do período, com tendência de queda ao longo dos anos, estreitando-se para 2,7 vezes em 2017 em comparação a 2009.

Conclusão:

O Brasil evidenciou uma política de fornecimento gratuito de insulina moderadamente sustentável e eficaz, ainda que imperfeita, no período que antecedeu o fornecimento obrigatório de análogos. Recomendam-se estudos futuros para avaliar a disponibilidade de tratamento e a sustentabilidade do financiamento nesse novo cenário.

Palavras-chave:
Diabetes Mellitus; Insulina; Financiamento da assistência à saúde; Aprovisionamento; Preço de Medicamento

INTRODUCTION

Insulin is essential to glycemic control and, often, for patient survival in diabetes mellitus (DM)¹1. Meneghini L, Liebl A, Abrahamson MJ. Insulin detemir: A historical perspective on a modern basal insulin analogue. Prim care 2010; 4, (Suppl. 1):S31-42. https://doi.org/10.1016/S1751-9918(10)60007-1
https://doi.org/https://doi.org/10.1016/... ^,22. Kahn CR, editor. Joslin’s Diabetes mellitus. 12a ed. Philadelphia: Lea & Febiger; 1985. 1,007 p.. The estimated global prevalence of DM for 2015 was 8.8% among the population aged 20-79³3. International Diabetes Federation. Diabetes Atlas. 7a ed. International Diabetes Federation; 2015.. There are four main clinical types of diabetes: type 1 (DM1); type 2 (DM2); gestational diabetes; and “other” types of diabetes²2. Kahn CR, editor. Joslin’s Diabetes mellitus. 12a ed. Philadelphia: Lea & Febiger; 1985. 1,007 p..

For a long time, insulin treatment was restricted to DM1 patients and to contexts of metabolic instability, such as surgeries and care of diabetics in intensive care units. However, both current management protocols recommending stricter control of glycemic levels with wider insulin use for all types of diabetes and the growth in disease prevalence have substantially expanded the use of insulin⁴4. Sociedade Brasileira de Diabetes. Diretrizes da Sociedade Brasileira de Diabetes: 2013-2014. São Paulo: AC Farmacêutica; 2014.^,55. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2014; 37(Suppl. 1): S14-80. https://doi.org/10.2337/dc14-S014
https://doi.org/https://doi.org/10.2337/... ^,66. Sociedade Brasileira de Diabetes. Diretrizes da Sociedade Brasileira de Diabetes: 2014-2015. São Paulo: AC Farmacêutica ; 2016.^,77. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2017; 40(Suppl. 1): S4-S5. https://doi.org/10.2337/dc17-S003
https://doi.org/https://doi.org/10.2337/... ^,88. Holden SE, Gale EAM, Jenkins-Jones S, Currie CJ. How many people inject insulin? UK estimates from 1991 to 2010. Diabetes Obes Metab 2014; 16(6): 553-9. https://doi.org/10.1111/dom.12260
https://doi.org/https://doi.org/10.1111/... ^,99. Centers for Disease Control and prevention. Treating Diabetes (insulin and oral medication use). Centers for Disease Control and Prevention; 2013.. In fact, half of all diabetics in the United Kingdom were insulin users in 2010⁸8. Holden SE, Gale EAM, Jenkins-Jones S, Currie CJ. How many people inject insulin? UK estimates from 1991 to 2010. Diabetes Obes Metab 2014; 16(6): 553-9. https://doi.org/10.1111/dom.12260
https://doi.org/https://doi.org/10.1111/... , just like the16.4% of diabetics in the USA in 2011⁹9. Centers for Disease Control and prevention. Treating Diabetes (insulin and oral medication use). Centers for Disease Control and Prevention; 2013..

