Financing of advanced new therapies, and regulatory status of gene therapies and orphan drugs

Rubens Granja
Lefosse Advogados, São Paulo
rubens.granja@lefosse.com  

Maira Materagia Imperatriz
Lefosse Advogados, São Paulo
maira.materagia@lefosse.com

Natássia Misae Ueno
Lefosse Advogados, São Paulo
natassia.ueno@lefosse.com

The emergence of advanced therapy products represents a significant milestone in contemporary medicine. These products involve innovative therapeutic approaches capable of enabling the treatment of previously incurable diseases, and more effective and convenient treatment for serious illnesses that do not respond appropriately to conventional treatment.

If, on the one hand, these products represent the hope of better days for patients suffering from rare diseases, cancer and other debilitating conditions, on the other hand, they pose significant challenges for health regulatory authorities because they present significant differences from conventional treatment, such as high costs, greater complexity in the production process, and uncertainty as to their long-term safety and efficacy.

In Brazil, the health sector is experiencing regulatory changes to accommodate these products. This topic can be approached and analysed from various standpoints; however, in this article, we propose focusing, at the current stage of such a process, on one of the main challenges, which has been to structure solutions to guarantee access to these therapies in public and private health systems.

Current regulatory context for advanced therapy products in Brazil

The Brazilian National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária or 'ANVISA') classifies advanced therapy products as a special category of drugs, which includes advanced cell therapy products, gene therapy products and tissue engineering products, subjecting them to specific regulatory treatment.

This personalised regulatory treatment is based on: (1) RDC No 505/2021, which provides for differentiated procedures for the registration of advanced therapy products; (2) RDC No 506/2021, which provides for the rules for conducting clinical studies with advanced therapy products in Brazil; (3) RDC No 836/2023, which defines Good Practices in Human Cells for therapeutic use and clinical research; and (4) Normative Instruction No 270/2023, which establishes Complementary Good Manufacturing Practices for advanced therapy products.

Advanced therapy products intended for rare diseases can also take advantage of a special procedure for approval before ANVISA according to the rules provided for RDC No 205/2017, which established mechanisms to shorten analysis deadlines. Prior to such a norm, there were no specific regulations for the approval of clinical trials, certification of good practices, and manufacturing and registration of new drugs for rare diseases. Some flexibilisation of the requirements were noticed without, however, compromising the quality, safety and effectiveness of drugs.

Although ANVISA has a solid regulatory framework to allow advanced therapy products to formally enter the Brazilian market, the development of solutions to guarantee effective access to this technology in public and private health systems is progressing at a slower pace.

In both the public and private health systems, the main challenge has been to find a financing model that can accommodate the high cost of these products without compromising the sustainability of the system.

As a result, the absence of a structured model for financing advanced therapies ends up contributing for the increase of the 'judicialisation' of health because patients need to obtain a court ruling granting access to these drugs.

Access within the Brazilian Unified Health System

In Brazil, health is a universal right guaranteed by the Brazilian Federal Constitution to all citizens, through the Unified Health System (Sistema Único de Saúde or 'SUS').^[1]

Under the terms of Law No 8,080/1990, which governs the operation of the SUS, for a certain drug, health product or procedure to be made available by public health services, it must first be approved for incorporation by the Ministry of Health (MoH) following an administrative process carried out by the National Commission for the Incorporation of Technologies into the SUS (Comissão Nacional de Incorporação de Tecnologias or 'CONITEC'), a technical body composing its internal structure.

The purpose of the incorporation process is to verify, based on an assessment of the clinical and economic evidence and the estimated budgetary impact of the health technology under analysis, whether its incorporation is advantageous, from a cost-effectiveness standpoint, for the SUS. The procedure to be followed is set forth in Decree No 7,646/2011, and in summary consists of the following flow:

• The interested party (any individual or legal entity) submits a request to CONITEC for the incorporation of a health technology.
• Once that the documentation has been verified as valid, a report is drawn up assessing the technology, its indications, alternatives available in the SUS and a critical analysis of the studies presented. Based on this report, CONITEC issues a conclusive technical opinion to be submitted for public consultation (after which it will be ratified or rectified), recommending, on a non-binding basis, the incorporation (or not) of the technology into the SUS.
• The process is then forwarded to the Secretariat of Science, Technology and Innovation and the Health Economic-Industrial Complex (Secretaria de Ciência, Tecnologia e Inovação e do Complexo Econômico-Industrial da Saúde or 'SECTICS') for a decision by the Secretary, who determines whether to incorporate the technology into the SUS.
• Once the decision determining incorporation has been published, the MoH has 180 days to make the technology available to SUS patients.

CONITEC has already evaluated the incorporation of two advanced therapy medicines: Luxturna® to treat hereditary retinal dystrophy (rejected in 2021 due to alleged uncertainty about its effectiveness and high budgetary impact according to the incorporation process) and Zolgensma® to treat spinal muscular atrophy in paediatric patients up to six months of age (approved in 2022 through the negotiation of a possible risk sharing agreement between the proposing company and the MoH for its supply within the scope of the SUS).

The risk sharing agreement is an innovative contractual model in which differentiated risk-sharing rules are established between public authorities and the private entity. Its implementation for the supply of drugs in the SUS is still widely debated in the Brazilian health context and there are no major regulations specifically addressing the topic.

