The bedaquiline market for drug-resistant tuberculosis treatment and the challenges for public production in BrazilAbstract
Tuberculosis continues to be a severe public health problem in the country, with high incidence and mortality rates, especially among vulnerable populations. The introduction of bedaquiline into the Unified Health System (SUS) in 2021 represented significant progress, but it also reveals the need for a comprehensive approach to ensure equitable access to treatment. This longitudinal case study, carried out from 2018 to 2024, analyzes the barriers that prevent the public production of bedaquiline in Brazil. The study describes the epidemiological scenario of tuberculosis and characterizes the bedaquline market, with data on medicine marketing authorization, production, acquisitions, and patent landscape. The study explores the barriers that prevent the public production of bedaquiline, discusses intellectual property issues, and analyzes the impact of a monopoly on prices and access to the medicine. The analysis concludes that the public production of bedaquiline is essential for the sustainability of access to drug-resistant tuberculosis treatment in Brazil, reducing costs and ensuring the availability of the medicine for all patients.
Key words:
Bedaquiline; Public health policy; Intellectual property; Drug price; Official laboratory
Resumo
A tuberculose continua a ser um grave problema de saúde pública no país, com altas taxas de incidência e mortalidade, especialmente entre populações vulneráveis. A introdução da bedaquilina no Sistema Único de Saúde (SUS) em 2021 representou um avanço significativo, mas revela a necessidade de uma abordagem abrangente para garantir o acesso equitativo ao tratamento. Este estudo de caso longitudinal entre 2018 e 2024 analisa as barreiras que impedem a produção pública da bedaquilina no Brasil. Descreve-se o cenário epidemiológico da tuberculose e caracteriza-se o mercado de bedaquilina, com dados de registro sanitário, produção, aquisições e mapeamento patentário. O estudo explora as barreiras que impedem a produção pública da bedaquilina, discute questões de propriedade intelectual e o impacto do monopólio sobre o preço e o acesso ao medicamento. A análise conclui que a produção pública da bedaquilina é essencial para a sustentabilidade do acesso ao tratamento da tuberculose resistente no Brasil, reduzindo custos e garantindo a disponibilidade do medicamento para todos os pacientes.
Palavras-chave:
Bedaquilina; Política de saúde pública; Propriedade intelectual; Preço de medicamento; Laboratório oficial
Resumen
La tuberculosis continúa siendo un grave problema de salud pública en el país, con altas tasas de incidencia y mortalidad, especialmente entre las poblaciones vulnerables. La introducción de la bedaquilina en el Sistema Único de Salud (SUS) en 2021 representó un avance significativo, pero revela la necesidad de un enfoque integral para garantizar el acceso equitativo al tratamiento. Este estudio de caso longitudinal, realizado entre 2018 y 2024, analiza las barreras que impiden la producción pública de bedaquilina en Brasil. El estudio describe el panorama epidemiológico de la tuberculosis y caracteriza el mercado de bedaquilina, con datos sobre registro sanitario, producción, adquisiciones y mapeo de patentes. El estudio explora las barreras que impiden la producción pública de bedaquilina, analiza cuestiones de propiedad intelectual y el impacto del monopolio en el precio y el acceso al medicamento. El análisis concluye que la producción pública de bedaquilina es esencial para la sostenibilidad del acceso al tratamiento de la tuberculosis farmacorresistente en Brasil, reduciendo costos y garantizando la disponibilidad del medicamento para todos los pacientes.
Palabras clave:
Bedaquilina; Política de salud; Propiedad intelectual; Precio de medicamento; Laboratorio oficial
Introduction
Tuberculosis (TB) is a curable and preventable disease; however, nearly 10.8 million people around the world were still living with the disease in 20231. Since it is a socially determined disease, tuberculosis has a strong impact in poor countries with a low socioeconomic profile, where most of the deaths caused by the disease occur2. In this scenario, Brazil is among the 30 high TB burden countries, recording approximately 103,000 new cases in 2023, which corresponds to an incidence rate of 49 per 100,000 individuals1.
In Brazil, the alarming social disparity is reflected in severe inequalities health care, accentuated in different social classes, racial and gender groups3. These injustices are particularly visible regarding tuberculosis, given that its high incidence exposes the profound social exclusion present in the country. Precarious living conditions and poor nutrition exacerbate vulnerability to tuberculosis, making it a significant health problem among the population living in slums, the street homeless people, and the prison population4. The disease also affects, severely and disproportionately, the indigenous people and traditional communities. The healthcare system fails to reach those populations, revealing the urgent need for intersectoral interventions that can guarantee equity and social justice in access to healthcare5.
Resistant tuberculosis reflects these same socioeconomic disparities and is more prevalent in vulnerable populations. The increase in drug-resistance to medicines, due to treatment abandonment or to irregular adherence to long-term treatments with adverse effects, makes the management of the disease even more challenging, especially among populations that face barriers in access to adequate healthcare. The profile of the impacted population includes mostly young black men, with a low educational level, and often with comorbidities associated with substance abuse6.
Drug-resistant tuberculosis (DR-TB) is characterized by resistance to at least one of the medicines commonly used, while multi-resistant tuberculosis (MDR-TB) is caused by mycobacteria that do not respond to isoniazid and rifampicin, the most efficient first-line tuberculosis medicines1.