Insulin may have a great impact on diabetes expenditures, ranging from 0 to 68% of disease costs¹⁰10. Beran D, Ewen M, Laing R. Constraints and challenges in access to insulin: a global perspective. Lancet Diabetes Endocrinol 2016; 4(3): 275-85. https://doi.org/10.1016/S2213-8587(15)00521-5
https://doi.org/https://doi.org/10.1016/... . This cost has increased over the years due to soaring insulin prices and gradual shifting to newer and more expensive insulin analogues¹¹11. Patel H, Srishanmuganathan J, Car J, Majeed A. Trends in the prescription and cost of diabetic medications and monitoring equipment in England 1991-2004. J Public Health (Bangkok) 2007; 29(1): 48-52. https://doi.org/10.1093/pubmed/fdl076
https://doi.org/https://doi.org/10.1093/... ^,1212. DiMario S, Seoane-Vazquez E, Eguale T, Tyrrell B. Analysis of trends in utilization and cost of insulin in the United States and Canada. Value Heal. 2016; 19(3): A209-10. https://doi.org/10.1016/j.jval.2016.03.1274
https://doi.org/https://doi.org/10.1016/... ^,1313. Arrieta FJ, Calvo MJ, Peréz A, Saavedra P, Cordobés FJ, Cabral R, et al. Prevalence and consumption of medication in diabetes mellitus in Madrid (1996-2002). Rev Clin Esp 2006; 206(3): 117-21. http://doi.org/10.1157/13086204
https://doi.org/http://doi.org/10.1157/1... ^,1414. Luo J, Kesselheim AS, Greene J, Lipska KJ. Strategies to improve the affordability of insulin in the USA. Lancet Diabetes Endocrinol 2017; 5(3): 158-9. http://doi.org/10.1016/S2213-8587(17)30041-4
https://doi.org/http://doi.org/10.1016/S... . This heightens concerns on the availability and affordability of insulin, particularly in resource-limited countries¹⁵15. World Health Organization (WHO). Global Reports on Diabetes. Geneva: World Health Organization; 2016..

Brazil has the fourth largest number of diabetic patients worldwide, and an estimated three in each 1,000 inhabitants have DM1³3. International Diabetes Federation. Diabetes Atlas. 7a ed. International Diabetes Federation; 2015.^,1616. Patterson C, Guariguata L, Dahlquist G, Soltész G, Ogle G, Silink M. Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes. Diabetes Res Clin Pract 2014; 103(2): 161-75. http://doi.org/10.1016/j.diabres.2013.11.005
https://doi.org/http://doi.org/10.1016/j... . Among Brazilian adults reporting diabetes in 2013, 18% informed insulin use in the preceding two weeks¹⁷17. Instituto Brasileiro de Geografia e Estatística. Pesquisa nacional de saúde, 2013: percepção do estado de saúde, estilos de vida e doenças crônicas: Brasil, grandes regiões e unidades da Federação. Brasil: Instituto Brasileiro de Geografia e Estatística; 2014.. This number exceeds the estimated DM1 prevalence of 5-10% of the population with diabetes, and already suggests the adoption of protocols recommending expanded insulin use in non-DM1 patients¹⁶16. Patterson C, Guariguata L, Dahlquist G, Soltész G, Ogle G, Silink M. Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes. Diabetes Res Clin Pract 2014; 103(2): 161-75. http://doi.org/10.1016/j.diabres.2013.11.005
https://doi.org/http://doi.org/10.1016/j... .

A pharmaceutical market monitoring report from 2016 ranked traditional human insulins as the 29^th highest expenditure in Brazil, with a market of 250M-500 million Brazilian Real (BRL) in 2016 (70-140 million United States Dollars [USD])¹⁸18. Brasil. Agência Nacional de Vigilância Sanitária (ANVISA). Relatório de Atividades 2016. Brasília: Agência Nacional de Vigilância Sanitária: 2017.. Insulin analogues had by then market shares worth 400-800 million BRL (115-230 million USD). Global insulin sales at the time were estimated at 35 billion USD, indicating that Brazil held a low share in the global market considering the disease prevalence in the country¹⁹19. Pharmacompass. Product Sales Data From Annual Reports of Major Pharmaceutical Companies [Internet]. 2016 [accessed on Feb. 13, 2018]. Available from: Available from: https://www.pharmacompass.com/data-compilation/product-sales-data-from-annual-reports-of-major-pharmaceutical-companies-2016
https://www.pharmacompass.com/data-compi... .

These relatively low levels of expenditure may be credited to public insulin provision policies in place since 2006. Households finance about 80% of pharmaceutical expenditures in Brazil, but the federal government provides insulin for free via the Unified Health System (SUS)²⁰20. Brasil. Ministério da Saúde. Conta-satélite de saúde: Brasil : 2010-2017 [Internet]. Brasília; 2019 [accessed on Jul. 13, 2019]. 12 p. Available from: Available from: https://biblioteca.ibge.gov.br/index.php/biblioteca-catalogo?view=detalhes&id=2101690
https://biblioteca.ibge.gov.br/index.php... .

