Navigating Brazil’s regulatory pathway
As the largest country in South America, with a population over 200 million inhabitants, Brazil is an important market for the pharmaceutical industry. Before navigating the various regulatory pathways for obtaining MA for biological products, it may help to understand the commercial environmet in Brazil as well as its public health system.
According to a 2020 report from Sindusfarma, there are a total of 441 pharmaceutical manufacturers in Brazil, 89 (20%) of which are of international origin and 352 (80%) are Brazilian.
Sales of medicines in 2020 accounted for BRL 76.98 billion (US$15.02 billion), an increase of 11.40% over the previous year. This corresponds to approximately 2% of the world market, and makes Brazil the 7th largest global economy in revenue.
The Brazilian public health system, known as the Unified Health System or SUS, is large and complex. It is composed of the Ministry of Health, states and municipalities, as determined by the Federal Constitution, and each entity has its co-responsibilities. The SUS aims to ensure comprehensive, universal access of health services for the entire population and is responsible for primary care, complex care, urgent and emergency services, hospital care, epidemiological services, sanitary and environmental surveillance, and pharmaceutical assistance.
The distribution of drugs for more complex conditions– from long-term chronic diseases to rare diseases – is managed by the Specialized Component of Pharmaceutical Assistance, or CEAF. The list of products and the lines of care are determined by the Clinical Protocols and Therapeutic Guidelines (PCDT) published by the Ministry of Health. Currently, CEAF’s list comprises 172 drugs in 321 pharmaceutical types or formats. The list includes biological drugs, used for the treatment of several conditions such as rheumatoid arthritis (abatacepte, etanercept), cystic fibrosis (alfadornase), mucopolysaccharidosis (alfaelosulfase), psoriasis (adalimumabe), Crohn’s disease (infliximabe), among others.
Marketing authorization of biological products
To market biological products in Brazil, companies must submit marketing approval to Anvisa, the National Agency of Regulatory Surveillance.
The regulatory framework comprises meeting the requirements for initial marketing authorization, post-registration variations, cancellation, and rules for stability studies. Additional recommendations are provided by Anvisa through other documents such as Guidelines, Clarifying Notes, Service Orientations and Questions & Answers documents. (See list of resolutions for more information on the legal requirements).
Resolution RDC 55/2010 covers a wide range of product categories: I – vaccines; II – hyperimmune sera; III – blood products; IV – biomedicines (classified into: a) medicines obtained from biological fluids or animal tissues; and b) medicines obtained by biotechnological procedures). V – monoclonal antibodies; and VI – medicines containing live, attenuated, or dead microorganisms.
This resolution establishes three possible pathways to obtain marketing authorization of biological products: a full data package pathway, a comparative development pathway, or the individual development pathway.
- Full data package pathway (complete dossier):
This is the mandatory pathway to obtain marketing authorization for a new biological product, with a new biological substance, not yet registered in Brazil.
The application dossier must include the complete data about development and characterization of the biological substance and the product itself, a detailed description of the production process, and quality control, demonstrating consistency in the manufacture of the drug. The company must also present substantial evidence of clinical safety and efficacy, through non-clinical and clinical studies in Phases I, II and III.
The biological product approved through this pathway is eligible to become a comparator, or reference product for registration of subsequent products with the same biological substance.
- Comparative development pathway
This pathway allows the registration of a “copy” of an approved comparator product through presentation of a complete dossier after expiration of patent protection.
Biological products registered through this pathway are usually referred to as biosimilars in scientific publications and by international agencies. It is interesting to note, however, that at the time RDC 55/2010 was published, Anvisa chose not to use this term and instead refers to these types of products simply as “biological products”.
Any company choosing to use the comparative pathway must demonstrate that the biological product intended for registration is similar to the comparator product in terms of quality, safety, and efficacy, by means of comparative studies.
Anvisa does not publish a consolidated list of biological comparator products. Therefore, before starting development of a biosimilar, companies are advised to work with Anvisa to determine if the product chosen to be a comparator is acceptable.
A classic example is the growth hormone. There are several products available on the market in Brazil that have been registered for many years. All of them presented information related to quality, safety, and efficacy in order to obtain registration. However, only four products presented a complete dossier to Anvisa, and only those can be used as comparators. Once the comparator is chosen, the company must perform all the comparative tests against the selected comparator.
The comparability exercise aims to demonstrate the similarity between both products. Anvisa has made guidelines available regarding the comparability exercise for the quality attributes (see resolutions and guidance notes). Companies must also perform comparative non-clinical and clinical studies but can also use data extrapolation to support their submission.
Data extrapolation is a potentially time and cost-saving path for the development of biosimilars, as there is no need to conduct new clinical studies for each indication previously approved for the reference biological product. Instead, the company selects the most relevant therapeutic indication and performs only one comparative Phase III trial, obtaining approval for the remaining indications through extrapolation of safety and efficacy data.
- Individual development pathway
This procedure requires presentation of complete data on the development, production, quality control and non-clinical data. Anvisa accepts non-comparative clinical studies for Phases I and II, but clinical studies for Phase III must be comparative (demonstrating non-inferiority, equivalence, or superiority), except for blood products, vaccines, and biological products for oncology, where the studies can be non-comparative.
This pathway would address those products situated in between the two previous categories. The product is not new, because it contains a biological substance already marketed in the country, and it is not biosimilar, as it was developed independently with no comparability exercise.
Data extrapolation is not permitted for products registered by individual pathway, and all therapeutic indications claimed in the marketing authorization dossier must be supported by specific clinical studies.
A possible advantage of the individual over the comparative pathway is the possibility to qualify the submission for a fast-track evaluation, or optimized review. According to Service Orientation 45/2018, biological products already approved by both the US Food and Drug Administration and European Medicines Agency (through the centralized procedure), qualify the submission for a fast-track evaluation. The detailed evaluation reports from these agencies must be included in the dossier or made available directly by the referenced agencies. Anvisa will then analyze a small number of sections of the dossier and rely on the evaluation reports from reference agencies to issue a decision about the approval of biological product.
Brazil represents a large and growing market for biological pharmaceuticals , and an internal procedure adopted by Anvisa since 2018 opens the way to accelerated approval under some conditions. Companies should carefully evaluate the available strategies and choose a path that suits the new product and what makes most sense for the company from a strategic and financial point of view.
Resolutions and Guidelines
- Resolution – RDC 323 of 10/11/2003 – registration of probiotic products
- Resolution – RDC 55 of 12/12/2010 – registration of biological products and new biological products
- Resolution – RDC 187 of 08/11/2017 – registration of hyperimmune sera
- Resolution – RDC 194 of 12/12/2017 – registration of allergenic products
- Resolution – RDC 505 of 27/05/2021 – registration of advanced therapy products
- Resolution – RDC 413 of 20/07/2020 – post-registration variation and cancellation for biological products
- Normative Instruction – IN 65 of 20/08/2020 – classification of variations for biological products
- Resolution – RDC 412 of 20/07/2020 – stability for biological products
- Guidelines to performing Comparability Exercise for registration of biological products – 2011
- Service Orientation 45/2018 – detailed versus optimized evaluation procedures