Approval of Biosimilars

Biological medicines (‘biologicals’) contain active substances from a biological source, such as living cells or organisms. The manufacture of biological medicines tends to be more complex than for chemically-derived molecules. Since biosimilars are a type of biological medicine, all features pertinent to biological medicines apply.

Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines approved in the EU. The aim of biosimilar development is to demonstrate biosimilarity - high similarity in terms of structure, biological activity and efficacy, safety and immunogenicity profile.

Demonstration of biosimilarity relies on comprehensive comparability studies with the reference medicine.

Data Requirements for Approval:

All medicines produced using biotechnology and those for specific indications (e.g. for cancer, neurodegeneration and auto-immune diseases) must be approved in the EU through the European Medicines Agency.

Medicines are approved when studies on their pharmaceutical quality, safety and efficacy convincingly demonstrate that the medicine’s benefits outweigh the risks (‘positive benefit-risk balance’). For any biological medicine with a new active substance, a positive benefit-risk balance is determined mainly from evidence of safety and efficacy in pivotal trials in humans, supported by solid pharmaceutical quality data and non-clinical data. It includes:

  • Pharmaceutical quality studies
  • Comparative studies
  • Risk management plan

Pharmaceutical Quality Studies

The studies to prove pharmaceutical quality should provide detailed data on:

  • structural characterisation and other physicochemical properties
  • purity (traces of residues from the manufacturing process have to be controlled and must not exceed acceptable levels)
  • biological activity
  • excipients and starting materials
  • strength and formulation the control of the manufacturing process (to ensure that the active substance and finished product conform with the accepted ranges for technical specifications)
  • stability of the active substance and finished product during shelf-life under defined storage conditions

Comparative Studies

Biosimilar development relies heavily on ‘comparability studies’ to establish biosimilarity to the reference medicine. This involves a comprehensive head-to-head comparison of the biosimilar and the reference medicine.

1. Comparative quality studies

  • In vitro studies compare the protein structure and biological function using sensitive techniques capable of detecting minor differences with clinical relevance between the biosimilar and its reference medicine.
  • These studies are much more sensitive than clinical trials for detecting such differences, as there is often variability among human subjects participating in trials.
  • Differences that may affect clinical safety, efficacy or immunogenicity need to be further studied.

2. Comparative non-clinical studies

  • These studies include pharmacodynamic studies in vitro, which look at binding and activation (or inhibition) of physiological targets and immediate physiological effects in cells.
  • Pharmacodynamic studies in vivo (animal models) are only done if no suitable in vitro model exists.
  • In vivo toxicological studies are only required in certain cases, for example when the biosimilar is produced in a new type of cell or organism, or when the formulation includes new excipients not used previously.

3. Comparative clinical studies

  • The aim of studies in humans is not to demonstrate safety and efficacy in patients, as these have already been established for the reference medicine.
  • Clinical trials are tailored to confirm biosimilarity and to address any questions that may remain from previous analytical or functional studies.

Risk Management Plan

Companies applying for marketing authorisation in the EU must submit a risk management plan (RMP) for each new medicine, including biological medicines. The RMP, which is tailored for each product, includes a pharmacovigilance plan and risk minimisation measures to identify, characterise and minimise a medicine’s important risks. The RMP of a biosimilar is based on knowledge and experience gained with the reference medicine.


By demonstrating biosimilarity, a biosimilar can rely on the safety and efficacy experience gained with the reference medicine. This avoids unnecessary repetition of clinical trials already carried out with the reference medicine.

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Report side effects

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety information. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare providers are asked to report any suspected adverse reactions. Reporting forms and information can be found at In order to support effective tracking and traceability of biologics including biosimilars, it is recommended that the brand name and batch number are recorded and used when reporting adverse events.

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