Publication date: January 09, 2025
A biosimilar is a medicine that is similar to another biological medicine that is already on the market in different countries of the European Union. A medicine that is close in similarity is a medicine that has only minor differences compared to another biological medicine that is already on the market. The term “Biosimilar” is used in the European Union and refers to the comparability between a biologically similar medicine and its reference medicine. Biosimilar medicines are made from living organisms and are used when a serious disease such as cancer occurs.
The introduction of a biosimilar drug to the market is facilitated by the reduction of clinical trials required, due to the significant similarity to the reference drug. It should be noted, however, that no regulations have introduced a clear definition of what a biosimilar drug really is. Therefore, there is a need for interpretation. Biosimilar drugs are covered by the EU legal definition that was introduced for a biological medicinal product.
Benefits of using a biological medicine (including biosimilars)
Biosimilar medicines help in the treatment and prevention of serious and rare diseases such as multiple sclerosis, cancer, stroke, diabetes, etc.
In the Polish legal system, there are no specific regulations concerning biological drugs (including biosimilars). This is related to the belief that these drugs meet the characteristics of medicinal drugs. Therefore, the regulations concerning chemical structure also apply to drugs with a protein structure. In the doctrine, there is a position that biological drugs should be treated differently from other medicinal drugs, due to the different circumstances of their production.[1]
In Poland, the legal status of biosimilars is regulated primarily by the Regulations of the Minister of Health on the registration of medicinal products, as well as in implementing provisions issued by the Agency for Registration of Medicinal Products, Medical Devices and Biocidal Products.
It is required that the biosimilar medicinal product and the corresponding reference medicinal product have the same safety and efficacy profiles. Biosimilar medicinal products are registered for all or selected indications of the reference medicinal product, on an individual basis.
The use of biosimilars in Poland is regulated by the Agency for Registration of Medicinal Products, Medical Devices and Biocidal Products (ARP). ARP is responsible for the registration, assessment of the quality, efficacy and safety of biosimilars to ensure their compliance with the relevant regulations.
As part of the Central Authorisation procedure, EMA carries out a thorough assessment of the documentation submitted by the manufacturer of a biosimilar medicine. This documentation includes the results of clinical and non-clinical studies, information on the quality, efficacy and safety of the medicine, as well as information on the manufacturing process. EMA analyses this data to assess whether the biosimilar medicine meets appropriate quality standards and is effective and safe compared to the reference biological medicine.
European Medicines Agency and the team of Directors of Registration Agencies in the EU (Heads of Medicines Agencies) have presented a common position on the recognition of interchangeability of biosimilar medicines registered in the EU. This statement was endorsed by the Committee for Medicinal Products for Human Use (CHMP) and Biologics Working Group (BWP).
According to the position, it was recognized that biosimilars can be used interchangeably with reference drugs, after the biosimilar has been registered in the EU. Interchangeability is possible from one biological drug to another drug with the same active substance, for which it is expected to have the same clinical effect.
Biosimilar-biologic interchangeability involves replacing a biologic with a biosimilar that has been found to be equivalent in terms of quality, efficacy, and safety. Biosimilars are manufactured using advanced biotechnology and are similar to biologics, but not identical. The interchangeability process must be carefully controlled and supervised by the appropriate regulatory authorities to ensure that patients receive effective and safe therapy. In some cases, when a biosimilar is considered an appropriate interchangeable alternative, it can be used interchangeably with a biologic, but this decision is usually made by a doctor based on available clinical data and treatment recommendations.
Biosimilars are usually available only on prescription. In Poland, as in most EU countries, biosimilars are classified as prescription drugs, meaning they are products made in a pharmacy based on a doctor’s prescription. Therefore, a prescription issued by a doctor is required to buy them.
The decision on whether a biosimilar medicine is prescription-only depends on several factors, such as its composition, potential side effects, the level of risk associated with self-medication, and the recommendations of regulatory authorities.
So in most cases, biosimilars require a prescription to buy and use. Often, these drugs are used to treat chronic diseases or serious conditions, so their use requires the supervision and assessment of a doctor. However, there are some exceptions, where some biosimilars may be available without a prescription, but it is worth checking with a doctor or pharmacist before using any medicine.
Biologics continue to be a huge pillar of medical resources in treating a variety of serious diseases, but they are usually a more expensive alternative, which often translates into an economic burden for payers. Over the years, biologics have become an increasing burden on the budget.[3]
However, like their original reference medicines, biosimilars are usually more difficult and expensive to develop than generic small molecule medicines.
Biosimilar medicinal products may therefore constitute a cheaper alternative to existing biological medicinal products which will no longer be the only treatment option for patients.
The introduction of substitutes may also strengthen the market competition. Thanks to such a solution, i.e. the introduction of registered, cheaper, biosimilar drugs, the availability of biological drugs for patients will increase. This may have a positive impact on the economy and help stabilize healthcare systems. This benefit will open the door to new treatment options.
It is therefore important to note that once registered and authorised for marketing, biosimilar medicines introduce an important element to the existing price race on the EU market.