Two provision modes have been adopted by the SUS. The first one, in place since 2006, is the acquisition of insulin via centralized tendering by the Department of Health Logistics of the Ministry of Health (DLOG-MOH) with direct dispensing in SUS facilities²¹21. Brasil. Ministério da Saúde. Portaria nº 1.105, de 5 de julho de 2005. Brasil: Ministério da Saúde; 2005.. As from 2008, insulin is also provided with reimbursement to private accredited retailers via the Brazilian Popular Pharmacy Program (PFPB)²²22. Brasil. Ministério da Saúde. Portaria nº 947, de 26 de abril de 2010. Brasil: Ministério da Saúde ; 2010.. Up to February 2011, a cost-sharing scheme was in place in PFPB, but since then insulin is provided entirely free of charge and reimbursed by the Federal Government, according to a reference price list²³23. Santos-Pinto CDB, Costa N do R, Osorio-de-Castro CGS. Quem acessa o Programa Farmácia Popular do Brasil? Aspectos do fornecimento público de medicamentos. Ciên Saúde Colet 2011; 16(6): 2963-73. http://doi.org/10.1590/S1413-81232011000600034
https://doi.org/http://doi.org/10.1590/S... . Reimbursement rates are regularly updated and eventually downrated, as a rule based on unilateral government decrees.

Until 2017, traditional human insulins, which are much cheaper than insulin analogues, were the mainstay of treatment for the population living with diabetes in Brazil. The SUS did not provide insulin analogues. Access to them depended mainly on out-of-pocket payments and, eventually, litigation²⁴24. Marçal KK de S. A Judicialização da Assistência Farmacêutica: o caso Pernambuco em 2009 e 2010 [dissertação]. Recife: Fundação Oswaldo Cruz; 2012. 130 p.^,2525. Chieffi AL, Barata R de CB. Ações judiciais: estratégia da indústria farmacêutica para introdução de novos medicamentos. Rev Saúde Pública. 2010; 44(3): 421-9. https://doi.org/10.1590/S0034-89102010000300005
https://doi.org/https://doi.org/10.1590/... ^,2626. Machado MA de Á, Acurcio F de A, Brandão CMR, Faleiros DR, Guerra Júnior AA, Cherchiglia ML, et al. Judicialização do acesso a medicamentos no Estado de Minas Gerais, Brasil. Rev Saúde Pública 2011; 45(3): 590-8. https://doi.org/10.1590/S0034-89102011005000015
https://doi.org/https://doi.org/10.1590/... ^,2727. Campos Neto OH, Acurcio F de A, Machado MA de Á, Ferré F, Barbosa FLV, Cherchiglia ML, et al. Médicos, advogados e indústria farmacêutica na judicialização da saúde em Minas Gerais, Brasil. Rev Saúde Pública 2012; 46(5): 784-90. https://doi.org/10.1590/S0034-89102012000500004
https://doi.org/https://doi.org/10.1590/... , often with state and municipal governments being mandated by courts to provide them²⁸28. Brasil. Ministério da Saúde. Portaria nº 204, de 29 de janeiro 2007. Brasil: Ministério da Saúde; 2007.^,2929. Brasil. Ministério da Saúde Portaria nº 2.048, de 3 de setembro de 2009. Brasil: Ministério da Saúde ; 2009.^,3030. Brasil. Ministério da Saúde Portaria nº 3.916, de 30 de outubro de 1998. Brasil: Ministério da Saúde ; 1998.^,3131. Brasil. Ministério da Saúde. Portaria nº 1.555, de 30 julho de 2013. Brasil: Ministério da Saúde ; 2013.. To avoid the high costs of emergency purchases, some states and municipalities started to include analogues in their procurement lists, together with traditional human insulins, to cover eventual shortages in the provision by the federal government. In 2017 and 2019, respectively, provision of rapid-acting and long-acting insulins by the SUS became mandatory for DM1 diabetics³²32. Brasil. Ministério da Saúde. Secretaria de Ciência- Tecnologia e Insumos Estratégicos. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Portaria no 10, de 21 de fevereiro de 2017. Brasil: Ministério da Saúde ; 2017.^,3333. Brasil. Ministério da Saúde. Secretaria de Ciência Tecnologia e Insumos Estratégicos. Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC) . Portaria Conjunta no 17, de 12 de novembro de 2019. Brasil: Ministério da Saúde ; 2019..

This mandate for incorporation of newer and more expensive versions of insulin coincides with a foreseeably long spell of budgetary restriction on the SUS, due to the Constitutional Amendment 95³⁴34. Brasil. Senado Federal. Emenda Constitucional 95 [Internet]. Brasil: Senado Federal; 2016 [accessed on Feb. 13, 2018]. Available from: Available from: http://legis.senado.leg.br/legislacao/DetalhaSigen.action?id=540698
http://legis.senado.leg.br/legislacao/De... . This Amendment limits yearly corrections of mandatory government contributions to the SUS to official inflation values, replacing the former and much more favourable indexing increase in government revenues and gross national product growth³⁴34. Brasil. Senado Federal. Emenda Constitucional 95 [Internet]. Brasil: Senado Federal; 2016 [accessed on Feb. 13, 2018]. Available from: Available from: http://legis.senado.leg.br/legislacao/DetalhaSigen.action?id=540698
http://legis.senado.leg.br/legislacao/De... .

