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Regulatory Focus™ > News Articles > EMA Releases Final Biosimilar Guidelines

EMA Releases Final Biosimilar Guidelines

Posted 18 June 2012 | By Alexander Gaffney, RAC 

The European Medicines Agency (EMA) has finalized two guidance documents pertaining to medicines containing monoclonal antibodies, further vaulting the agency ahead of its US counterpart when it comes to the development of a biosimilar framework.

The two guidance documents address two different aspects of the development of biosimilar medicines: in vivo clinical testing of medications and aspects related to non-clinical and clinical testing. EMA said its call for comments on the draft guidance had received a "large number" of responses, which it summarized and posted along with the final guidelines (here, here and here).

Comparability Testing

EMA's first guideline, Guideline on similar biological medicinal products containing monoclonal antibodies-non-clinical and clinical issues, establishes the "general principles" of a development program to test the comparability of a biosimilar product to an innovator biologic.

"The focus of the guidance is on the careful demonstration of the comparability of a biosimilar monoclonal antibody with the monoclonal antibody in the original, authorized medicine," explained EMA in a statement. "This is needed to make sure that the efficacy and safety demonstrated for the original medicine are conserved in the biosimilar medicine."

The agency said it is recommending the use of a step-wise approach to biosimilar evaluation in which each biosimilar is subject to in vitro and in vivo studies on a "case-by-case basis," which in vitro studies occurring first. EMA noted "the conduct of toxicological studied in non-human primates is usually not recommended."

Clinical trials thereafter are to be characterized relative to the amount of evidence obtained during pre-clinical testing, explained EMA. Most initial studies will involve a comparative pharmacokinetic study in a small, healthy, homogeneous study population, using the principles of blinded, randomized clinical trials based on "a sound scientific rationale." While EMA recommends single-dose studies, it notes multi-dose studies or studies using non-healthy volunteers may be conducted if the product warrants such studies and the sponsor can justify the changes to EMA.

The guideline stresses the need to establish the comparability of the biosimilar to the innovator, and notes "deviations from disease-specific guidelines issued by the CHMP may be warranted. Sponsors should select the "most sensitive dose…to detect potential differences in pharmacokinetics between the biosimilar and the reference products."

"For mAbs licensed in several clinical indications, it is not generally required to investigate the pharmacokinetic profile in all of them," explains EMA. "However, if distinct therapeutic areas are involved for one particular mAb (e.g. autoimmunity and oncology), separate PK studies may be needed if different target-mediated clearance exists for different therapeutic areas."

Potential Problems

EMA's other guideline, Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use, addresses the potential for immunogenicity problems in patients treated with biologic products, including biosimilars.

In particular, the guideline addresses potential problems that can occur at various stages of testing, including with screening assays, antibody assessment response testing, confirmatory assays and testing controls. EMA's guidelines instructs sponsors to work to identify and manage risk factors present within their products through analysis of prior knowledge, understanding of the mAb structure, understanding of the mAb's mechanism of action and understanding of other clinical factors. Sponsors should "understand the rate of occurrence and the clinical consequences of an unwanted immune response, and if these consequences can be prevented, appropriately measured, and/or treated medically," explained EMA.

Both guidelines come into effect on 1 December 2012.

Read more:

Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use.

Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues

EMA - European Medicines Agency finalises guidance on medicines containing monoclonal antibodies

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