In 2023, the first cases with extensive DR-TB (XDR-TB) were identified in Brazil. In this kind of tuberculosis, the bacillus demonstrates resistance to rifampicin, isoniazid, to any type of fluoroquinolone, and to at least one of the following medicines: bedaquiline or linezolid. This makes treatment more complex and prolonged, potentially lasting up to 18 months7. The increasing detection of cases of drug resistance highlights the need for early treatment and for continuous investment in research and development (R&D) of new medicines.
DR-TB is a serious global health problem, especially in high TB burden countries8. In the last decade, many medicines were approved by the Food and Drug Administration (FDA) for the treatment of MDR-TB, such as bedaquiline (TMC-207), a diarylquinoline that inhibits mycobacterial ATP synthase; pretomanid; and linezolid9. The World Health Organization (WHO) guidelines recommend a six-month regimen consisting of bedaquiline, pretomanid and linezolid (BPaL) or bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM), as treatment options for MDR-TB10.
Brazil has the capability of producing many healthcare products, but there is still a strong dependency on the importation of medicines and active pharmaceutical ingredients (APIs)11. Brazil is one of the few countries that has public pharmaceutical industries spread throughout its territory, producing medicines and vaccines to supply, preferably, the pharmaceutical care programs of the Unified Health System (SUS)12,13.
Faced with the epidemiological scenario of tuberculosis in Brazil, and considering the importance of bedaquiline for treatment, as well as the crucial role of public production to guarantee sustainable access in the Brazilian context, the present article aims to analyze the barriers that prevent the public production of bedaquiline, considered to be a key element in combating DR-TB, as well as to discuss how to overcome challenges related to pharmaceutical care.
Methodology
This work is a longitudinal study conducted from 2018 to 2024 in Brazil. The study consisted of the following methodological stages: characterization of the epidemiological landscape of tuberculosis, characterization of the bedaquiline market, and discussion concerning the barriers for public production in Brazil.
The epidemiological overview was constructed based on the Tuberculosis Epidemiological Bulletin14. Information was collected on the number of new cases, incidence per 100,000 inhabitants, total number of deaths from tuberculosis, and the number of drug-resistance cases between 2018 and 2024.
The characterization of the bedaquiline market was developed based on marketing authorization, production, acquisitions, and patent landscape. The information on marketing authorization was obtained from the National Agency of Health Surveillance (ANVISA)15.
Patent landscape was performed based on publicly available information in Orange Book16, Patent Register17, Patent Opposition Database18, MedsPaL19, WIPO PatentScope20, Espacenet21 databases and in the Chaves & Di Giano document (2021)22. Verification of the situation and the content of the Brazilian patent applications was conducted through consultation at the patent portal of the National Patent Office (Instituto Nacional da Propriedade Industrial - INPI)23.
The acquisition price of bedaquiline by the Ministry of Health was accessed through the Integrated Ombudsman and Access to Information Platform of the Comptroller General of Brazil (Controladoria Geral da União - CGU)24. Information was collected regarding the years of acquisition, pharmaceutical forms, unity price, amounts purchased, and suppliers. For comparison with international prices, the unit price of the medicines, in dollars, was estimated, based on the average exchange rate registered by the Central Bank for each year25, as well as the cost of treatment, considering the use of 188 tablets for a six-month treatment26.
Epidemiological landscape
The number of people diagnosed with tuberculosis, the incidence index per 100,000 inhabitants, and the number of deaths from tuberculosis in Brazil between 2018 and 2024 are shown in Table 1. Brazil has a record of more than 84,000 people diagnosed with tuberculosis in 2023 and 2024. The number of cases of tuberculosis increased again after two years of relative decline: from 78,400 new cases in 2019, to 69,600 in 2020, and 73,100 in 2021. Concerning the number of deaths from tuberculosis, nearly 16 Brazilians lose their lives every day due to the disease, totaling more than 6,000 deaths in 2023. There has been a significant increase, especially during the COVID-19 pandemic years, despite considering a lower number of diagnoses.
The number of DR-TB cases between 2018 and 2024, according to the pattern of resistance, is shown in Table 2, with the highest resistance recorded in 2019 and the lowest in 2024.
The bedaquiline market: marketing authorization, acquisitions, patents, and production
The marketing authorization of bedaquiline fumarate in Brazil, the commercially available formulation, was granted in February 2019 to the Belgian pharmaceutical company, Janssen-Cilag, and its production is carried out by the Indian company, Recipharm.
Bedaquiline began to be commercialized in Brazil after its adoption into SUS for the treatment of DR-TB in 2021. The data concerning acquisitions between 2021 and 2024 is shown in Table 3, and an increase of 83% is noticeable in the number of tablets acquired from 2021 to 2023, followed by a decrease in 2024. Compared to 2021, there was a 12.23% decline in unit price in 2022 and of 58.30% in 2024. An alternance of suppliers was also observed, between Janssen and the Global Drug Facility (GDF), which is a mechanism of acquisition and provision of products for tuberculosis treatment.