This new financing reality may threaten the sustainability of public insulin provision arrangements. The main objective of this study is to describe budget commitment for provision of insulin provision by the Brazilian Federal government, insulin prices and treatment availability from 2009 to 2017, a scenario preceding the mandatory provision of rapid-acting and long-acting insulins and current fiscal constraints.

METHODS

This is a drug utilization study, using retrospective administrative healthcare data on drug purchases and reimbursement. Insulin DLOG-MOH (centralized competitive bidding procurement) and PFPB (decentralized private retail reimbursement) data were used as proxies of insulin provision to the population and, hence, for utilization³⁵35. Capellà D. Descriptive tools and analysis. In: DUKES M-N-G, editor. Drug Utilization Studies Methods and Uses. Copenhagen: WHO Regional Publications/WHO Regional Office for Europe; 1993..

Expenditures on insulin by other Brazilian federal government agencies, municipalities and states were not included. These usually correspond to hospital acquisitions dedicated to inpatient use of insulin or to small-scale subnational government purchases during shortages in federal-provided insulin, which are not usually recorded in the databases used in this study.

We adopted a bottom-up accounting approach³⁶36. Chapko MK, Liu C-F, Perkins M, Li Y-F, Fortney JC, Maciejewski ML. Equivalence of two healthcare costing methods: bottom-up and top-down. Health Econ 2009; 18(10): 1188-201. https://doi.org/10.1002/hec.1422
https://doi.org/https://doi.org/10.1002/... to consolidate data on budgets comitted due to insulin acquisition. The data source for DLOG-MOH insulin procurement expenditures and volumes was the federal procurement administrative database: the Integrated General Services Administration System (Sistema Integrado de Administração de Serviços Gerais - SIASG). SIASG contains detailed information on all items purchased by the federal government, including goods and services. In accordance with federal law, every central government agency and organization is individually required to record data on product specification, number of purchases, estimated volume of procured goods, dosage forms and unit prices in SIASG. These variables were collected for Regular and NPH insulin purchases for the years 2009-2017.

PFPB reimbursement data (volumes and values reimbursed by the federal government according to insulin product from 2009 to 2017) were obtained from the Central Management Coordination of the Department of Pharmaceutical Services of the Brazilian Ministry of Health, by means of a special query via the Electronic System of the Information Service to Citizens (E-SIC)³⁷37. Brasil. Presidência da República. Lei no 12.527, de 18 de novembro de 2011. Brasil: Presidência da República; 2011., based on original data contained in Popular Pharmacy Program Authorization System. In accordance with federal law, every accredited retailer in the program is individually required to record data on patient identity, product specification, dosage form and unit price.

Given that data for the initial years in both databases showed inconsistencies, we collected data for both modes of provision from 2009 to 2017 to ensure better quality of data.

Population data was based on the Brazilian Institute of Geography and Statistics (IBGE)³⁸38. Instituto Brasileiro de Geografia e Estatística - IBGE. Estimativas de População [Internet]. [accessed on Feb. 13, 2018]. Available from: Available from: https://www.ibge.gov.br/estatisticas-novoportal/sociais/populacao/9103-estimativas-de-populacao.html
https://www.ibge.gov.br/estatisticas-nov... estimates, which were collected in the 2000 and 2010 Brazilian population censuses.

For comparing budgets committed to insulin purchases, prices and availability for treatment for the two insulin provision modes we initially determined the total volume of acquired insulin (Regular and NPH) and related budgets in current local currency units (BRL), according to provision mode (DLOG-MOH or PFPB) and year.

Insulin volumes were recorded in international units (IU) of insulin acquired year by year for each provision mode according to the formula expressed by Equation 1:

Budgets committed to insulin purchases were recorded in USD and BRL. In order to allow comparisons among budgets by year, all monetary values were corrected to the values from December 2017, using the Brazilian National Consumer Price Index (IPCA-IBGE) (Supplementary Table S1)³⁹39. Banco Central do Brasil. Calculadora do Cidadão [Internet]. 2016 [accessed on Feb. 13, 2018]. Available from: Available from: https://www3.bcb.gov.br/CALCIDADAO/publico/exibirFormCorrecaoValores.do?method=exibirFormCorrecaoValores
https://www3.bcb.gov.br/CALCIDADAO/publi... . For each year under analysis, the value of the BRL was then converted into average USD, considering the conversion rates of Banco Central do Brasil (Supplementary Table 2).

