What is a biological medicinal product and a biosimilar?
Why a specific approach for biosimilars?
Biosimilars and pharmacovigilance
Switch and substitution of biological medicinal products
Switching of biological medicinal products
Substitution of biological medicinal products
Biosimilars with a marketing authorisation in Europe
Questions and answers on biosimilars
A biological medicinal product, or biological, is a medicinal product whose active substance is made by a living organism.
A biosimilar is a biological medicinal product that contains a version of the active substance of an original biological medicinal product (reference medicinal product) already authorised in the European Economic Area (EEA). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety (including immunogenicity) and efficacy needs to be established based on a comprehensive comparability exercise.
The European legislation has provided a legal framework for biosimilars since 2006, and the European Medicines Agency (EMA) is responsible for evaluating the majority of applications to market biosimilars in the European Union (EU).
The concept and methodology of the comparative investigation can be found in the guidelines of the European Medicines Agency. These guidelines include general and more targeted recommendations, taking into account the biological reference properties of the biological product concerned (see EMA Guidelines and European Commission Q&A document).
A biosimilar is not regarded as a generic of a biological medicine. This is mostly because the natural variability and more complex manufacturing of biological medicines do not allow an exact replication of the molecular micro-heterogeneity.
Bio(techno)logical medicines are prepared using living biological systems. Heterogeneity and complexity are inherent to the nature of biological products and their production process. The process (and therefore the final product) is highly sensitive to changes in the production process (preparation, purification, formulation, etc.). Two production processes developed independently for the same medicinal product can therefore lead to similar, but never identical, biological medicinal products.
The active substance of a biosimilar and that of the reference medicinal product are in fact the same biological substance, although there may be small differences due to its complex nature and the used production methods. Like the reference medicinal product, the biosimilar will also show some natural variability. A biosimilar is only authorised when it can be stated with sufficient certainty that the variability and the differences from the reference medicinal product will not have a relevant impact on the safety or efficacy.
Detailed investigations comparing the two medicinal products will be conducted. These investigations include a step-by-step customised process, which first compares the structure, biological activity and quality. If these are sufficiently comparable, investigations can later be conducted to compare the safety and effectiveness. Since the reference product is already authorised in the EEA for a number of years and the clinical benefit has been established, some investigations which have been conducted for the reference medicinal product, need not be repeated.
The number and extent of these investigations are determined by the results of the previous steps in the process and the guidelines issued by the EMA. The results of these investigations 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 main part of the assessment is the comparability between the biosimilar and the reference medicinal product, where it must be demonstrated that there is no evidence of 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.
As for all other medicinal products, the safety of biological and biosimilar medicinal products is subject to continuous monitoring once the marketing authorisation has been granted.
With each new marketing authorisation for a medicinal product, a risk management plan (RMP) is prepared and an appropriate pharmacovigilance system is implemented. This system allows continuous surveillance of the safety of the medicinal product placed on the market. The risk management plan is introduced and approved at European level. Any additional risk mitigation activities are carried out at national level.
Particular attention should be paid to immunological reactions to the use of biological and biosimilar medicinal products, because data on immunogenicity (relating to the ability of any substance to provoke a specific immune response) for the reference biological medicinal product cannot be extrapolated and applied to the biosimilar medicinal product. Therefore, it is important that the same analyses are used in the immunogenicity comparative trials between the biosimilar and its reference medicinal product. Biosimilars cannot be approved if an increased risk of immunogenicity has been observed.
If you suspect you have an adverse reaction to your medicine, report it to your doctor, pharmacist or nurse. You can also report adverse reactions directly to the FAMHP. Identification of the biological or biosimilar medicinal products is very important when reporting adverse reactions.
All suspected adverse reactions for medicinal products with an authorisation in the European Union are available in the EudraVigilance database.
Many biosimilars may exist for the same reference biological medicinal product. Because different biosimilars of a reference medicinal product are often compared separately to the reference product, there is no information on comparability between these biosimilars.
Interchangeability means changing one medicine for another that is expected to achieve the same clinical effect. This could involve replacing a reference product with its biosimilar (or vice versa) or replacing one biosimilar with another biosimilar of the same reference product. If such a change is done by a physician, this is called switching. If such a change is done in a pharmacy without consulting the prescriber, the change is called substitution.