In Brazil, at least eleven patent applications related to bedaquiline have been filed in the INPI, most of which by the transnational pharmaceutical company, Janssen, and two were filed by TB Alliance, a non-profit organization for the development of tuberculosis treatment products. The first patent application filed in Brazil (PI0312927-6) refers to the protection of the API, the patent was granted and is already expired. The others correspond to secondary patent applications, which protect processes, composition (including fumarate salt), combinations with other medicines, and use and method of treatment. Among those, two patents were granted and are still valid (PI0506400-7 and PI0611166-1), two applications were rejected (PI0506121-0 and PI0719693-8), one was granted and then revoked (BR112017015784-5), one granted patent expired (PI0510414-9), one application was withdrawn (BR112019017901-1), and three applications are still pending a final decision (BR112018007625-2, BR122021025600-4 and BR112020000687-4). If all these patent applications were granted, the patent monopoly could extend until 2038, accumulating 35 years of monopoly. The patent information for bedaquiline in Brazil is synthesized in Figure 1.
Timeline of potential patent protection related to bedaquiline in Brazil, based on an estimated 20-year monopoly.
Since 2024, there have been some important administrative decisions related to those patent applications. In June 2024, the application for bedaquiline fumarate salt (PI0719693-8) was rejected, thus ending that process administratively. This patent application was the target of a pre-grant opposition by the Brazilian Interdisciplinary Aids Association (Associação Brasileira Interdisciplinar de Aids - ABIA) in May 2020, it was rejected in October 2020, but an appeal delayed the final decision for almost four years.
Also in June 2024, the patent application that protects the BPaL combination (BR112018007625-2) was rejected at first instance. But that was not the final decision, as an appeal was filed by the applicant company. Additionally, its divided patent application (BR122021025600-4), also protecting the BPaL combination, for which a pre-grant opposition by ABIA was presented, was rejected at first instance in August 2024, but it is still subject to appeal.
In August 2024, a patent that was granted in March 2023 (BR112017015784-5) was revoked. The revocation occurred after a post-grant opposition was submitted in November 2023 by ABIA. The patent specifically protected the formulation of the dispersible tablet used in pediatric treatment, prolonging the monopoly until 2036. Finally, a patent (PI0510414-9) was granted, which protected the combination of bedaquiline with other antimycobacterial agents, but it expired in May 2025.
There are still two granted patents that could make the production and commercialization of generic versions of bedaquiline unfeasible before their expiration dates, especially the patent (PI0506400-7) that protects the use of bedaquiline for the production of a medicine until 2025. The patent (PI0611166-1) that protects, until May 2026, the separation process for bedaquiline active isomer, which is the molecule used in the commercially available product, is only a barrier if the same synthesis route is used.
Discussion
The analysis of the epidemiological landscape reveals that the number of tuberculosis cases in Brazil continues to be alarming, with an increase in incidence since 2017 and from 2022 onwards, following a decrease between 2020 and 2022, and without a substantial decline in the number of drug-resistant cases. This suggests that current interventions have not been sufficient, and efforts are required in terms of public health policies, focusing on prevention and treatment strategies, as well as intersectoral actions.
Brazil has the unfortunate record of having the highest number of tuberculosis cases recorded in the Americas, with a negative impact after the COVID-19 pandemic, with rates in 2022 higher than those of 20191. At this paralyzing pace, it will be difficult for the country to fulfill the commitment of eliminate tuberculosis as a public health problem by 203027. The potential impact of the COVID-19 health crisis must be considered, because of increased poverty and social vulnerability, or because of the collapse of the public health system, which may have contributed to the rise in tuberculosis-related deaths, despite a possible underreporting in the number of recorded cases diagnosed between 2020 and 2021.
In April 2023, the Interministerial Committee for the Elimination of Tuberculosis and Other Socially Determined Diseases (Comitê Interministerial para a Eliminação da Tuberculose e de Outras Doenças Determinadas Socialmente - CIEDDS)28 was created. According to Decree no. 11,494/2023, the acronym for the Interministerial Committee for Elimination of Tuberculosis and Other Socially Determined Diseases was CIEDS; with the new text defined in Decree no. 11,908/2024, it was changed to CIEDDS. The purpose of this committee is to promote initiatives aimed at the eradication, by 2030, of tuberculosis and other socially determined diseases, considered public health problems in Brazil. Concerning tuberculosis, the established goal is to reduce incidence to less than 10 cases per 100,000 inhabitants and reduce the number of deaths to less than 230 per year29.
The discussion regarding equity in access to medicine is crucial from a global point of view: by September 2019, only 36,000 patients had received bedaquiline, although the estimated annual demand was 160,000, mainly because, among other reasons, of its high price30. In Brazil, social and economic inequalities that permeate society are reflected in access to tuberculosis treatment. In this regard, the recent adoptions into SUS for the treatment of DR-TB26,31,32 are very important, since they are advancing the implementation of BPaL and BPaLM therapeutic schemes, recommended by WHO.
Although it has been in the global market since 2013, the marketing authorization of bedaquiline in Brazil, a high TB burden country1, did not take place until 2019. Bedaquiline was approved by the US FDA in December 201233 and was recommended by the European Medicines Agency (EMA) in December 201334. Still in 2013, the WHO began to recommend bedaquiline for MDR-TB35, and the WHO 2018 guidelines recommended bedaquiline as the first-line medicine in an oral therapeutic scheme designed to maximize the treatment outcomes and, at the same time, minimize the toxicity of injectable agents36.