Public authorities have to follow specific administrative procedures through which the drugs' purchase processes are carried out. Such processes are guided by the Public Administration's duty to meet the needs for drugs in terms of quantity and quality, and with the lowest possible cost-effectiveness, always aiming for the regularity of the supply system. Reconciling the population's access to advanced therapy treatment with the lowest possible cost guidelines is one of the current main challenges.

Access within the scope of Brazilian supplementary health

The Brazilian Federal Constitution allows the private sector to offer healthcare services independently of the SUS.^[2] Access to these services to the population provided by private hospitals, laboratories and clinics occurs mainly through the supplementary health sector, which comprises a set of actions and services within the scope of healthcare plans and insurance.

General rule for access

Law No 9,656/1998, which regulates these healthcare plans and insurance, establishes the general rule that they must offer coverage for all procedures, exams, therapies and events in the List of Health Procedures and Events, established and updated by the Brazilian National Supplementary Health Agency (Agencia Nacional de Saude Suplementar or 'ANS'), under the terms of Law No 9,961/2000 (the 'ANS List').

The administrative process for updating the ANS List is defined by Normative Resolution RN No 555/2022, which provides a specific flow for health technology assessment for incorporation into the supplementary health sector. In summary, the departments concerned analyse criteria such as efficacy, effectiveness, safety, cost-effectiveness and budgetary impact, and the result of the analysis is made available for public consultation (and, if appropriate, a public hearing) before ANS issues a final decision.

In the case of advanced therapy products, the ANS has determined that they are also subject to this technical evaluation and social participation procedure so that they can be included in the ANS List and then come under mandatory coverage for health maintenance organisations (HMOs).

Exceptional access

There are some exceptions to facilitate access to mandatory coverage in the context of health plans and insurance. Law No 14,307/2022 and Law No 14,454/2022 directly impact the process of incorporating new technology into supplementary healthcare.

Pursuant to Law No 14,307/2022, health technology is exempt from the ordinary administrative procedure for updating the ANS List if it has already been recommended by CONITEC and if the decision on incorporation into the SUS has already been published. In this case, health technology must be automatically included in the ANS List within 60 days of the publication of the decision to incorporate it into the SUS.

Law No 14,454/2022 determined that HMOs must also cover procedures and treatment prescribed by physicians if there is: (1) proof of efficacy based on scientific evidence and a therapeutic plan; or (2) recommendations by CONITEC; and (3) a recommendation from at least one internationally renowned health technology assessment body, provided they are also approved in its country.

Judicial repercussion

There are some judicial discussions that significantly impact both the general rule for access and the exceptional access to advanced therapy products in supplementary healthcare.

The Superior Court of Justice (Superior Tribunal de Justiça or 'STJ') has ruled that, although the ANS List is exhaustive, in exceptional situations, HMOs must cover non-listed procedures, therapies or exams if there is a medical recommendation with no therapeutic substitute on the list, on the condition that they have validation from technical bodies and approval from regulatory institutions like ANVISA. This decision was issued in 2022, shortly before the publication of Law No 14,454/2022, sparking discussions about its legal effectiveness.

Lower courts have also been analysing the matter, and recently, the 10th Federal Civil Court of the State of São Paulo issued a preliminary injunction to suspend the effects of ANS's determination that advanced therapy products should be subject to the general rule for access for inclusion in the ANS List. This decision was issued on 25 March 2024, and its effects have significantly impacted the sector. The lawsuit is still subject to various developments in the judicial sphere and its outcome is uncertain. Due to the complexity of the issue and its significant interest to sector stakeholders and authorities, it is expected that the matter will evolve in the coming months and reach higher courts.

In addition, there have also been some lawsuits discussing the exhaustiveness of the ANS List, including a case in the Supreme Court (Supremo Tribunal Federa or 'STF'), where some HMOs challenged the constitutionality of Law No 14,454/2022. No final decision was made.

Conclusions

This scenario makes it clear that the discussion on access to advanced therapy products in Brazil still has a long way to go. The evolution of the topic, despite being noted, is happening at a slow pace, with progress being made based on specific cases, as can be noted by the processes of incorporation of Zolgensma® into the SUS and ANS List.

With regard to possible ways of financing the acquisition of advanced treatment, and considering that, in Brazil, the risk sharing model is one of the pathways already considered by the Public Administration, it is important to highlight the initiative within the scope of the National Congress through Bill No 667/2021, which intends to amend Law No 8,080/1990 to expressly regulate the possibility of executing risk sharing agreements within the scope of incorporating technology into the SUS.

The bill establishes the foundations for structuring risk sharing agreements, such as their goals, mandatory minimum content for these agreements, conditions for access by patients, and the monitoring and evaluation of clinical outcomes.

It is expected that the development of a legal framework for the use of risk sharing agreements and, eventually, other financing models compatible with advanced therapy products, will provide legal certainty and predictability for companies, and a legal basis to support the actions of the responsible public agents, encouraging them to negotiate the availability of these products for the SUS.

In the same way, the supplementary healthcare sector faces uncertainty regarding access to advanced therapy products, as the predictability of coverage that must be offered is uncertain. It is expected that the legislative, administrative or judicial powers will define clear and objective criteria that allow for predictability as to what should be guaranteed by HMOs, in what form and to what extent. Given the relevance of the issue, the expectation is that this agenda will have new developments in the legal field later this year.

Although, as private entities, health insurance companies can negotiate a solution directly with pharmaceutical companies, guidance from the ANS is essential to ensure that the solutions being discussed do not negatively impact the regulated sector and to encourage health insurance companies to take an active role in discussing solutions.

Notes