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  • Writer's pictureInovatie Serviços em Saúde

Challenges in the development and registration of biosimilars

On October 18th, 2023, Inovatie Serviços em Saúde held a webinar on the development and registration of biosimilars. The event was presented by the managing partners of Inovatie, Claudia Cilento, responsible for the Regulatory Affairs area, and Camille Rodrigues, responsible for Clinical Research and Medical Affairs. 


In the beginning of the webinar, Claudia addressed the differences between the development of a new biological medicine and a biosimilar. She highlighted that, due to the size of the molecule of a biological medicine, its development becomes more complex when compared to that of a synthetic medicine. 


Due to its elaborate structure, the molecule can undergo post-translational changes, such as acetylation, alkylation, phosphorylation and several other modifications. These changes can occur after the protein is manufactured inside the cell. 


The complexity in producing a biosimilar lies in the need for it to come as close as possible to the post-translational modifications of the innovative medicine. This is essential to ensure that their efficacy, safety, immunogenicity, among other characteristics, are demonstrably similar. 


Comparability studies 


To prove that a medicine is biosimilar to an innovative biological product, comparability studies are necessary. According to Claudia, this is a complex process and a challenge for registering the biosimilar, as it requires in-depth knowledge of the structure of the molecule. Differences in relation to the comparator molecule can directly impact the efficacy and safety of the biosimilar. 


The comparability study has several steps and must be carefully designed and designed to demonstrate the high similarity between the quality attributes of the biosimilar and the innovative biological medicine. 


The objective of this investigation is to be as comprehensive as possible and sensitive enough to detect differences, since, as Claudia highlights, it is highly unlikely that a biosimilar molecule is absolutely identical to the new drug molecule. The comparability study must include several analyzes to determine the structure of the molecule, function, purity and heterogeneity of the product. 


Due to this complexity, it is quite likely that differences between molecules will be identified. However, this is not necessarily a problem that prevents medication registration. The important thing is to highlight, explain and contextualize these differences with ANVISA. 


The justification must be prepared considering the impact that the differences found will have on the activity of the molecule and, consequently, on the safety and efficacy of the medicine. 


If it is impossible to register the biosimilar medicine via comparability, there is the option of doing so via individual registration. But in this case, the medicine will be registered only for the indication for which the clinical study was carried out and cannot be used for indications that go beyond those of the new biological medicine. 


Claudia highlighted that, in her opinion, a large part of the challenges in developing biosimilars lies in the difficulty of finding specialized professionals. In Brazil, there are few specialists capable of developing and designing a comparability study. Added to this is the scarcity of laboratories with adequate structure to carry out the necessary tests and the persistent difficulty in importing inputs. 


Clinical development of the biosimilar 


In the past, the development of biosimilars generated many doubts and there was great concern about the safety of these products, especially in relation to interchangeability. However, as noted by Camille, what has been seen, over the years, and after more than 90 biosimilar products registered with the European Regulatory Agency EMA, is that developing biosimilar medicines is a safe and effective process. 


Camille even commented that, from a clinical point of view, when considering biological products with a simpler structure, developing a biosimilar can be as uncomplicated as developing a generic medicine. 


For molecules with a less complex structure, currently, the European Union has no longer required phase 3 clinical efficacy and safety studies, but only comparative studies of the pharmacokinetic and/or pharmacodynamic type, in the vast majority of cases sufficient to prove the similarity between the products. In fact, the EMA created guides to prove biosimilarity for some simpler products. 


In the case of more complex molecules, when the medication is being developed through comparability, studies that prove, from a pharmacokinetic and pharmacodynamic point of view, the comparability of the products are essential. Furthermore, it is necessary to compare efficacy and safety through phase 3 studies. 


Camille highlighted the importance of proving, during the product development process, that the immunogenicity of the biosimilar is similar to that of the original medicine. 


How to select the indication for the phase 3 study 


In the assessment of regulatory agencies, such as ANVISA, the ideal is for clinical development to be based on the main indication, or the most sensitive indication of the product. To do this, it is important to observe the properties of the product and, among the available indications, evaluate those most frequently used and for which the product was originally developed. 


Camille further commented that, to optimize a phase 3 study, it is important that it is simple, while also providing all the necessary information. 




Since 2010, when Resolution of the Collegiate Board of Directors (RDC) No. 55, of December 16, was published, which provides for the registration of biological products - and which is currently undergoing review -, we have learned a lot, we can say. 


From a clinical point of view, Camille highlights the assessment of immunogenicity, as well as the importance of the analytical phase of comparability, which, if not properly carried out, can invalidate the following steps. On the other hand, Claudia highlights interchangeability, which, although it has been widely questioned in the past, can now be carried out safely. Recently, the EMA issued a statement on the scientific basis that supports the interchangeability of biosimilar medicines in the European Union. 


Real life study 


Finally, another point highlighted in the webinar was the valuable contribution of real-life studies for already approved biosimilars. These studies present data related to safety, the absence of adverse events and the benefits of using the medication, thus consolidating the experience of using the product. Such studies reproduce the results of the use of biosimilars in patients' daily lives, where medication changes occur frequently, providing safety in the use of these products for the medical community, patients and families. 

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