The data collected so far from practice and from switching investigations show that changing a reference biological medicinal product to its biosimilar, biosimilar to another biosimilar of the same reference product and biosimilar to its reference product is safe. Therefore, the EMA and the Heads of Medicines Agencies (HMA) have emphasised that biosimilars approved in the European Union are interchangeable from a scientific viewpoint, meaning that a biosimilar can be used instead of its reference product, or vice versa. A biosimilar can likewise be used in place of another biosimilar of the same reference product. Any interchange should only take place after careful consideration of the product information.
The decision, however, on whether to allow interchangeable use and substitution of the reference biological medicine and the biosimilar is taken at national level.
If the prescriber decides to move from one to the other (original/original; original/biosimilar; biosimilar/original or biosimilar/biosimilar, also called "switching"), then this must be done with the necessary follow-up and the modification must be recorded accurately.
The FAMHP recommends excluding biological medicinal products of the international nonproprietary name (INN) prescription. The exclusion of INN prescription avoids multiple switches without follow-up by the prescriber.
Substitution means the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber.
This form of substitution is not authorised in Belgium for biological medicinal products (including biosimilars).
A list of all authorised biosimilars in the European Union is available on the EMA website.
The scientific discussion for each medicinal product registered under the centralised procedure is publicly available in the form of a European Public Assessment Report (on the EMA website). It is also possible to register biosimilars through other registration procedures (national, mutual recognition, decentralised) when it is a biological medicinal product that does not necessarily follow the centralised procedure.
Visit the website of the Belgian Center for Pharmacotherapeutic Information for information on biosimilars marketed in Belgium.
- What is a biological medicine?
Biological medicinal products contain active substances of biological origin (from humans, animals, bacteria). Active substances (e.g. proteins) of biological medicines are usually larger and more complex than those of non-biological medicines. Biological medicinal products are commonly used for a wide range of conditions.
- What is a biosimilar medicine?
A biosimilar is a biological medicinal product highly similar to another biological medicinal product already approved in the European Union (the so-called ‘reference product’). A biosimilar may have minor differences in the quality characteristics of the active substance compared to the reference product, but these differences have been shown by appropriate testing not to influence the efficacy and safety (adverse reactions) of the biosimilar.
- Are biosimilar medicines the same as generic medicines?
A biosimilar may have minor differences in the quality attributes of the active substance compared to the reference product. Because of the variability in the active substance, biosimilars are not regarded as generics of a biological medicine.
- Is a biosimilar medicine as effective as the reference biological medicine?
Yes. A biosimilar medicine is tested to make sure it is as effective as the reference biological medicine.
- Is a biosimilar medicine as safe as the reference biological medicine?
Yes. A biosimilar medicine is as safe as the reference biological medicine. A biosimilar medicine should not have more side effects than its reference medicine.
It is important to know that all medicines can have adverse reactions. If you have any questions about adverse reactions, talk to your doctor, nurse or pharmacist.
- Is a biosimilar medicine the same quality as the reference biological medicine?
Yes. Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicinal products. Therefore, biosimilar medicine has the same quality as the reference biological medicine.
- How do I know if I have been prescribed a biosimilar medicine?
You can always ask your doctor, nurse or pharmacist. In addition, a list of biosimilar medicines approved by the European Commission is available on the EMA website.
- What should you do if you experience adverse reactions?
If you suspect having an adverse reaction from your medicine, report it to your doctor, pharmacist or nurse. You can also report adverse reactions directly to the FAMHP.
When you report an adverse reaction, try to include the brand name and batch number of the medicine, if you know them. You will find the batch number on the package. This helps linking the report to the correct medicine.
- Are there benefits to being prescribed a biosimilar medicine?
Biological medicines have changed and improved the treatment of many serious diseases. Biological medicines are usually very expensive, but biosimilar medicines encourage competition and may reduce the cost of biological medicines. This means that the healthcare system can save money and be more efficient.
- What do I need to know about the biological medicine I take?
You need to know the brand name of your medicine. Biological medicines with different brand names are not identical, even when the name of the active substance is the same. Knowing the brand name means that you can report side effects for the correct medicine. It also means that your medicine will not be changed to a different brand by mistake.
It is also very important to read the patient information leaflet carefully which is included in the package. Contact your doctor, nurse or pharmacist if you have any questions.