To compare the availability of insulin in each provision mode, we estimated the number of defined daily doses (DDD) per 1,000 inhabitants/day/year⁴⁰40. Dukes MNG. Drug Utilization Studies. Methods and Uses. Copenhagen: WHO Regional Publications/WHO Regional Office for Europe ; 1993.. This was performed by initially determining the total number of IU of insulin (both regular and NPH), as described above. We then proceeded to determine the total number of DDD, using the DDD listed value (40UI for all insulin types)⁴¹41. WHO Collaboration Centre for Drug Statistics Methodology. ATC/WHO Index. WHO Collaboration Centre for Drug Statistics Methodology; 2019., as in Equation 2:

We described the availability for treatment as DDD/1,000 inhabitants/day. For finding out the amount of DDD/1,000 inhabitants/day⁴²42. World Health Organization (WHO) . Essential medicines and health products - 4. DDD Indicators [Internet]. World Health Organization [accessed on Jan. 10, 2020]. Available from: Available from: https://www.who.int/medicines/regulation/medicines-safety/toolkit_indicators/en/index1.html
https://www.who.int/medicines/regulation... , we proceeded as follows (Equation 3):

No. of days in the period of data collection = 365 days.

On detailing overall availability for treatment for studied years and provision modes, we reported both gross overall availability and adjusted overall availability in DDD/1,000 inhabitants/day.

Gross availability depicts volumes translated into availability for treatment (DDD/1,000 inhabitants/day), referring to actual years of acquisition.

Adjusted overall availability refers to overall availability, considering the redistribution of DLOG-MOH-acquired insulin for years with no insulin tenders (2015 and 2016), or tenders for very small volumes (2011) of insulin. We assumed that the volumes of DLOG-MOH tendered in 2014 and resulting purchased volumes were evenly dispensed during 2014, 2015 and 2016. This redistribution is warranted by stated manufacturer shelf-life, which defines a 3-year storage period as admissible. Redistribution of availability for treatment with DLOG was made according to the formula (Equation 4):

For years with very small volumes of tenders (2011), volumes of tender and the year before it were added and divided by two, also providing equal adjusted volumes for both years.

To obtain adjusted overall availability, PFPB availability was added to DLOG adjusted values for 2010, 2011, 2014, 2015 and 2016. For other years, gross and adjusted values are identical.

To obtain prices per DDD of human insulin in the two delivery modes in USD currency from 2017, we determined the yearly average acquisition prices per DDD for each provision mode, according to the following formula (Equation 5):

Weighed overall prices in USD currency from 2017 per DDD stand for the average price per DDD paid by the federal government each year, considering the varying yearly provision mode mixes. These were calculated as follows (Equation 6):

Results for budgets committed to insulin acquisition in million BRL and USD from 2017, insulin volumes and types in 1,000 IU, availability for treatment (DDD of insulin/1,000 inhabitants/day) and prices (in USD currency from 2017) per DDD were shown for the two provision modes on a yearly basis using tables and graphs generated in Microsoft Excel (Microsoft Corp 2013).

This study did not involve human subjects and is based solely on publicly available administrative secondary data, devoid of sensitive data and, thus, has not undergone a formal ethics committee evaluation, according to Brazilian ethical legislation (Resolution 510, from April 7^th, 2016)⁴³43. Brasil. Ministério da Saúde. Conselho Nacional de Saúde. Resolução no 510, de 7 de abril de 2016. Brasil: Ministério da Saúde ; 2016..

RESULTS

Budgetary commitments due to insulin acquisition over nine years amounted to 1,027 billion USD currency from 2017, averaging 114.1 million USD/year. Budgetary commitments due to DLOG tendering were rather erratic, falling to particularly low levels in 2011, with a complete absence of tenders in 2015 and 2016. As a contrast, PFPB yearly comitted budgets steadily increased and, by the end of the series, the average committed budgets due to PFPB was higher than the DLOG average (Table 1).

Despite the increase in PFPB provision along the study time frame, DLOG-MOH was the main insulin provider (Table 2). Tenders were won by Novo Nordisk (for 5 years, for both insulin types), Lilly (for one year, for both insulin types) and Aspen Pharma (for one year, for regular insulin).