Linezolid, since it has other indications as a broad-spectrum antibiotic, has been approved and acquired in Brazil since the 2000s15. Although it does not have a definitive marketing authorization, pretomanid is in the marketing authorization process and has been acquired, through the Pan-American Health Organization (PAHO), from the Indian pharmaceutical company, Mylan, since 202424. Meanwhile, delamanid, although its adoption has been recommended by National Commission for the Incorporation of Technologies in SUS (Comissão Nacional de Incorporação de Tecnologias no SUS - CONITEC) since 2020, still does not have a marketing authorization, but it can be acquired through international organizations32.
The delay in marketing authorization in Brazil by this company is not something new, as documented in the case of the medicine rilpivirine, for which there was never a request for marketing authorization by the pharmaceutical company Jansen, regardless of the filing of many patent applications. As emphasized in this report, there is no direct relationship between patent protection and marketing authorization of a medicine; however, the lack of authorization may hinder a series of stages in the operationalization of access to the medicine and keep other competitors from entering the market37.
Still concerning the medicine marketing authorization, it is important to highlight that, even though the authorization is under the name of the transnational pharmaceutical company, Janssen-Cilag, bedaquiline is produced by an Indian industry, which works as a Contract Development & Manufacturing Organization (CDMO). This outsourcing and offshoring production practice is not a new phenomenon, but it has had increasing importance in recent years. It is a cost reduction practice38, and it constitutes a profit maximization strategy by transnational pharmaceutical companies39.
The price of bedaquiline has been the topic of an international discussion for some years. In a 2015 WHO document, the price varied between US$30,000 and US$900 in high- and low-income countries, respectively40. In July 2023, Janssen granted GDF a license to bid for, acquire, and supply generic versions of bedaquiline to low- and middle-income countries, where the medicine is still under patent. One month later, Janssen began to supply GDF with the medicine for US$130 for the six-month treatment. However, other middle-income countries, such as South Africa, which do not acquire it through GDF, continue to pay the US$306 price for the six-month treatment41.
In Brazil, bedaquiline price is also an issue to be addressed, since the Ministry of Health operates in this market in a monopsonistic manner, as it is the sole buyer. Despite this position, which theoretically could allow the government to negotiate lower prices, the extent of the patent monopoly restricted competition and kept the prices high, draining SUS resources and resulting in a direct impact on the State’s ability to guarantee adequate treatments.
According to the report on recommendation for bedaquiline adoption, the initial price proposed for adoption was US$400/treatment with tablets (unit price of US$2.13 or R$10.88 at an exchange rate of R$5.11715) in 2020. After public consultation, the company submitted a new proposal of a US$340/treatment price, which was the price offered in more than 135 middle-income countries, including Brazil26.
The study by Gotham et al. (2017)42, which estimated prices for generic versions of medicines for DR-TB treatment, stated that bedaquiline could be produced at an average monthly price between US$7.8 and US$17.2 for high and low demand, respectively (or US$46.8-103.2/six-month treatment). In comparison with the price paid in the 2023 acquisition, the Brazilian price was between 2.8 and 6.2 times higher than this estimate. However, from 2024 onwards, the acquisition price of bedaquiline became much closer to the estimate, which coincided with the beginning of the changes in the patent landscape in Brazil.
The analysis presented in the article suggests that generic versions of bedaquiline and other medicines could be produced at lower prices, improving access to treatment for people with MDR-TB worldwide, especially in low-income countries or those with health systems with limited resources. The article highlights the importance of exploring strategies that allow for the production of generic medicines at affordable prices, seeking to improve access to treatment and reduce the impact of MDR-TB, one of the main global public health concerns42.
Moreover, it is important to mention that, according to investigations, there have been significant public investments in the development and introduction of bedaquiline, estimated to be something between US$451 and US$742 million, supporting the critical work that was left unfinished by Janssen. The amount that Janssen invested in bedaquiline R&D is not known due to lack of transparency by the company, which did not publish the details of its expenses. Bedaquiline is a successful example of clinical development carried out through publicly funded projects. Hence, the credit for bedaquiline development belongs to the public and its price should reflect this in order to guarantee, primarily, the lives and the health of people30,43. It is crucial to remember that we are dealing with an essential medicine for treating a disease deeply interconnected with poverty.
Issues related to intellectual property are essential when analyzing the bedaquiline market. As a signatory of the Agreement on Trade-Related Aspects of Intellectual Property (TRIPS Agreement), Brazil grants patent monopoly privileges to pharmaceutical products and processes for 20 years if the patent applications fulfills the requirements and conditions of patentability predicted in the Brazilian Industrial Property Law (Lei da Propriedade Industrial - LPI)44. However, decisions regarding patent granting are territorial, in other words, each country has the autonomy to establish guidelines for the analysis of patentability conditions and to prevent abuse within the system. The Brazilian Constitution establishes health as a right, and this must guide public policies, especially in terms of access to essential medicines or those with a high budgetary impact.
Although the first bedaquiline patent, which protects the API, expired in most of the countries in 2023, the company resorted to the practice of evergreening45, filing additional patent applications to extend its monopoly over the medicine in many high TB burden countries. The extension of monopolies through multiple patent applications compromises the sustainability of health systems and goes against the principle of equity, which should guide public health policies.
