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Onasemnogene abeparvovec—the world’s most expensive treatment to date—received Brazilian marketing authorisation for the treatment of spinal muscular atrophy in August 2020.
In the absence of convincing evidence supporting the drug’s added therapeutic benefit over existing alternatives, the Brazilian drug pricing authority later approved a maximum price that was 77% lower than the manufacturer’s intended price.
In response, the drug’s manufacturer decided not to commercialise onasemnogene abeparvovec in Brazil.
Yet, courts have obliged the Ministry of Health to fund the treatment citing the right to health legislation, at prices that are more than three times higher than the maximum approved price in the country.
The case of onasemnogene abeparvovec in Brazil highlights the ever-growing chasm between the promise of medical innovation and affordable access for those who need it in resource-constrained health systems.
Introduction
The US Food and Drug Administration (FDA) approval of onasemnogene abeparvovec in 2019 has been a matter of significant controversy. Onasemnogene abeparvovec is a gene therapy indicated for children less than 2 years old with a certain type of spinal muscular atrophy (SMA). Its clinical development benefited from considerable public funding.1 2 When the medicine received the green light from the FDA, it was hailed as a ‘cure’ for this debilitating and life-threatening condition. At a list price of US$2 125 000 for a one-time infusion, onasemnogene abeparvovec is the most expensive drug treatment to date.1 Much has been written about the drug’s price, the uncertainties about its efficacy and payer strategies to facilitate access to the treatment for severely ill children in high-income countries.1
The dilemmas faced by families, decision-makers and health systems in middle-income countries have received relatively less attention. The ongoing saga of onasemnogene abeparvovec in Brazil illustrates the ever-growing chasm between the promise of medical innovation and affordable access for those who need it, in the context of a complex upper middle-income country health system that also influences health regulation in other Latin American countries.3
As the first Latin American regulator to do so, Brazil’s Anvisa (Brazilian Health Regulatory Agency) granted marketing authorisation to onasemnogene abeparvovec for the treatment of SMA on 17 August 2020. SMA affects approximately 250–300 newborns in Brazil every year.4 The approval was based on data that were nearly identical to those for the initial US FDA approval: three single-arm clinical trials involving a total of 48 patients. Following regulatory approval, important uncertainties remained about the long-term safety and clinical effectiveness of the drug.1 According to the latest results of an ongoing single-arm study, the therapy does not appear to be as effective as initially thought.1 5
In the absence of convincing evidence supporting the treatment’s added therapeutic benefit over existing alternatives, the Brazilian drug pricing authority [Drug Market Regulation Chamber (CMED)] approved in December 2020 a maximum provisional price that was 77% lower than the manufacturer’s intended price (BRL2.9 million; US$531 173.2; £396 516.4).6 Brazil was not alone in recommending such substantial price reductions for onasemnogene abeparvovec, as health authorities in several high-income countries, based on limitations in clinical evidence, recommended price reductions that ranged from 50% to 90% of the manufacturer’s asking price (table 1).
Appraisal of onasemnogene abeparvovec and recommendations from different health authorities
Nevertheless, in March 2021, after the rejection of its first appeal of the pricing decision, the drug’s manufacturer, Novartis, issued a public statement arguing that the authorised price was commercially unviable ‘in view of the research and development, production, logistics and distribution costs’. The manufacturer later appealed to the CMED Minister’s council and decided not to commercialise the treatment in Brazil, urging the authorities to consider the innovative value of the therapy.7 As of January 2022, the case had not yet been resolved. The medicine therefore remains unavailable in Brazil—at least officially.
Right to health
While the regulatory assessment of the treatment was underway, families of children with SMA sued the government for immediate access to onasemnogene abeparvovec on the grounds of the right to health legislation. The courts have obliged the Ministry of Health to provide families of patients with the resources to import the therapy at prices considerably higher than those ultimately approved in the country (box 1).
Litigation or ‘judicialization’ and the right to health in the Brazilian Unified Health System
In Brazil, the right to health is a constitutional right. The Brazilian Unified Health System (Sistema Único de Saúde, known as SUS) is a universal national health system, free at the point of care. It is decentralised; the federal level, states and municipalities share its governance and funding through tax revenue and social contributions. Health expenditure corresponded to 9.1% of gross domestic product (GDP) in 2015, with public spending accounting for 42.8%, and 75% of Brazilians relying solely on SUS. About 5% of families, disproportionally poor, incur catastrophic out-of-pocket expenditures due to the cost of certain medicines not covered free of charge by SUS.
Marketing authorisation by the Brazilian Health Regulatory Agency (Anvisa) and maximum price approval by the Drug Market Regulation Chamber (CMED) are mandatory for medicines to reach the Brazilian market. CMED is responsible for the economic regulation of the pharmaceutical market for promoting sustainable access to medicines. All authorised prices are publicly available. Medicines and other health technologies need to be assessed by the National Commission for the Incorporation of Technologies in the SUS (Conitec) and approved by the Ministry of Health to be provided by the SUS.11
Health litigation or judicialisation occurs in many countries where a ‘right to health’ legal framework clashes with limited government resources and is very common in Brazil, Colombia and South Africa. Lawsuits can contribute to increasing inequalities by forcing the allocation of resources for unplanned expenses under an already constrained budget, posing an ethical dilemma for the payer.12 Patient advocacy groups and law firms, often financed by pharmaceutical companies, support families in the process of suing for government coverage of a therapy, specifically a highly priced medicine.13
In several court cases, medicines were provided even before marketing authorisation and price approval, at much higher prices than authorised by CMED.13 Judges have been found to rule frequently in favour of patients and their families. In addition, patients can apply for anticipated or urgent relief measures, even before the court decision is issued.
