Biosimilars

Definition of a biosimilar

A biosimilar is a biological medicinal product which is equivalent to a reference product registered within the European Community. A comparative study is needed to demonstrate that the product is equivalent in terms of quality, safety and efficacy to the reference product chosen in the European Community. 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 ref. Guidelines EMA and Q&A document).
For biosimilars, less (non) clinical data (modules 4 and 5) are needed than for the original reference product. The requirements for administrative data (module 1), technical (module 2) and chemical-biological-pharmaceutical (module 3) are identical to those for the biological reference product.

Why a specific approach for biosimilars

Bio(techno)logicals drugs are prepared by using living biological systems. Heterogeneity is inherent to the nature of biological products and their production process. The process (and therefore the final product) is also 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. A biosimilar will therefore almost always show differences in relation to a reference medicinal product.

That is why we must carry out detailed studies in which both medicinal products are compared. These studies include a stepwise process, during which the chemical-pharmaceutical quality is first compared. When one considers that they are sufficiently comparable, studies are also done later to compare the safety and effectiveness. The number and scale of these studies are lower than those for the reference medicinal product and need to demonstrate in the rather short term (see below), that no significant differences exist with respect to efficacy and safety between the biosimilar and the reference medicinal product.

Biosimilars and pharmacovigilance

As for all bio(techno)logical medicinal products, also biosimilars can be immunogenic, and this may affect the safety and efficacy. It is difficult if not impossible, to predict the immunogenicity based on non-clinical studies. These rare, but serious, side effects can also often be detected only within a larger population of patients and after a longer use. An extrapolation based on data of the reference product is obviously not possible. For biosimilars, EMA asks normally immunogenicity data from one year before the registration of the biosimilar. The safety of all medicinal products, including biosimilars, is also investigated after the marketing authorisation has been granted.

For each bio(techno)logical 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 minimisationa ctivities are treated nationally.

It is also stated in the EMA guidelines that identification of bio(techno)logical medicinal products is very important.

Other particularities

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.

Biological medicinal products with the same active substance, including biosimilars, are in general not interchangeable in view of their complexity. The FAMHP recommends excluding biological medicinal products of the INN prescription (see INN). If the prescriber decides to move from one to the other (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. 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.

How many and what biosimilars received marketing authorization in Europe (status 2010)

• somatropin – Genotropin : Omnitrope (Sandoz), 2006
• somatropin – Humatrope : Valtropin (Biopartners), 2006
• epoetin alpha – Eprex :

- Binocrit (Sandoz), 2007
- Epoetin alfa Hexal (Hexal), 2007
- Abseamed (Pütter Medice Arzneimittel GmbH & Co.), 2007

• epoetin zeta - Eprex:

- Silapo (Stada Arzneimittel), 2007
- Retacrit (Hospira), 2007

• filgrastim - Neupogen:

- Biograstim (CT Arzneimittel GmbH), 2008
- Filgrastim Ratiopharm (Ratiopharm), 2008
- Ratiograstim (Ratiopharm), 2008
- Tevagrastim (Teva Generics GmbH), 2008
- Zarzio (Sandoz), 2009
- Filgrastim Hexal (Hexal), 2009
- Nivestim (Hospira), 2010

Scientific discussion for each medicinal product registered under the central procedure is available publicly in the form of a European Public Assessment Report (see ref. 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 (PDF, 50.48 Kb) of authorized and marketed biological medicinal products in Belgium (update: January 2012).

References

- Guidelines of the European Medicines Agency (EMA). ► Home ► Regulatory  ► Human Medicines ► Scientific guidelines ► Multidisciplinary ► Biosimilar

- "Questions and Answers on biosimilar medicines (PDF, 27.52 Kb)" (Similar Biological medicinal products) EMEA/74562/2006 Rev. 1, 22 October 2008

- 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) (PDF, 221.26 Kb) prescription .Proposals for the practical application in medical practice in the electronic medical record (10 March 2010).