**Introduction **
A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (Reference Medicinal Product, RMP), where similarity to the reference medicinal product based on a comprehensive comparability exercise has been established. Biosimilars have become important therapeutic options, improving patient access to essential treatments. Therefore, CHMP (EMA) acknowledges the significance of biosimilars. Currently, the required comparability exercise comprised quality data (analytical comparability exercise), in vitro and in vivo non-clinical data, and comparative pharmacokinetic, pharmacodynamic, safety and efficacy studies. However, considering the advances in the analytical sciences and the extensive regulatory experience gained, in vivo non-clinical data and, at least for some less complex biologicals with a straightforward mechanism of action, the importance of dedicated clinical efficacy and safety data should be re-evaluated. Currently, the need for Comparative Efficacy Studies (CES) is increasingly questioned in general.
**Problem statement **
Biosimilar medicines cover a broad array of products, ranging from relatively simple to more complex molecules. The CHMP has accumulated substantial experience in assessing biosimilars with high complexity such as monoclonal antibodies(mAbs), resulting in a robust regulatory framework that ensures product efficacy and patient safety. An ever-growing number of biosimilars has been successfully authorized through rigorous evaluation of scientific data, including the assessment of comparability for quality, non-clinical, and clinical aspects. By building upon this extensive knowledge, CHMP aims to further optimize the development and evaluation process for biosimilars.
Constantly striving for scientifically sound yet efficient processes, the Biosimilar regulatory framework has constantly been evolving towards increasingly tailored developments, starting from smaller and “simpler” biologics, such as recombinant Granulocyte-Colony Stimulating Factor (rG-CSF), insulins or somatropin where the need for comparative clinical efficacy trials is in general not required any more. With growing knowledge and the increasing possibilities of analytical and functional characterisation, revisiting the need for clinical efficacy trials for biosimilars (especially recombinant proteins and mAbs) is considered the next important step in order to keep the Biosimilar pathway attractive for developers and, at the same time, guarantee future access to safe and efficacious biologics for European patients
**Discussion (on the problem statement) **
CHMP has gained extensive insight into assessing the quality attributes of biosimilars through the evaluation of critical quality attributes, manufacturing processes, and comparability exercises. The Agency has closely examined physicochemical and functional characteristics, as well as the overall similarity to the RMP . This experience has led to the establishment of stringent requirements and guidance that ensure the quality of biosimilars, including biosimilar mAbs. The CHMP recognizes that there may be the potential to waive certain clinical data requirements even for complex biosimilars such as mAbs based on solid evidence of quality comparability. When the biosimilar demonstrates a high degree of similarity to the RMP at the analytical and functional level, it may be possible to justify the omission of dedicated CES.
This approach aims to streamline the development and evaluation process while maintaining the highest standards of safety and efficacy. Whether and which clinical data will be required may depend on how well the clinical performance of the biosimilar can be predicted from comparative experiments on the analytical/functional level, knowledge regarding the molecule’s mode of action (primary and secondary pharmacology) and also the clinical profile of the RMP, e.g. the potential and impact of immunogenicity. The aim of the proposed reflection paper will be to discuss CHMP’s perspective on the development and evaluation of biosimilars, taking into account the wealth of experience gained from previous marketing authorizations, particularly in relation to analytical/functional comparability exercises. More accurately, the reflection paper will explore how far well-defined analytical/functional (quality) data can be predictive for the clinical outcome.
In consequence, it will be evaluated, whether, or not, findings from a quality comparability exercise, together with clinical PK/PD trials could prospectively lead to the conclusion of clinical similarity, without the need for large CES in patients.
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