The task of the European Medicines Agency is to evaluate biological medicines before they are introduced to the market. Before a biosimilar medicine is introduced to the market, it is important to demonstrate that there are more advantages than disadvantages associated with them. The task of the European Medicines Agency is to issue an assessment of the medicine and then its marketing authorization. Applications for marketing authorization of a biosimilar medicine must be submitted to the EMA. The European Union was the first to introduce legal regulations for “similar biological medicines”, i.e. biosimilar medicines.
The European Medicines Agency has introduced and developed scientific guidelines for biologically similar medicines. Within these guidelines, the registration of biosimilar medicines by the EMA is being developed. Marketing authorization for a biosimilar product involves an assessment of whether the applicant has sufficiently demonstrated the similarity of the biologically similar product to its reference product. Each application is subject to individual assessment. This must be done in accordance with the guidelines that have been indicated on the official EMA website. The guidelines are developed by the Committee for Medicinal Products for Human Use.
All medicinal products undergo thorough checks and are scientifically assessed by the EMA on behalf of the European Commission, and the EMA publishes a set of documents for each biosimilar medicinal product on its website.
Development of Comparability of Medicines
A biological and chemical comparison is made with respect to the molecular structure of the drug and its full characterization and functionality.
Comparative studies that take place preclinically are designed to ensure that any differences that arise between these drugs do not have any impact on their effectiveness and safety.
Concerns comparative clinical trials in terms of quality, safety, and effectiveness.
Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use:
The above directive specifies legal regulations concerning biological medicines, including biosimilars, which are in force at the level of the European Union community. It should also be mentioned that the regulation of the issue of substitution and reimbursement of biosimilars is the responsibility of the Member States.
In accordance with the provisions of the Directive, due to the diversity of medicinal products, the specific properties of each individual biological medicinal product must be taken into account.
In case the reference product has more than one indication, efficacy and safety than the product indicated as biosimilar, all of them must be justified separately for each claimed indication.
Marketing authorisations granted under the ‘centralised procedure’ allow the marketing authorisation holder to market a medicine and make it available to patients and healthcare professionals throughout the EU through a single marketing authorisation.
Such authorisation is granted by the European Commission after a scientific evaluation of the application by the European Medicines Agency.
The centralised procedure is laid down in Regulation (EC) No 726/2004
Under the centralised procedure, a company can only obtain one marketing authorisation for each medicinal product.
The process is in line with the guidelines on the official EMA website
Companies wishing to market a medicinal product eligible for the centralised marketing authorisation procedure submit an application directly to the European Medicines Agency. EMA is responsible for validating and scientifically assessing the application.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) carries out a scientific assessment of the application and issues a recommendation on whether the medicine can be marketed. A positive opinion is accompanied by a draft summary of product characteristics, a package leaflet and a proposed packaging text.
The evaluation procedure has a time limit of 210 days and can be extended if additional issues need to be clarified. Within 15 days of adoption, the EMA will forward its opinion to the European Commission to start the decision-making phase.
Within 15 days, the Commission sends the draft implementing decision to the Standing Committee on Medicinal Products for Human Use, for scrutiny by EU countries. They have 15 days to send linguistic comments and 22 days for substantive comments.
After receiving a positive opinion, the draft decision is adopted through the empowerment procedure. The decision should be taken within 67 days of receiving the EMA opinion.
The Secretariat General of the Commission then notifies the decision to the marketing authorisation holder. The decision is then published in the Union Register.
Marketing authorisations are initially valid for five years. Applications for renewal must be submitted to the EMA at least six months before the expiry of the five-year period.
The introduction of biosimilars increased competition on the market, which translated into greater availability of modern therapies and lower total treatment costs. Other factors also influenced their increase in use, such as initial drug use, local healthcare standards and payer actions. A key factor was the treatment co-financing system, which determined the costs borne by patients. Different countries had different co-financing models, in which the payer and the patient shared the costs of the drug.
One of the first biosimilars registered in Europe was filgrastim (recombinant G-CSF produced in E. coli cells), used in the treatment and prevention of chronic and chemotherapy-induced neutropenia. Before the introduction of biosimilars, the G-CSF market was dominated by two products: short-acting filgrastim (Neupogen®) and long-acting PEG- filgrastim (Neulasta®). This changed in the years 2008-2014, when the EMA approved a biosimilar version of filgrastim. The shortened registration process reduced the R&D costs of biosimilars, although the savings were not the same for all sponsors. The strategy of Sandoz, which introduced its product in Europe (2008) and the United States (2015) based on an optimized set of studies, turned out to be the most cost-effective. By reducing the costs of introducing the drug to the market, the company was able to compete on price, which led to lower prices for both reference preparations and the entire product group. However, the analysis of the shares of the biosimilar market showed a lack of correlation between these shares and prices in European countries. Even a small share of biosimilars in the market significantly influenced price competition, while a large share did not always translate into a significant price reduction[4].