Costs of lawsuits increased from 8% in 2012 to 22% of the public pharmaceutical expenditure on specialty medicines in 2018, of which 20 medicines were responsible for 95% of the expenditures following lawsuits, 60% of them without marketing authorisation and none of them approved to be covered by the SUS.14 Exceptions for SUS coverage of medicines not yet approved should be based on recommendations by the National Council of Justice (CNJ). In 2015, the Technical Support Centres of the Judiciary Power (NATJUS) and its repository of technical documents (e-NATJUS) were created to provide evidence-based support for the State Courts of Justice and the Federal Regional Courts’ decision-making in litigation cases related to health. In addition, the High Court established parameters for judicial decisions, the thesis of general repercussion, and the CNJ established consensus (enunciados) to guide future lawsuit decisions. In 2020, the CNJ stated that the SUS should not provide medicines without proven efficacy, safety and marketing authorisation by Anvisa. The challenge is to make sure the court decisions are aligned with these recommendations.
The court cases have been accompanied by an intensely politicised and concerted media campaign with celebrities advocating for the regulatory approval and reimbursement of the drug. Import tax for the therapy was waived ahead of marketing authorisation, and two bills currently in the Brazilian Congress propose the mandatory provision of onasemnogene abeparvovec by the Ministry of Health without any health technology assessment, even though the latter is a legally mandated step for any medicine or technology to be incorporated into the Brazilian Unified Health System.8
By October 2021, court decisions had forced the Ministry of Health to fund the treatment of 46 patients with onasemnogene abeparvovec, at a total cost of US$79 million (£58.9 million). The average cost of the drug (US$1.7 million, £1.3 million) per patient is more than triple the maximum approved price by the Brazilian CMED. Lawsuits against states and private health insurance plans resulted in additional mandates for payment, including children older than 2 years for whom the therapy is not indicated in Brazil.
The court-mandated provision of onasemnogene abeparvovec comes with high opportunity costs, as the Ministry is obliged to provide the resources for patients to import the drug at unregulated prices. The resources spent by the Ministry of Health on the treatment of 46 patients would have been more than sufficient to treat all babies born with SMA type 1 in Brazil in a year (189 patients) at the approved maximum government procurement price. At least US$60 million (£44.6 million) (75% of the expenditures on the therapy) could have been saved if their treatments were purchased at the approved maximum government procurement price. The lawsuit expenses correspond to 3.8% of the Ministry of Health’s entire pharmaceutical expenditures in 2020, enough to treat 5805 patients with specialty drugs (10.3% of the expenditure on specialty medicines) in the same year or to procure 4.3 million doses of the COVID-19 vaccine.9
What is at stake?
Brazil has a universal health system with regulatory, pricing and reimbursement frameworks carefully designed to provide access to medicines to its population while stewarding limited resources. CMED’s mandate is to ensure that prices are commensurate with drug benefits within the constraints of affordability. The manufacturer of onasemnogene abeparvovec did not comply with the Brazilian regulator’s pricing decision. Instead, the drug’s manufacturer benefited from a combination of judicial routes, efforts to change the legislation and an extensive media presence—all conducted through proxies—to promote a narrative that pricing policies are responsible for restricting patient access to innovative medicines. This case shows how a country’s regulatory and pricing system can be rendered ineffective and indeed the entire health system threatened when powerful multinational pharmaceutical companies do not respect its underlying principles and the legal system inadvertently facilitates an industry strategy that exploits the vulnerabilities of the country’s governance.
Conclusion
The right to health is an important achievement in Brazil. It is necessary to ensure access to appropriate care for those who need it. Exploitation of that right through judicialisation of onasemnogene abeparvovec access has placed on the society the burden of funding the provision of an extremely expensive medicine with high opportunity costs. Efforts are needed to minimise the impacts of current and avoid future lawsuits, and to enforce the application of the existing regulatory, pricing and coverage regulations to prevent provision of new medicines without robust evidence at excessively high prices and enormous societal cost.
The unfolding saga of onasemnogene abeparvovec reminds us that the regulation and pricing of medicines is at the intersection of societal values, science, medical culture, patient needs and expectations, economics and politics.10 We therefore suggest that corporate social responsibility, market approval, pricing and reimbursement policies be considered in a broader, societal context.
Abstract translation
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.Data availability statement
The information on pharmaceutical expenditure and prices is publicly available. The expenditure and number of patients receiving onasemnogene abeparvovec were provided by the Ministry of Health under the provisions of the Brazilian Law of Access of Information (LAI). Novartis later removed the original statement issued on March 8th 2021 (https://www.novartis.com.br/news/atualizacao-sobre-o-preco-de-zolgensma) from their website. A copy of the original statement is available from the first author upon request.
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This study does not involve human participants.
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This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Handling editor Seye Abimbola
Contributors AMIB and HN had substantial contributions to the conception of the work. AMIB was responsible for drafting the work and data acquisition. All authors had substantial contributions to the analysis and interpretation of the data, revised critically and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Disclaimer The views expressed in this commentary do not necessarily reflect those of the Brazilian Health Regulatory Agency (Anvisa) or the Executive Secretariat of the Drug Market Regulation Chamber (SCMED).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.