Recently, the Brazilian Health Regulatory Agency (ANVISA) took a significant step by approving RDC No. 875 on May 28, 2024. This new regulation establishes for the registration of biosimilars in Brazil, marking an important milestone for the pharmaceutical industry. Biosimilars represent a viable alternative to original biological drugs, potentially reducing treatment costs for various diseases. With this regulation, ANVISA aims to ensure that these products meet the highest standards of quality, safety, and efficacy, benefiting patients and healthcare professionals.
What Are Biosimilars
Biosimilar medicines are a specific class of biological drugs that emerge as an alternative to the original (reference) biological products already registered and marketed. They are developed to be highly similar to the original biological medicine in terms of molecular structure, biological function, and clinical profile, including quality, safety, and efficacy.
The similarity between a biosimilar and its reference biological product is established through a rigorous comparative assessment process. This process includes the detailed analysis of several critical parameters, such as:
- Quality: The molecular composition of the biosimilar must be nearly identical to that of the reference medicine, ensuring that any variation is minimal and clinically insignificant.
- Biological Activity: The biosimilar must demonstrate the same biological activity as the reference product, verified through laboratory tests and preclinical studies.
- Safety and Efficacy: Clinical studies are conducted to confirm that the biosimilar has a safety and efficacy profile equivalent to that of the original biological medicine.
The development of a biosimilar is a complex and rigorous process that requires advanced technology and specialized knowledge. Unlike generic drugs, which are exact copies of reference medicines with small molecules, biosimilars involve large biological molecules produced in living systems, such as mammalian cells or bacteria. This makes the manufacturing process more challenging and requires stricter quality controls.
Additionally, biosimilars play a crucial role in increasing access to high-quality treatments for complex diseases such as cancer and autoimmune diseases. With the new regulation by ANVISA, the introduction of biosimilars in the Brazilian market is expected to not only expand the available therapeutic options but also promote competitiveness and innovation in the pharmaceutical industry.
Challenges in Biosimilar Development
Developing and commercializing biosimilars involve several challenges:
- Variability of large molecules: Biological molecules are complex and variable, requiring highly controlled manufacturing processes.
- Clinical safety evidence: Providing robust safety evidence is essential for regulatory approval.
- Reducing production expenses: Manufacturing biosimilars must be economically viable without compromising quality.
- Cell growth under specific conditions: Ensuring proper cell growth during production is crucial.
- Limited analytical tools: Current tools may be insufficient to detect all differences between the original therapeutic protein and the biosimilar.
- Lack of experience: Researchers and clinical centers are still familiarizing themselves with the development and use of biosimilars.
Registration Requirements
To register a biosimilar, companies must submit several essential documents:
General Information
- A statement indicating the name of the comparator biological medicine, its country of origin, and manufacturing locations.
- A statement proving that the same comparator biological medicine was used in all development studies of the biosimilar candidate.
- A detailed description of the comparability exercise steps, showcasing the ability to detect differences in quality attributes between the biosimilar candidate and the comparator biological medicine.
Analytical Comparability Report
- Description of tests and analytical methodologies used to evaluate the analytical comparability of quality attributes between the biosimilar candidate and the comparator biological medicine.
- Information on the expression system used to manufacture the biosimilar candidate and the comparator biological medicine.
- Assessment of contaminants and impurities identified in the biosimilar candidate, discussing their potential impact on quality, safety, and efficacy.
- Results obtained for each test conducted to evaluate the analytical comparability of quality attributes.
- Description and justification of the number of batches used in the comparability exercise.
- Conclusions on the demonstration of analytical comparability, containing sufficient information to predict whether detected differences in quality attributes have a potential adverse impact on the safety and efficacy of the biosimilar candidate.
Criteria for the Comparator Biological Medicine
The biological medicine used as a comparator in the comparability exercise must be registered with ANVISA and supported by a complete dossier. The comparability exercise includes the assessment of primary and higher-order structures, purities and impurities (including acidic and basic variants, when applicable), functional characterization, and stability. All applicable analytical studies, whether non-clinical or clinical, in the biosimilar development program must be comparative in nature.
Non-Clinical and Clinical Study Reports
When applying for registration, companies must submit complete reports of non-clinical and clinical studies:
Non-Clinical In Vivo Studies
- Pharmacodynamic studies relevant to intended therapeutic indications.
- Cumulative (repeated-dose) toxicity studies, including the characterization of toxicity kinetic parameters, conducted in relevant species.
Clinical Studies
- Pharmacokinetic studies.
- Pharmacodynamic studies.
- Immunogenicity, safety, and clinical efficacy studies.
Regulatory Considerations
Some clinical studies and/or parameters of comparative clinical evaluation can be waived provided that high comparability, functionality and characterization of the biosimilar candidate product are demonstrated, and through a technical-scientific justification to be evaluated by Anvisa.
ANVISA emphasizes the need for specified and statistically supported design and comparability margins in safety and efficacy studies. Phase IV study results should be included when available. Additionally, ANVISA may require further proof of identity and quality of biosimilar components or request new studies to confirm efficacy and safety.
Future Prospects
The regulation of biosimilars in Brazil is expected to increase the availability of these medicines, especially for treatments against cancer and autoimmune diseases.