In defense of access to medicine, the humanitarian organization, Doctors Without Borders (Médecins Sans Frontières - MSF) campaigned for the company to abandon the monopoly on secondary patents for bedaquiline46. Furthermore, organizations from several countries petitioned oppositions to secondary patent applications for bedaquiline, including the one that protects bedaquiline fumarate, which could extend the monopoly until December 2027 in Brazil. As happened in Brazil in 2024, this patent application was rejected by the Indian patent office in 202347.
Given the epidemiological landscape of tuberculosis in Brazil, the importance of bedaquiline on the treatment of DR-TB, the high unit price of the medicine, the lack of patent protection for the API, the proximity of the expiration date of some secondary patents that could be potential barriers, it is crucial to analyze the feasibility of public production of bedaquiline, with the aim of strengthening the country’s autonomy, thereby guaranteeing supply and reducing costs.
The most complex and expensive component in the pharmaceutical formulation is API production48. Price is also affected by its concentration in the pharmaceutical form; therefore, a more expensive API will have a proportionally greater impact on production cost and on the final price of the medicine49. The intermediate compounds in the synthesis of bedaquiline are not expensive and can be synthesized from very low-cost raw materials. However, there is critical step in the synthesis of the molecule used in the commercially available product, due to the low yield for obtaining the active isomer42.
Some publications50-52 deal with the different synthesis routes for bedaquiline, considering the yield and the processes of isomer separation, since the initial synthesis53 or even the most likely industrial process54 showed low yield, low enantioselectivity and low efficiency55. Recent studies address possibilities of increasing yield, stereoselectivity and efficiency, by reducing the process duration, the number of organic solvents and the number of steps in the synthesis route55, considering the state of the art and routine practices for a person skilled in the field.
Bedaquiline does not have the Letter of Suitability of the API (Carta de Adequação de Dossiê de Insumo Farmacêutico Ativo - CADIFA), which is an instrument that certifies the Good Manufacturing Practices (GMP) of a given API in Brazil15, but it is possible to find international suppliers that sell to the Indian company, Recipharm, which produces the medicine used in Brazil56. The study by Gotham et al. (2017) considered, based on 2015 data, that bedaquiline’s API would cost between US$2,300/kg and US$3,450/kg, with quality assured by the WHO prequalification program or by a rigorous regulatory authority, respectively42.
Some critical steps in the production of medicines are related to knowledge of API analytical methodologies and of the formulation process itself. When there is a commercially available product, as in the case of the bedaquiline tablets registered by Janssen, it is possible to perform API analysis by reverse extraction, with the purpose of integrating excipients and the pharmaceutical formulation that will be produced, in this case, the tablets. Based on the dossier of marketing authorization, it is possible to identify the inert excipients and even test other excipients to adapt the process to the machinery available in the industry. Starting from the production of 2 kg pilot batches, there are also other critical steps, such as accelerated stability studies, pharmaceutical equivalence and bioequivalence studies, to finally reach industrial production with the validation of batches of more than 100 kg57.
In some countries, the authorization of generic medicines takes approximately 24 months58, and this development can be conducted even before the expiration of the patents. The BOLAR exception, a safeguard in the TRIPS Agreement, present in Article 43, line VII, of the LPI, predicts that all development prior to commercialization, including marketing authorization, does not violate the patent barrier44.
This detailed description of stages and possible barriers for the public production of bedaquiline reveals that this is a complex path, even though it is a routine procedure for generic pharmaceutical companies. Public pharmaceutical industries have a long history in the development of antiretrovirals without patents in Brazil at the beginning of the HIV/AIDS59 epidemic, through reverse engineering. Resuming the agenda of local development and production of bedaquiline seems to be a possible path for comprehensiveness in pharmaceutical care, guaranteeing sustainable access to treatment and fulfilling the commitment to eliminate tuberculosis as a public health problem by 2030.
Final considerations
The analysis of tuberculosis status in Brazil, together with the evaluation of the bedaquiline market, reveals a complex intersection between public health, policies of pharmaceutical access, and social inequalities. Brazil, a country with one of the highest tuberculosis indexes in the Americas, faces a significant challenge, which demands a coordinated and effective response. The adoption of bedaquiline into SUS in 2021 represented important progress, as did the creation of the CIEDDS, reinforcing the need to combat the inequalities in terms of access to treatment and healthcare services.
However, the multiple patenting strategy or evergreening of bedaquiline in Brazil, which is a common practice of pharmaceutical companies, veils the extension of monopolies and high prices. The Brazilian Federal Government should prevent the abuse of patent rights, guaranteeing that the granting of monopolies takes into account, in addition to patentability criteria, aspects concerning the medicine’s essentiality and budgetary impact, making use of public health safeguards present in Brazilian legislation, especially considering that it is a disease with a high burden and high mortality rate among vulnerable populations, it is drug-resistant, there is low investment in new medicines, and it is associated with other neglected diseases.
Public production of bedaquiline emerges as a requirement to guarantee the availability of the medicine, to expand access to the treatment of drug-resistant tuberculosis, and to reduce costs. The production cost study, suggesting the capacity for generic production at more accessible prices, highlights the importance of exploring strategies for the national development of technologies for public interest, strengthening the country’s health sovereignty, ensuring the sustainability of SUS, and boosting the comprehensiveness of pharmaceutical care.
