The Brazilian FDA, ANVISA, approved Rule RDC #875 of May 28, 2024, which provided, in an ancillary manner, for the registration of biosimilars through the comparability development route, aiming to guarantee the quality, safety, and efficacy of these products.
A biosimilar medicine is any biological medicine that is highly similar to a medicine already registered with ANVISA (comparator biological product), whose similarity in terms of quality, biological activity, safety, and efficacy was established based on an adequate comparability assessment.
The main challenges for the manufacture and commercialization of biosimilars are (i) the variability of large molecules, (ii) providing clinical safety evidence, (iii) reducing production expenses, (iv) ensuring cell growth under specific cultivation conditions, (v) the scarcity of adequate analytical tools to demonstrate differences between the original therapeutic protein and the biosimilar, (vi) the complex nomenclature of biological molecules, and (vii) the lack of experience of researchers and clinical centers with biosimilars.
After the new regulation, for a company to register a biosimilar medicine for comparability, it is necessary for it to present the following documents:
GENERAL DATA
a. statement indicating the name of the comparator biological medicine, its country of origin and manufacturing locations;
b. statement proving that the same comparator biological medicine was used throughout the development studies of the biosimilar candidate; and
c. detailed description of the steps of the comparability exercise, indicating the ability to detect differences in quality attributes between the biosimilar candidate and the comparator biological medicine.
REPORT OF THE ANALYTICAL COMPARABILITY EXERCISE BETWEEN THE BIOSIMILAR CANDIDATE AND THE COMPARATOR BIOLOGICAL PRODUCT, IN THAT THE FOLLOWING INFORMATION IS MINIMALLY MANDATORY
a. description of the tests and analytical methodologies used to evaluate the analytical comparability of the quality attributes of the biosimilar candidate product and the comparator biological medicine;
b. information on the expression system used to manufacture the biosimilar candidate and the comparator biological medicine;
c. assessment of contaminants and impurities identified in the biosimilar candidate, with discussion of the potential impact on its quality, safety, and efficacy;
d. results obtained for each test conducted to evaluate the analytical comparability of quality attributes;
e. description of the batches and justification of the number of batches used for the biosimilar candidate product and the comparator biological product in the comparability exercise; and
f. conclusions on the demonstration of analytical comparability, containing sufficient information to predict whether the differences detected in quality attributes have a potential adverse impact on the safety and efficacy of the biosimilar candidate.
The biological medicine to be used as a comparator in the comparability exercise must be the product registered with ANVISA. Its registration must also be supported by a complete dossier, given that the comparability exercise encompasses the comparative assessment of primary and higher order structures, of purities and impurities (including charge, size, acidic, and basic variants, when applicable), of functional characterization and of stability between the biosimilar candidate product and the comparator biological product. In fact, all applicable analytical studies, whether non-clinical or clinical, of the biosimilar candidate development program must be of comparative nature.
When filing the application for registration of the biosimilar candidate, the requesting company must submit the complete reports of the non-clinical and clinical studies as described below:
NON-CLINICAL IN VIVO STUDIES
a. pharmacodynamic studies relevant to the intended therapeutic indications; and
b. cumulative (repeated-dose) toxicity studies, including the characterization of toxicity kinetic parameters, conducted in relevant species(s).
CLINICAL STUDIES
a. pharmacokinetic studies;
b. pharmacodynamic studies; and
c. immunogenicity, safety, and clinical efficacy studies.
It is important to highlight that the design and comparability margins of safety and efficacy studies must be specified and statistically and clinically supported. Furthermore, when available, the results of phase IV studies must be submitted in the submission of the registration.
Finally, ANVISA makes it clear that it may, at its discretion and upon technical justification, require additional proof of the identity and quality of the components of the biosimilar medicine or request new studies to prove the efficacy and safety of the medicine for which registration is sought.
According to what has been seen lately in the context of countries with already planned regulation for biosimilars, a significant increase in the number of these medicines for treatments against cancer and autoimmune diseases is expected. However, at first, they need to gain the medical community’s trust, so that its prescription can be increased.
On the other hand, biosimilars have the valuable encouragement of patient associations, which envision the possibility of maximizing access and reducing the treatment cost for patients suffering from diseases combated by such medicines.
