EU Sets Guidelines for Biosimilar Monoclonal Antibodies - Pharmaceutical Technology

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EU Sets Guidelines for Biosimilar Monoclonal Antibodies
The European Medicines Agency has added granularity to its biosimilars approval pathway by releasing a guideline on biosimilar monoclonal antibodies (mAbs).


Pharmaceutical Technology
Volume 36, Issue 11, pp. 42-45

Biosimilar mAb development clarified

The mAb guideline's overall aim is to lay down general principles for nonclinical and clinical studies on any potential differences between a biosimilar mAb and a reference mAb and how much these differences may amount to a dissimilarity between the two products. The guideline recommends a step-wise approach, with both in vitro and in vivo studies being conducted on a case-by-case basis. For example, comparative in vitro studies would be conducted first to assess differences in binding or function, with the necessity for additional steps involving in vivo work being determined by the need for additional information.

Extrapolation of clinical efficacy and safety data to other indications of the biosimilar, based on the overall evidence from the comparability exercise, would be acceptable, according to the guideline.

In its draft guideline on quality of biosimilars, EMA states that, "it is not expected that all quality attributes (between the biosimilar and the reference product) will be identical and minor differences may be acceptable, if appropriately justified" (2). In the mAb guideline, the agency points out that assays have been developed in recent years allowing more in-depth characterization of complex proteins both at the physicochemical and functional levels. These assays have enabled more effective assessment of minor quality differences in manufacturing processes for mAbs. Nonetheless, EMA warns that "in the current state of knowledge it may be difficult to interpret the relevance of minor quality differences" when comparing a biosimilar with a reference mAb (1) .

Pharmacovigilance requirements

Regulators expect that during the postauthorization pharmacovigilance stage, unpredicted adverse results from differences in manufacturing process could be detected. Incorrect extrapolations from nonclinical or clinical data during comparability assessments could also be revealed.

The EU's pharmacovigilance legislation, approved in 2010, simplifies reporting of adverse drug reactions and the submission of periodic safety update reports (PSURs), data from both of which will be held centrally.

Postauthorization safety and efficacy studies can be requested from drug-licence holders by the authorities. Applicants for marketing approvals of medicines will have to submit postauthorization risk-management plans.

For biosimilars, particularly mAbs, pharmacovigilance requirements will be tougher than for conventional medicines. "The pharmacovigilance system is an essential part of monitoring biosimilars after approval," says Morrison. "[The legislation] provides for additional monitoring for biological products, including biosimilars."

The mAb guideline states that applicants for marketing authorization of their mAbs or other biosimilars will have to provide a "comprehensive concept" of how further postauthorization safety studies will be carried out. The safety plan will cover safety claims based on extrapolations of efficacy and safety data during the comparability exercise and occurrences of rare and particularly serious adverse effects. In addition, because adverse reactions to biosimilars could be due to defects in manufacturing processes, the products should be clearly identifiable by name and batch number, according to the mAb guideline.


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