References
- 1 World Health Organization (WHO). Global tuberculosis report 2024. Geneva: WHO; 2024.
- 2 Moreira ASR, Kritski AL, Carvalho ACC. Social determinants of health and catastrophic costs associated with the diagnosis and treatment of tuberculosis. J Bras Pneumol 2020; 46(5):e20200015.
- 3 Cobo B, Cruz C, Dick PC. Desigualdades de gênero e raciais no acesso e uso dos serviços de atenção primária à saúde no Brasil. Cienc Saude Colet 2021; 26(9):4021-4032.
- 4 Polidoro M, Mahoche MJ, Bairros F, Meneghel SN, Rainone FN, Canavese D. Geografia das disparidades em saúde entre brancos e negros em Porto Alegre, Rio Grande do Sul. Cad Saude Colet 2023;31(1):e31010454.
- 5 Ferreira TF, Santos AM, Oliveira BLCA, Caldas AJM. Tendência da tuberculose em indígenas no Brasil no período de 2011-2017. Cienc Saude Colet 2020; 25(10):3745-3752.
- 6 Jacobs MG, Pinto Junior VL, Caracterização da tuberculose drogarresistente no Brasil, 2014. Epidemiol Serv Saude 2019; 28(3):e2018294.
-
7 Jornal da USP. Instituto Adolfo Lutz e USP detectam primeiros casos de tuberculose extensivamente resistente no Brasil [Internet]. 2023 [acessado 2024 set 15]. Disponível em: https://jornal.usp.br/ciencias/instituto-adolfo-lutz-e-usp-detectam-primeiros-casos-de-tuberculose-extensivamente-resistente-no-brasil/
» https://jornal.usp.br/ciencias/instituto-adolfo-lutz-e-usp-detectam-primeiros-casos-de-tuberculose-extensivamente-resistente-no-brasil -
8 World Health Organization (WHO). Tuberculosis [Internet]. 2023 [cited 2024 set 15]. Available from: https://www.who.int/news-room/fact-sheets/detail/tuberculosis#:~:text=In%202022%2C%20an%20estimated%2010.6,TB%20is%20curable%20and%20preventable
» https://www.who.int/news-room/fact-sheets/detail/tuberculosis#:~:text=In%202022%2C%20an%20estimated%2010.6,TB%20is%20curable%20and%20preventable - 9 Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M, the ZeNix Trial Team. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis. N Engl J Med 2022; 387(9):810-823.
- 10 World Health Organization (WHO). WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva: WHO; 2022.
- 11 Banta D, Almeida RT. The development of health technology assessment in Brazil. Int J Technol Assess Health Care 2009; 25(Suppl. 1):255-259.
- 12 Oliveira EA, Labra ME, Bermudez J. A produção pública de medicamentos no Brasil: uma visão geral. Cad Saude Publica 2006; 22(11):2379-2389.
- 13 Magalhães JL, Antunes AMS, Boechat N. Laboratórios farmacêuticos oficiais e sua relevância para saúde pública do Brasil. R Eletr Com Inf Inov Saude 2011; 5(1):85-99.
- 14 Brasil. Ministério da Saúde (MS). Boletim Epidemiológico: tuberculose 2025. Brasília: MS; 2025.
- 15 Agência Nacional de Vigilância Sanitária (Anvisa). Consultas [Internet]. 2024 [acessado 2024 set 15]. Disponível em: consultas.anvisa.gov.br
-
16 US Food and Drug Administration. Orange Book [Internet]. 2024 [cited 2024 set 15]. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
» https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm -
17 Health Canada. Patent Register [Internet]. 2024 [cited 2024 set 15]. Available from: https://pr-rdb.hc-sc.gc.ca/pr-rdb/index-eng.jsp
» https://pr-rdb.hc-sc.gc.ca/pr-rdb/index-eng.jsp -
18 Patent Opposition Database [Internet]. 2024 [cited 2024 set 15]. Available from: https://www.patentoppositions.org/
» https://www.patentoppositions.org -
19 Medicines Patent Pool. MedsPaL [Internet]. 2024 [cited 2024 set 15]. Availabe from: https://www.medspal.org/
» https://www.medspal.org -
20 World Intellectual Property Organization (WIPO). PatentScope [Internet]. 2024 [cited 2024 set 15]. Available from: https://patentscope.wipo.int/search/en/search.jsf
» https://patentscope.wipo.int/search/en/search.jsf -
21 European Patent Office. Espacenet [Internet]. 2024 [cited 2024 set 15]. Available from: https://worldwide.espacenet.com/patent/
» https://worldwide.espacenet.com/patent - 22 Chaves GC, Di Giano ML. Hepatitis C and tuberculosis long-acting medicines: analysis of patenting trends and implications for access. New York: Treatment Action Group; 2021.
