EMA publishes final version of Biosimilar guideline

On 29 October 2014, EMA presented the final version of their guideline on biosimilars. This document replaces the previous guidance document of 2005, provides several clarifications and introduces one important change intended to ease global development of biosimilars.

On 29 October 2014, EMA presented the final version of their guideline on biosimilars. This document replaces the previous guidance document of 2005, provides several clarifications and introduces one important change intended to ease global development of biosimilars.
November 9, 2014
The European Medicines Agency (EMA) has just published its revised Guideline on similar biological medicinal products. The original biosimilar guideline was published back in September 2005, providing the initial regulatory framework for biosimilars in Europe. Unsurprisingly, in this young and fast evolving field of biosimilars, the original guideline became outdated rather quickly. EMA reacted and presented a draft update of the guideline in May 2013, for which it took 17 months until its finalization and adoption now in October 2014.
Use of foreign comparators
Undoubtedly, the biggest news of this guideline is that for certain studies EMA will permit the use of foreign comparator products. The guideline states that “it may be possible for an Applicant to compare the biosimilar in certain clinical studies and in in vivo non-clinical studies (where needed) with a non-EEA authorised comparator“, a move that is aimed to reduce the duplication of unneeded clinical studies, thus “facilitating global development of biosimilars“, as claimed by EMA on their website.

While this clearly opens up the possibility for generating bridging data using foreign comparators, naturally, several limitations apply and it will be the responsibility of the applicant to “scientifically justify the relevance of these comparative data” and to build an “acceptable bridge to the EEA-authorized product“. According to the guideline, the acceptability of such data will be a “case-by-case/product-type decision” for which the quality of the analytical data will be crucial (comparing biosimilar, EEA reference product and foreign comparator). Obviously, previous discussions with EMA are highly recommended before counting on foreign comparator data in the development and registration strategy.


Principles of establishing biosimilarity 

EMA has included a complete section on the topic of biosimilarity principles, offering several clarifying statements. As already understood by all stakeholders, the overall objective of the biosimilar approach is defined as “ensuring that the previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar“. For this, EMA recommends a stepwise approach, which shall start with a comprehensive physicochemical and biological characterisation. Based on this initial step, the applicant shall choose the non-clinical and clinical studies to be conducted. Notably, the regulators state that “clinical data is to address slight differences shown at previous steps and (…) cannot be used to justify substantial differences in quality attributes“. The agency position is very clear at this point and further emphasises that if the “comparability exercise indicates (…) relevant differences (…) making it unlikely that biosimilarity will eventually be established, a stand-alone development (…) should be considered instead“.
Key principles and general guidance

The new guideline also provides refined general guidance and several clarifications, such as: posology and route of administration of biosimilar must be the same as the reference product. Deviations in strengths, pharmaceutical form, formulation may be acceptable, but require justification. Intended changes to improve efficacy are not acceptable, yet potential improvements relevant for safety should be addressed.

No additional information is provided regarding the hot topic of interchangeability, as this will need to be regulated on a national level (“substitution policies are within the remit of the EU member states“). Neither is justification of extrapolation of indications addressed, but the EMA has indicated that the current guideline on the clinical and non-clinical aspects related to biosimilar development which deals with this issue is currently being revised and is expected to be published by the end of 2014.

The effective date of this guideline is 30 April 2015, however applicants can already apply some or all provisions of the guideline as of 29 October 2014.

(This guidelines is to be read along with the already adopted biosimilar guidelines on non-clinical and clinical (EMEA/CHMP/BMWP/42832/2005) and quality issues (EMEA/CHMP/BWP/49348/2005)).
ASPHALION expert services for biosimilars development and registration

ASPHALION is one of the leading consulting firms in Europe in the area of Biologicals and Advanced Therapy Medicinal Products. ASPHALION’s regulatory consultants and medical and technical writers assist companies since 2005 during development phases and product registration, generating all required documentation and managing all procedural tasks.

Specifically in the field of biosimilars, ASPHALION has already gained substantial experience through the projects of its clients, providing strategic consulting and generating complete CTD marketing authorisation application dossiers. For more information, please contact the ASPHALION team.

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