DLOG-MOH and PFBP together provided an average of 6.08 DDD/1000 inhabitants/day over the study years. Gross overall availability for treatment peaked at 11.22 DDD/1,000 inhabitants/day in 2017, whereas expenditures were the highest in 2013 (242.13 million USD). The minimum adjusted overall availability of insulin occurred in 2010, with 3.47 DDD/1,000 inhabitants/year (Table 3).

Average prices/reimbursement rates in PFPB were higher than in DLOG along the series, but differences showed a decisively downward trend throughout the years. Reimbursement rates for PFPB were 7.2 times higher than DLOG tendering prices in 2009, but gradually fell to 2.7 times in 2017. An analysis of the prices weighed by volume provides actual overall mean prices/DDD paid each year by the federal government. Peak prices/DDD for DLOG were seen for 2013. Weighed overall prices were the highest in years of greater participation of the PFPB mode in provision, namely, 2011, 2015 and 2016 (Table 4).

DISCUSSION

The average availability of 6.08 DDD/1000 inhabitants/year for federal-government financed insulin was twice the estimated prevalence of DM1 (insulin-dependent) diabetes in Brazil. This means that patients who cannot live without the drug would be easily covered by the government-financed scheme and some non-DM1 patients under stricter glycemic control protocols would also benefit from it. Given the disease prevalence and the size of the global insulin market, it seems that Brazil managed to achieve reasonable availability of insulin at affordable costs during the study period.

There were significant differences in patterns of provision according to provision mode. Although PFPB dispensed a third of the treatments provided by the SUS by 2017, there were consistent treatment availability increases in this provision mode since the beginning of the program in 2008. The centralized tendering process in DLOG, on the other hand, showed very erratic patterns. Insulin shelf-life in closed vials may extend from 2-3 years according to the manufacturer⁶6. Sociedade Brasileira de Diabetes. Diretrizes da Sociedade Brasileira de Diabetes: 2014-2015. São Paulo: AC Farmacêutica ; 2016.. This may explain the existence of years for which no insulin tender is recorded. However, there are reports of delivery disruption in several states in these same years.

In other low-income countries, centralized tenders show robust price-elasticity⁴⁴44. Srivastava D, McGuire A. Analysis of prices paid by low-income countries - how price sensitive is government demand for medicines? BMC Public Health 2014; 14: 767. https://doi.org/10.1186/1471-2458-14-767, meaning countries tend not to buy if prices rise. Increase in price in the international market⁴⁵45. Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P. Expenditures and Prices of Antihyperglycemic Medications in the United States: 2002-2013. JAMA 2016; 315(13): 1400-2. https://doi.org/10.1001/jama.2016.0126
https://doi.org/https://doi.org/10.1001/... coincides with years of missing insulin tenders. The last year of the study (2017) stands out for the very favorable DLOG tendering prices. Novo Nordisk provided the insulin, probably based on the company’s equity pricing scheme to reduce price for government-provided 10mL vial of human insulin in least developed and middle-income countries⁴⁶46. Novo Nordisk. Strategy for global access to diabetes care- Closing the gap [Internet]. Novo Nordisk; 2013 [accessed on Jul. 2, 2018]. 12 p. Available from: Available from: https://www.novonordisk.com/content/dam/Denmark/HQ/aboutus/documents/our-positions/Novo-Nordisk-strategy-global-access-diabetes-care.pdf
https://www.novonordisk.com/content/dam/... .

Reimbursement is apparently less price-elastic than tenders. Prices/DDD for PFPB were substantially higher than for DLOG-MOH, but showed a decreasing trend, in line with reimbursement rates adjustments by the federal government. Differences in prices/reimbursement rates between the two provision modes must be adequately contextualized. Dispensing fees, logistics to outlet⁴⁷47. Silva RM da, Caetano R. Costs of Public Pharmaceutical Services in Rio de Janeiro Compared to Farmácia Popular Program. Rev Saúde Pública 2016; 50. https://doi.org/10.1590/s1518-8787.2016050006605
https://doi.org/https://doi.org/10.1590/... and eventual product losses due to insulin cold chain storage requirement must be considered in pricing differences. Moreover, PFPB drug acquisition is the responsibility of retail pharmacies, which tend to have less purchasing power than DLOG-MOH.

Decreasing reimbursement rates for human insulins may discourage distribution via PFPB in remote areas of the country, possibly increasing reliance on the tender-based provision mode. This would demand closer attention to tendering practices and point of care delivery processes-including both securing an adequate budget and supply chain monitoring. Effects of PFPB reimbursement rates should be contrasted with the increased transaction costs involved in enhancing supply chain performance for DLOG-tendered insulin to define the most cost-effective approach.

