Definition of a biosimilar
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) in the European Economic Area (EEA). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established.
The European legislation offers since 2006 a legal framework for biosimilars.
The concept and methodology of the comparative investigations are further treated in the guidelines of the European Medicines Agency (EMA). These guidelines include general and more targeted recommendations, taking into account the biological reference properties of the biological product concerned (see EMA Guidelines and Q&A document).
Why a specific approach for biosimilars
Bio(techno)logical drugs are prepared by using living biological systems. Heterogeneity and complexity is inherent to the nature of biological products and their production process. The process (and therefore the final product) is very sensitive to changes in the production process (preparation, purification, formulation, etc.). Two production processes developed independently for the same medicinal product may therefore lead to biological medicinal products that are equivalent, but never identical medicinal products. The active substance of a biosimilar and that of the reference medicinal product are actually the same biological substance, although there may be small differenes as a consequence of its complex nature and the used production methods. As the reference medicinal product does, the biosimilar will also show some natural variability. A biosimilar is only authorised when it can be stated with appropriate certainty that its variability and the differences with the reference medicinal product will not have a relevant influence on the safety or efficacy. Detailed studies are carried out in which both medicinal products are compared. These studies include a stepwise process, during which the structure, biological activity and quality is first compared. When they are sufficiently comparable, studies are also done later on to compare the safety and effectiveness. As the reference product is already authorised for a number of years in the EEA, and the clinical benefit has beeen determined, some experiments which have been conducted for the referecne medicinal product, do not need to be repeated. The number and scale of these studies are determined by the results of the previous steps in the process and the guidelines issued by the EMA. The results of these studies are provided in the non-clinical and clinical parts of the marketing authorisation application, which will be less extensive as those for the reference medicinal product.
In summary, the most important part of the assessment is the comparability between the biosimilar and the reference medicinal product, where it must be demonstrated that there are no signs for therapeutically relevant differences.
If biosimilarity has been demonstrated in one indication, extrapolation to other indications of the reference product could be acceptable with appropriate scientific justification.
Biosimilars and pharmacovigilance
As for all medicinal products, the safety of biosimilars is monitored continuously after the authorised has been approved. For each new marketing authorisation of a medicinal product, including biosimilars, a risk management plan (RMP) is developed and an adequate pharmacovigilance is set up ensuring a permanent follow-up of the safety of the medicinal product after it has been brought on the market. The RMP is submitted and approved on a European level. Possible additional risk minimisation activities are treated nationally.
Permanent vigilance for immune reactions is needed following the use of biotechnological medicinal products, including biosimilars. An extrapolation based on immunogenicity data of the reference product is obviously not possible. It is of importance that Immunogenicity testing of the biosimilar and the reference product should be conducted within the biosimilar comparability exercise by using the same assay format.
Biosimilars cannot be approved if an increased risk for immunogenicity has been observed. Also, intended changes to improve efficacy are not compatible with the biosimilarity approach. However, differences that could have an advantage as regards safety (for instance lower levels of impurities or lower immunogenicity) should be addressed, but may not preclude biosimilarity.
It is also stated in the EMA guidelines and the new legislation concerning pharmacovigilance that identification of bio(techno)logical medicinal products is very important when reporting adverse events.
Many biosimilars may exist for the same reference medicinal product (see below). Because different biosimilars of a reference medicinal product are compared each completely separate to the reference product, there is no information on comparability between these biosimilars. Famhp recommends excluding biological medicinal products of the INN prescription (International nonproprietary name). If the prescriber decides to move from one to the other (original/original; original/biosimilar; biosimilar/original or biosimilar/biosimilar, often also called "switch" in this context), then this must be done with the necessary follow-up and the modification must be recorded accurately. The exclusion of INN prescription avoids switching without follow-up by the prescriber. However, since the biosimilar medicinal product can only be authorised if it has the same safety and efficacy profile as the reference medicinal product, relevant changes in treatment are not expected upon switching from the reference product to a biosimilar medicinal product (or vice versa).
Substitution (the passage of a specialty subject to a prescription to another specialty by the pharmacist, without consulting the doctor) is not allowed in Belgium for biologicals (including biosimilars).
A detailed information paper on biosimilar medicinal products has been provided by the European Commission in 2013. In addition to the regulation of biosimilars, the economic consequences are being discussed. Specific Question & Answer documents are included targeting patients, physicians and payers. (see EC Consensus Information Paper).
A report on the situation in Belgium has been published by the Federal Health Care Knowledge Centre (KCE): ‘Barriers and opportunities for the uptake of biosimilar medicines in Belgium’ (see KCE website).
How many and what biosimilars received marketing authorization in Europe (status Jan 2014)
|Name||Active substance||Date of autorisation|
|Epoetin Alfa Hexal||epoetin alfa||28.08.2007|
|Inhixa||enoxaparin sodium||CHMP opinion July 2016|
|Thorinane||enoxaparin sodium||CHMP opinion July 2016|
Scientific discussion for each medicinal product registered under the central procedure is available publicly in the form of a European Public Assessment Report (see EMA website). It is also possible to register biosimilars via other registration procedures (national, mutual recognition, decentralized) when it is concerning a biological medicinal product which does not necessarily follow the central procedure.
See the Belgian Center for Pharmacotherapeutic Information (http://www.cbip.be/) for information on biosimilars marketed in Belgium.
List of authorized and marketed biological medicinal products in Belgium (see French or Dutch version)
- Guidelines of the European Medicines Agency (EMA). ► Home ► Regulatory ► Human Medicines ► Scientific guidelines ► Multidisciplinary ► Biosimilar
- "Questions and Answers on biosimilar medicines" (Similar Biological medicinal products) EMEA/837805/2011, September 27th 2012
- European Public Assessment Report (EPAR) http://www.ema.europa.eu/ ► Find Medicine ► Human medicines ► European Public Assessment Reports
- International Non-proprietary Name (INN) (French version) prescription .Proposals for the practical application in medical practice in the electronic medical record (10 March 2010).
- Consensus Information paper on ‘What you need to know about Biosimilar Medicinal Products’ of the European Commission’s project group ‘Market Access and Uptake of Biosimilars’http://ec.europa.eu/DocsRoom/documents/8242/attachments/1/translations/en/renditions/native.
- Barriers and opportunities for the uptake of biosimilar medicines in Belgium, KCE report, March 2013,https://kce.fgov.be/publication/report/barriers-and-opportunities-for-the-uptake-of-biosimilar-medicines-in-belgium