-
23 Instituto Nacional da Propriedade Industrial (INPI). Base de dados de patentes [Internet]. 2024 [acessado 2024 set 15]. Disponível em: https://busca.inpi.gov.br/pePI/
» https://busca.inpi.gov.br/pePI -
24 Controladoria Geral da União (CGU). Plataforma Integrada de Ouvidoria e Acesso à Informação [Internet]. 2024 [acessado 2024 fev 29]. Disponível em: https://falabr.cgu.gov.br/Login/Identificacao/Identificacao.aspx?idFormulario=3&tipo=8&ReturnUrl=%2fpublico%2fManifestacao%2fRegistrarManifestacao.aspx%3fidFormulario%3d3%26tipo%3d8%26origem%3didp%26modo%3d
» https://falabr.cgu.gov.br/Login/Identificacao/Identificacao.aspx?idFormulario=3&tipo=8&ReturnUrl=%2fpublico%2fManifestacao%2fRegistrarManifestacao.aspx%3fidFormulario%3d3%26tipo%3d8%26origem%3didp%26modo%3d -
25 Banco Central do Brasil. Taxa de câmbio - Livre - Dólar americano (compra) [Internet]. 2025 [acessado 2025 jul 7]. Disponível em: https://www3.bcb.gov.br/sgspub/consultarvalores/consultarValoresSeries.do?method=consultarGraficoPorId&hdOidSeriesSelecionadas=10813
» https://www3.bcb.gov.br/sgspub/consultarvalores/consultarValoresSeries.do?method=consultarGraficoPorId&hdOidSeriesSelecionadas=10813 - 26 Brasil. Ministério da Saúde (MS). Relatório de recomendação n° 546: Bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistentes. Brasília: MS; 2020.
- 27 World Health Organization (WHO). Global strategy and targets for tuberculosis prevention, care and control after 2015 (Resolution WHA67.1, Agenda item 12.1). Geneva: WHO; 2014.
- 28 Presidência da República. Decreto nº 11.494 de 17 de abril de 2023. Institui o Comitê Interministerial para a Eliminação da Tuberculose e de Outras Doenças Determinadas Socialmente - CIEDS. Diário Oficial da União 2023; 18 abr.
- 29 Brasil. Ministério da Saúde (MS). Brasil livre da tuberculose: plano nacional pelo fim da tuberculose como problema de saúde pública. Brasília: MS; 2017.
- 30 Gohtam D, McKenna L, Frick M, Lessem E. Public investments in the clinical development of bedaquiline. PLoS One 2020; 15(9):e0239118.
-
31 Brasil. Ministério da Saúde (MS). Relatório de recomendação nº 547: Delamanida para o tratamento de tuberculose multirresistente e tuberculose com resistência extensiva [Internet]. 2020 [acessado 2024 set 15]. Disponível em: http://antigo-conitec.saude.gov.br/images/Consultas/Relatorios/2020/Relatorio_delamanida_TB_MDR_XDR_547_33_2020_final.pdf
» http://antigo-conitec.saude.gov.br/images/Consultas/Relatorios/2020/Relatorio_delamanida_TB_MDR_XDR_547_33_2020_final.pdf -
32 Brasil. Ministério da Saúde (MS). Relatório de recomendação nº 849: Pretomanida para o tratamento da tuberculose resistente a medicamentos [Internet]. 2023 [acessado 2024 set 15]. Disponível em: https://www.gov.br/conitec/pt-br/midias/relatorios/2023/Relatorio_849_pretomanida_TB_Resistente.pdf
» https://www.gov.br/conitec/pt-br/midias/relatorios/2023/Relatorio_849_pretomanida_TB_Resistente.pdf - 33 Mahajan R. Bedaquiline: first FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res 2013; 3(1):1-2.
-
34 European Medicines Agency (EMA). European Medicines Agency recommends approval of a new medicine for multidrug-resistant tuberculosis [Internet]. 2013 [cited 2024 set 15]. Available from: https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-approval-new-medicine-multidrug-resistant-tuberculosis
» https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-approval-new-medicine-multidrug-resistant-tuberculosis - 35 World Health Organization (WHO). The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance. Geneva: WHO; 2013.
- 36 World Health Organization (WHO). Rapid communication: key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva: WHO; 2018.
-
37 van der Ploeg SRC, Silva AR, Scopel CT. O caso da rilpivirina: bloqueio do mercado e extensão inconstitucional do prazo das patentes no Brasil [Internet]. 2023 [acessado 2024 set 15]. Disponível em: https://www.jota.info/artigos/o-caso-da-rilpivirina
» https://www.jota.info/artigos/o-caso-da-rilpivirina - 38 Abecassis P, Coutinet N. Caractéristiques du marché des médicaments et stratégies des firmes pharmaceutiques. Horizons Strategiques 2008; 1(7):111-139.
- 39 Scopel CT. Estratégias de acumulação de capital das Big Pharma: estudo de empresas selecionadas entre 2008 e 2019 [tese]. Rio de Janeiro: Fiocruz; 2023.
- 40 World Health Organization (WHO). The selection and use of essential medicines. Report of the WHO Expert Committee, 2015 (including 19th WHO model list of essential medicines and 5th WHO model list of essential medicines for children). Geneva: WHO; 2015.
-
41 Dall C. J&J agrees to lower price of TB drug bedaquiline, allow production in South Africa [Internet]. 2024 [cited 2024 set 15]. Available from: https://www.cidrap.umn.edu/tuberculosis/jj-agrees-lower-price-tb-drug-bedaquiline-allow-production-south-africa
» https://www.cidrap.umn.edu/tuberculosis/jj-agrees-lower-price-tb-drug-bedaquiline-allow-production-south-africa - 42 Gotham D, Fortunak J, Pozniak A, Khoo S, Cooke G, Nytko FE, Hill A. Estimated generic prices for novel treatments for drug-resistant tuberculosis. J Antimicrob Chemother 2017; 72(4):1243-1252.