Many factors may interfere in individual insulin requirements, such as age, weight, meal ingestion and physical activities⁶6. Sociedade Brasileira de Diabetes. Diretrizes da Sociedade Brasileira de Diabetes: 2014-2015. São Paulo: AC Farmacêutica ; 2016.. There is a striking inter-country variation across DM2 treatment regimens, which depends both on patient’s profiles and on differences in countries’ healthcare environments⁴⁸48. Polinski JM, Kim SC, Jiang D, Hassoun A, Shrank WH, Cos X, et al. Geographic patterns in patient demographics and insulin use in 18 countries, a global perspective from the multinational observational study assessing insulin use: understanding the challenges associated with progression of therapy (MOSAIc). BMC Endocr Disord. 2015; 15. https://doi.org/10.1186/s12902-015-0044-z
https://doi.org/https://doi.org/10.1186/... .

The SUS provision scheme for human insulins seems to be a decisive factor in explaining patterns of insulin use in Brazil. In an 18-country study on insulin-using DM2 patients, Brazil had the lowest use of pens (17% versus 74% all countries) and 79% of insulin regimes were based on basal insulin only (all countries 51%). This pattern possibly reflects the provision of insulin to a substantial number of Brazilians by the SUS⁴⁸48. Polinski JM, Kim SC, Jiang D, Hassoun A, Shrank WH, Cos X, et al. Geographic patterns in patient demographics and insulin use in 18 countries, a global perspective from the multinational observational study assessing insulin use: understanding the challenges associated with progression of therapy (MOSAIc). BMC Endocr Disord. 2015; 15. https://doi.org/10.1186/s12902-015-0044-z
https://doi.org/https://doi.org/10.1186/... .

This scenario may be undergoing significant change. Preliminary data for 2018⁴⁹49. Brasil. Ministério da Economia. Painel de preços [Internet]. 2018 [accessed on Jul. 3, 2019]. Available from: Available from: http://paineldeprecos.planejamento.gov.br/
http://paineldeprecos.planejamento.gov.b... show tendering of 3mL insulin cartridges for use with injection pens not previously available via DLOG. The 2018 DLOG comitted budget due to insulin purchase was more than doubled in relation to previous years, with a modest reduction in the number of DDD provided⁴⁹49. Brasil. Ministério da Economia. Painel de preços [Internet]. 2018 [accessed on Jul. 3, 2019]. Available from: Available from: http://paineldeprecos.planejamento.gov.br/
http://paineldeprecos.planejamento.gov.b... .

Most of the world’s insulin is produced by three major pharmaceutical companies, and their market power is not to be underestimated⁵⁰50. Wirtz VJ, Knox R, Cao C, Mehrtash H, Posner NW, McClenathan J. Insulin Market Profile. Health Action International Overtoom 2016; 60: 412-4523. Available from: https://haiweb.org/wp-content/uploads/2016/04/ACCISS_Insulin-Market-Profile_FINAL.pdf
https://haiweb.org/wp-content/uploads/20... ^,5151. Prescient & Strategy Intelligence. Human Insulin Market Overview [Internet]. 2018 [accessed on Jul. 1, 2018]. Available from: Available from: https://www.psmarketresearch.com/market-analysis/human-insulin-market
https://www.psmarketresearch.com/market-... ^,5252. Beran D, Hirsch IB, Yudkin JS. Why Are We Failing to Address the Issue of Access to Insulin? A National and Global Perspective. Diabetes Care 2018; 41(6): 1125-31. https://doi.org/10.2337/dc17-2123
https://doi.org/https://doi.org/10.2337/... . The average price of insulin skyrocketed in recent years, nearly increasing threefold between 2002 and 2013⁴⁵45. Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P. Expenditures and Prices of Antihyperglycemic Medications in the United States: 2002-2013. JAMA 2016; 315(13): 1400-2. https://doi.org/10.1001/jama.2016.0126
https://doi.org/https://doi.org/10.1001/... . Additionally, we are apparently witnessing a trend toward wider use of 3mL insulin cartridges, injection pens and analogues.

Expenditures on insulin were already substantial relative to SUS overall pharmaceutical budget in 2017. It is thus increasingly necessary to understand how expenditures on insulin impact the SUS budget to plan future actions and purchasing policies. With the increasing incorporation of newer devices and analogues, the Brazilian federal government expenditures on insulin will tend to rise. This could gradually jeopardize the availability for treatment and pharmaceutical budgets in very similar ways to antiretroviral (ARV) and oncologicals.

