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New EMA Guidelines for Biosimilars


The EMA has published a new draft biosimilars guideline outlining the general principles that must be taken into account when developing an application to the agency. Summary of this guideline is given below:

  • 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). A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological  activity, safety and efficacy based on a comprehensive comparability exercise.
  • The success of developing a biosimilar will depend on the ability to produce a close copy to the reference medicinal product and demonstrate the similar nature of the concerned products. This  includes physicochemical and biological characterisation and requires knowledge on how to interpret any differences between a biosimilar and its reference medicinal product.
  • The standard generic approach (demonstration of bioequivalence with a reference medicinal product by appropriate bioavailability studies) which is applicable to most chemically-derived  medicinal products is in principle not appropriate to biological/biotechnology-derived products due  to their complexity. The “biosimilar” approach, based on a comprehensive comparability exercise,  will then have to be followed.
  • The scientific principles of such a biosimilar comparability exercise are based on those applied for  evaluation of the impact of changes in the manufacturing process of a biological medicinal product (as outlined in ICH Q5E).
  • Whether the ‘biosimilar’ approach would be applicable for a certain biological medicinal product  depends on the state of the art of analytical procedures, the manufacturing processes employed,  as well as clinical and regulatory experiences, e.g. as regards the possibility to identify comparability margins, availability of sensitive clinical endpoints and model conditions etc.
  • Biosimilar comparability exercises are more likely to be applied to products that are highly purified and can be thoroughly characterised (such as many biotechnology-derived medicinal products). The ‘biosimilar’ approach is more difficult to apply to other types of biological medicinal products, which by their nature are more difficult to characterise, such as biological substances arising from extraction from biological sources and/or those for which little clinical and regulatory experience has been gained.
  • The posology and route of administration of the biosimilar should be the same as that of the reference medicinal product. Deviations from the reference product as regards formulation or excipients require justification or further studies.
  • Intended changes to improve efficacy are not compatible with the biosimilarity approach.
  • The biosimilar shall, with regard to the quality data, fulfill all requirements for Module 3 as defined  in Annex I to Directive 2001/83/EC.
  • Safety and efficacy of biosimilars have to be demonstrated in accordance with the data requirements laid down in Directive 2001/83/EC.
  • A single reference medicinal product, defined on the basis of its marketing authorisation in the EEA,  should be used as the comparator throughout the comparability programme for quality, safety and  efficacy studies during the development of a biosimilar in order to allow the generation of coherent  data and conclusions.
  • It may be possible for an Applicant to compare the biosimilar in certain clinical studies and in vivo non-clinical studies (where needed) with a non-EEA authorised comparator (i.e. a non-EEA authorised version of the reference medicinal product) which will need to be authorised by a regulatory authority with similar scientific and regulatory standards as EMA (i.e. ICH countries).
  • The guiding principle of a biosimilar development programme is to establish similarity between the  biosimilar and the reference product.
  • A biosimilar should be highly similar to the reference medicinal product in physicochemical and  biological terms. Any observed difference would have to be duly justified with regard to their potential  impact on safety and efficacy.
  • A stepwise approach is normally recommended throughout the development programme, starting with  a comprehensive physicochemical and biological characterisation.
  • The ultimate goal of the comparability exercise is to exclude any relevant differences between the  biosimilar and the reference medicinal product.

In general, approaches should always be discussed with Regulatory Authorities before  commencement of such development concludes the agency.