-
43 McKenna L. The price of bedaquiline [Internet]. 2018 [cited 2024 set 15]. Available from: https://www.treatmentactiongroup.org/publication/the-price-of-bedaquiline/
» https://www.treatmentactiongroup.org/publication/the-price-of-bedaquiline - 44 Brasil. Presidência da República. Lei nº 9.279 de 14 de maio de 1996. Regula direitos e obrigações relativos à propriedade industrial. Diário Oficial da União 1996; 15 maio.
- 45 Kapczynski A, Park C, Sampat B. Polymorphs and prodrugs and salts (oh my!): an empirical analysis of "secondary" pharmaceutical patents. PLoS One 2012; 7(12):e49470.
-
46 Médicos Sem Fronteiras (MSF). MSF pede que Johnson & Johnson abandone monopólio de patentes sobre medicamento para tuberculose [Internet]. 2023 [acessado 2024 set 15]. Disponível em: https://www.msf.org.br/noticias/msf-pede-que-johnson-johnson-abandone-monopolio-de-patentes-sobre-medicamento-para-tuberculose/
» https://www.msf.org.br/noticias/msf-pede-que-johnson-johnson-abandone-monopolio-de-patentes-sobre-medicamento-para-tuberculose -
47 Ali F, Rajagopal S, Raman VS, John R. Pharmaceutical patent grants in India: how our safeguards against evergreening have failed, and why the system must be reformed [Internet]. 2018 [cited 2024 set 15]. Available from: https://accessibsa.org/media/2018/04/Pharmaceutical-Patent-Grants-in-India.pdf
» https://accessibsa.org/media/2018/04/Pharmaceutical-Patent-Grants-in-India.pdf - 48 Pinheiro ES, Antunes OAC, Fortunak JMD. A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations. Antiviral Res 2008; 79(3):143-165.
- 49 Pinheiro ES, Brüning K, Macedo MF, Siani AC. Prodution of antiretroviral drugs in middle- and low-income countries. Antiviral Ther 2014; 19(Suppl. 3):49-55.
- 50 Ding HX, Leverett CA, Kyne RE Jr, Liu KK-C, Sakya SM, Flick AC, O'Donnell CJ. Synthetic approaches to the 2012 new drugs. Bioorg Med Chem 2014; 22(7):2005-2032.51.
- 51 Saga Y, Motoki R, Makino S, Shimizu Y, Kanai M, Shibasaki M. Catalytic asymmetric synthesis of R207910. J Am Chem Soc 2010; 132(23):7905-7907.
- 52 Chandrasekhar S, Babu GSK, Mohapatra DK. Practical syntheses of (2S)-R207910 and (2R)-R207910. Eur J Org Chem 2011; 2011:2057-2061.
-
53 Van Gestel JFE, Guillemont JEG, Venet MG, Poignet HJJ, Decrane LFB, Vernier DFJ, Odds FC. WO2004011436. Quinoline derivatives and their use as mycobacterial inhibitors [Internet]. 2004 [cited 2024 set 15]. Available from: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004011436
» https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004011436 -
54 Porstmann FR, Horns S, Bader T. WO2006125769. Process for preparing (alpha S, beta R)6-bromo-alpha[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol [Internet]. 2006 [cited 2024 set 15]. Available from: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006125769
» https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006125769 - 55 Lubanyana H, Arvidsson PI, Govender T, Kruger HG, Naicker T. Improved synthesis and isolation of bedaquiline. ACS Omega 2020; 5:3607-3611.
-
56 Infodrive India. India export data and top export products from India [Internet]. 2024 [cited 2024 set 15]. Available from: http://www.infodriveindia.com/india-exports-trade-data.aspx
» http://www.infodriveindia.com/india-exports-trade-data.aspx -
57 Fortunak JM, Antunes OAC. A produção de ARVs no Brasil: uma avaliação [Internet]. 2006 [acessado 2024 set 15]. Disponível em: https://www.abiaids.org.br/_img/media/ARV.pdf
» https://www.abiaids.org.br/_img/media/ARV.pdf -
58 Amuasi JH. Technology transfer and local manufacturing of pharmaceuticals: the South African case [Internet]. 2009 [cited 2024 set 15]. Available from: https://www.tralac.org/images/docs/5550/amuasi-presentation-december-2009.pdf
» https://www.tralac.org/images/docs/5550/amuasi-presentation-december-2009.pdf - 59 Lago RF, Sousa ACA. A oferta pública de medicamentos para aids e o papel de Farmanguinhos. Physis 2022; 32(2):e320210.
The data sources adopted in the research are indicated in the article’s body.
Patent applications are aligned according to the filing date in Brazil. Classification of the main content of the patent application is shown in colors: related to the API (green), to processes (blue), to salt or polymorph (yellow), to composition or combination (purple), and to use or method of treatment (grey). The files of each patent application are indicated with asterisks (* or **). Sources: Orange Book, Patent Register, Patent Opposition Database, MedsPaL, WIPO PatentScope, Espacenet, Chaves & Di Giano document (2021), and INPI.