Thus, models for dealing with insulin provision should increasingly follow those adopted in ARV negotiations⁵²52. Beran D, Hirsch IB, Yudkin JS. Why Are We Failing to Address the Issue of Access to Insulin? A National and Global Perspective. Diabetes Care 2018; 41(6): 1125-31. https://doi.org/10.2337/dc17-2123
https://doi.org/https://doi.org/10.2337/... . Pressure of international disease associations should be placed not only on governments but also on laboratories to allow balance in demand and provision. Some low and medium income countries are already working on joint strategies for ARV and insulin acquisition⁵³53. Bennett CA. Urban Health Systems Strengthening: The Community Defined Health System for HIV/AIDS and Diabetes Services in Korogocho, Kenya [dissertation] [Internet]. Washington, D.C.: The George Washington University; 2016 [accessed on Feb. 1, 2018]. Available from: Available from: https://pqdtopen.proquest.com/doc/1813675188.html?FMT=ABS
https://pqdtopen.proquest.com/doc/181367... .

To the best of our knowledge, this is the first study to estimate insulin procurement volume and expenditures based on purchasing data. Prior studies⁵⁴54. Aurea AP, Magalhães LCG de, Garcia LP, Santos CF dos, Almeida RF de. Programas de assistência farmacêutica do governo federal: Estrutura atual, evolução dos gastos com medicamentos e primeiras evidências de sua eficiência, 2005-2008. Report No. 1,658. Brasília: Instituto de Pesquisa Econômica Aplicada (IPEA); 2011.^,5555. Aurea AP, Magalhães LCG de, Garcia LP, Santos CF dos, Almeida RF de, Stivali M, et al. Compras Federais de Medicamentos da Assistência Farmacêutica: evidências recentes. Radar 2010; 9: 12-8. examined overall insulin expenditures, but none have analyzed federal drug provision based on comprehensive procurement and reimbursement data.

The present study has some limitations. Actual data on delivery and consumption, number of diabetics and number of insulin users in Brazil are lacking, and tendering and reimbursement data are utilization proxies. Assuming the federal government is the main provider of human insulin in Brazil and that 100% of this volume is available to users, we may also accept that we have a proxy for consumption. However, as insulins require a cold chain structure for distribution, which can lead to loss, its utilization may easily have been overestimated.

The use of DDD to estimate treatment provision must also be approached carefully. The DDD is a unit of measurement, employed for comparability, and real-life doses may substantially differ from standardized DDD. Continuous consumption may be reflected in average DDDs over time, but the number of DDDs may not reflect actual number of patients under treatment. Besides that, employing the entire population, number of diabetics or number of insulin users in the denominator changes the interpretation of this indicator.

Impact of the recent incorporation of insulin analogues and increasing expenditures on newer insulin-delivery devices by the SUS is still not measurable in this study, which may serve as a baseline for future comparisons.

In conclusion, Brazil has apparently managed to hold a moderately successful, although imperfect, public provision arrangement for insulin in place, striving with the trade-offs of private and public provision modes and prices. Future studies need to address availability for treatment and financial sustainability in the new scenario of analogue incorporation.

The ascending number of insulin users among the diabetic population and the development of DM2 treatment protocol⁵⁶56. Brasil. Ministério da Saúde. Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC). Protocolos e Diretrizes do Ministério da Saúde [Internet]. Brasil: Ministério da Saúde ; 2019 [accessed on Jan. 5, 2020]. Available from: Available from: http://conitec.gov.br/pcdt-em-elaboracao
http://conitec.gov.br/pcdt-em-elaboracao... will result in more intensive use of insulin and may significantly burden financing by the SUS. Therefore, a last recommendation addresses integrated diabetes care and prevention policies, which must be strengthened to rationalize population insulin requirements¹¹11. Patel H, Srishanmuganathan J, Car J, Majeed A. Trends in the prescription and cost of diabetic medications and monitoring equipment in England 1991-2004. J Public Health (Bangkok) 2007; 29(1): 48-52. https://doi.org/10.1093/pubmed/fdl076
https://doi.org/https://doi.org/10.1093/... ^,5757. Gill G-V, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries. A way forward? Diabetologia 2011; 54(1): 19-24. https://doi.org/10.1007/s00125-010-1897-3
https://doi.org/https://doi.org/10.1007/... .

ACKNOWLEDGMENTS

We thank Dr. Jing Luo (Harvard B&W Hospital) for his helpful insight and criticism and Dr. Rondineli Mendes (NAF/ENSP/Fiocruz) for helping with information sources and discussions. We also would like to thank José Roberto Peters from the Health Economy, Investment and Development Department of the Brazilian Ministry of Health for data systematization support. Research was funded by the Brazilian Ministry of Health (grant number 304975/2016-8), CNPq and CAPES.

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