A biosimilar is a biological medicinal product whose active substance is highly similar to that of an already authorised biological reference medicinal product. Authorisation requires that a comprehensive comparability exercise demonstrate no clinically meaningful differences in quality, biological activity, safety and efficacy compared with the reference medicinal product. A biosimilar is therefore not identical, but scientifically justified as comparable.
Legal basis and demonstration of biosimilarity
The European legal framework for similar biological medicinal products is set out in Article 10(4) of Directive 2001/83/EC and the specific dossier requirements in Annex I thereto. Unlike small, chemically defined molecules, the complete identity of a biologically manufactured product cannot be described solely by a structural formula. Cell lines, the manufacturing process and analytical methods shape the product profile. Therefore, the focus is not on repeating the full development programme of the reference medicinal product, but on providing convincing evidence of similarity.
For this purpose, the EMA describes a stepwise, scientifically justified comparability exercise. It begins with a direct comparison of quality attributes, such as structure, purity and functional properties. Depending on the remaining uncertainty, comparative non-clinical, pharmacokinetic, pharmacodynamic or clinical studies may follow, together with an assessment of immunogenicity. Product-specific guidelines supplement the overarching approach. Data from the different stages must be brought together in a coherent overall body of evidence; a single clinical trial cannot replace robust analytical characterisation. The reference medicinal product must be authorised in the European Economic Area on the basis of a complete dossier.
Indication extrapolation and pharmacovigilance
A biosimilar is not necessarily tested in a separate efficacy study for every indication of the reference medicinal product. Extrapolation to additional indications may be considered if the complete comparability exercise, including the mechanism of action, target receptors, relevant safety aspects and available data, provides a scientifically sound basis for this transfer. It is therefore not merely an adoption of the reference authorisation, but part of the benefit-risk assessment of the specific biosimilar by the authorities.
Following authorisation, biosimilars are subject to the same basic pharmacovigilance requirements as other biological medicinal products. For reporting suspected adverse reactions, unambiguous identification of the medicinal product is important; the brand name and batch number support traceability. The product information specifies the authorised indications, dosages and warnings. Changes to the manufacturing process or new safety information may trigger a new regulatory assessment.
Distinction from generic, biobetter and interchangeability
Under Article 10(1) of Directive 2001/83/EC, a generic medicinal product follows a different abbreviated route: as a rule, it demonstrates the same qualitative and quantitative composition in active substances and bioequivalence with the reference medicinal product. For biological medicinal products, these requirements are often insufficient because of their complexity; in that case, the biosimilar route under Article 10(4) applies. Biosimilar and generic are therefore not interchangeable legal terms.
A biobetter is likewise not a synonym. This term is generally used for a further-developed biological product that claims an intended additional clinical benefit compared with an existing product. Such a claim differs precisely from the biosimilar principle, which requires no clinically meaningful differences from the reference medicinal product. The term biobetter is not a separate European authorisation category.
Interchangeability describes whether the same clinical effect can be expected when switching. In a joint statement, first published in 2022 and available in the April 2023 version, the EMA and HMA stated that biosimilars authorised in the EU are interchangeable: A biosimilar may be used instead of its reference medicinal product, the reference medicinal product instead of the biosimilar, or one biosimilar may be replaced by another biosimilar of the same reference medicinal product, in each case following careful consideration of the authorised conditions of use. Under the same statement, how this interchangeability is implemented, whether as a switch under the supervision of the prescribing person or as automatic substitution at pharmacy level, does not fall within the remit of the EMA, but is regulated by the individual Member States. A biosimilar authorisation alone therefore does not result in a uniform Union-wide substitution rule.
Relevance for clinical trials
In biosimilar studies, early coordination between analytics, clinical development and regulatory strategy determines the scope of the programme. Comparative studies require an appropriately selected reference medicinal product, sensitive endpoints and a comprehensible rationale for the population, dosage and indication. Authorities assess in particular whether remaining uncertainties from the quality and functional analysis are addressed in a targeted manner and whether the evidence for a possible indication extrapolation is coherent.
Full-service CROs such as Mediconomics support development planning, the selection and operational conduct of comparative clinical trials, data management, biostatistics, immunogenicity assessment, medical writing and the compilation of regulatory dossiers. Consistent interfaces between CMC documentation, clinical reports and pharmacovigilance are important so that the overall demonstration of biosimilarity remains verifiable.
Frequently Asked Questions (FAQ)
Is a biosimilar a generic medicinal product?
No. A biosimilar is a biological medicinal product with its own comparability exercise under Article 10(4), whereas the bioequivalence route under Article 10(1) is decisive for generics.
Must a biosimilar be clinically tested in every indication?
Not necessarily. Additional indications may be extrapolated if the complete scientific evidence justifies the transfer and the authority accepts it.
May a biosimilar be automatically substituted?
Biosimilar authorisation does not establish automatic substitution. Whether and how substitution is permitted is decided by the Member States.
Regulatory references
- Directive 2001/83/EC, Article 10(4) and Annex I Part II Section 4 — legal basis for similar biological medicinal products.
- EMA guideline CHMP/437/04 Rev. 1 — describes the overarching scientific biosimilar approach.
- Joint statement by the EMA and HMA on the interchangeability of biosimilars (EMA/627319/2022) — establishes interchangeability and assigns substitution decisions to the Member States.
- Regulation (EC) No 726/2004, Article 6 — governs applications under the centralised procedure.