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3.2.4. Safety and Immunogenicity

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While comparative PK studies primarily focus on establishing equivalence in drug exposure between 558 the biosimilar and the reference medicinal product, they can also provide supportive safety and 559 immunogenicity data that help ascertain similarity in immunological responses between the biosimilar 560 and the reference medicinal product. In cases with a comprehensive quality package showing close 561 analytical similarity and high purity of the biosimilar, a limited but well-defined set of comparative 562 safety and immunogenicity data as part of the PK study could provide sufficient confidence in the 563 biosimilar's safety and immunogenicity profile. If relevant uncertainties remain from the quality 564 package, longer and/or larger studies may be needed to ensure the absence of a clinically relevant 565 impact. 566 In case relevant uncertainties remain, longer and/or larger studies may be needed to ensure no clinical 567 meaningful impact (see also 3.1.7.5, 3.1.7.6.). 568 In some cases, immunogenicity data from a single-dose PK study may not be enough,. especially if 570 anti-drug antibodies (ADAs) are known to exert relevant effects on efficacy (e.g., due to neutralising 571 antibodies) or safety (e.g., serious infusion reactions) developing later in the treatment course. In such 572 cases, two or even more administrations may be necessary in an appropriate healthy volunteer or 573 patient population. The applicant should assess the timeframe of ADA development and the 574 immunogenic risk of the reference medicinal product to design a comparative PK study of adequate 575 duration. 576 Taken together, biosimilars may be approved without providing CES or even PD data if similar clinical 578 efficacy and safety pharmacology can be inferred from a sufficiently stringent evaluation of analytical 579 comparability, in vitro pharmacology, and a comparative clinical PK trial. Whether a development 580 programme without a CES could be envisaged depends on the ability to extensively characterise the 581 structure and function of the RMP, and understanding whether the differences in particular QAs have a 582 meaningful impact on clinical outcomes (see prerequisites for similarity assessment). 583 In any case, a well-defined comparative human PK study would still be required. 584 3.2.4.1. Extended PK studies with more than one dosing 569 3.3. Conclusion 577

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Reflection paper on a tailored clinical approach in biosimilar development EMA/CHMP/BMWP/60916/2025

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