The basic division of biological drugs results from the distinction between naturally occurring substances, which include active substances usually obtained from living organisms that have not been genetically engineered. The latter include active substances obtained using cells or organisms into which foreign genes have been introduced.
This division is not without significance for the patent protection of individual drugs. This division is also significant from the point of view of patent protection. In the case of natural drugs, not subjected to genetic engineering, patent protection is limited in scope and may only cover the method of producing the drug. In the case where the biological material has been modified or produced by man, standard protection applies to the active substance.
Currently, the first patents for original (innovative, reference) biological drugs are expiring, which enables the introduction, registration, sale and reimbursement of biosimilar drugs.
The patent system is one of the important instruments of economic policy. In the field of biotechnology, legal protection in the form of a patent is particularly important due to the enormous costs incurred in connection with the introduction of reference drugs to the market. Today, patents are to serve to encourage entrepreneurs to invest in research and development activities. In fact, as often emphasized in the literature, a manufacturer would not be willing to spend several billion dollars and wait several dozen places for the registration of a biological drug, when, without patent protection, the substance could be immediately copied and sold by the manufacturer of generic drugs, without allocating funds for the research activity of the given drug.
Data exclusivity is a period during which the data of the first marketing authorisation holder is protected. This is a period during which noanother company cannot use the first entity’s data for another marketing authorisation application for generics, hybrids, biosimilars . Therefore, the relevant authorities may not accept such an application during this period. In Europe, this protection period lasts for at least eight years and is intended to encourage innovation.
Directive on the protection of biotechnological inventions
The objectives of the above directive[5] are to promote research and development in the field of genetic engineering in the European Union and to harmonize the laws of the Member States in the field of:
Directive on the Community code relating to medicinal products for human use
Article 10 of this directive [6] introduces a shortened procedure for the marketing authorisation of generic medicines whose innovative equivalents have previously been authorised for marketing. The manufacturer is entitled to use the shortened procedure provided that it proves that its medicinal product is a generic medicinal product in relation to the reference product.
This provision introduces two important deadlines:
Which in practice means that a generic medicinal product, authorized for marketing according to the abbreviated procedure, cannot be authorized for the market before 10 years have passed since the first authorization for marketing of the reference product. The only way for the manufacturer of a generic medicine to shorten this period is to provide its own research results – as in the case of the ordinary procedure regulated in Article 8 of the aforementioned directive.
The purpose of introducing the instrument of data exclusivity was, similarly to patent protection, to encourage entrepreneurs to introduce innovative drugs to the market at the cost of difficulties related to the introduction of biosimilar drugs.
Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS)
The Act on Combating Unfair Competition meets the requirements of Article 39 paragraph 3 of the TRIPS Agreement[7] in terms of protecting trade secrets, but the institution of data exclusivity has a separate function and serves different purposes. It is worth emphasizing that although a theoretical analysis of the nature of data exclusivity may give rise to different opinions, in practice it is an important tool for protecting the interests of producers of innovative medicines against competition from producers of generic medicines. This explains why the doctrine often postulates the application of Article 39 paragraph 3 of TRIPS also to the issue of data exclusivity.
Formally, manufacturers of innovative drugs have the option to consent at any time to the use of research results for the purpose of registering a generic drug, although in practice, due to the strong competition between these sectors, such situations are rare. Importantly, the use of research results in the registration process does not mean the actual disclosure of these data or their sharing with manufacturers of generic drugs.
In the context of patent law, the European Patent Convention[8] sets out the criteria for patentability, exclusions from patentability and rules for filing a European patent application. Although the effects of filing and granting a European patent refer to national law, the convention itself regulates certain issues, such as the duration of patent protection (20 years), the scope of protection covering products obtained directly by the manufacturing process covered by the patent, the effects of invalidation of the patent in opposition proceedings (retroactive), and the substantive scope of patent protection.
In European countries, including EU Member States, there are two main ways of obtaining patent protection: national mode and regional mode, based on the Convention on the Grant of European Patents (EPC). In the first case, patents are granted by national patent offices, in accordance with the provisions of the legislation of a given country. In Poland, this is the Patent Office of the Republic of Poland (UP), which applies the provisions of the Industrial Property Law.
In turn, within the EPC, European patents are granted by the European Patent Office (EPO) in Munich. Although the name suggests unitary protection, the European patent is in fact a collective collection of national patents. It grants the same rights as a national patent in the country where it was validated. The validation of a European patent in each country party to the EPC is carried out by a national patent authority, as in Poland – the Patent Office of the Republic of Poland, which requires a translation of the patent description into Polish. The publication of these translations ensures their universal availability, which helps to avoid infringements of other people’s patent rights.
[1]Świerczyński Marek (ed.), Biological Medicinal Products. Legal Aspects
[2] Information from the President of the Office of 04/10/2022 on the issuance of a statement by the EMA and HMA on the possibility of interchangeable use of biosimilar medicines in the European Union.
[3] European Commission, “What you need to know about biosimilar medicinal products, The process of increasing the responsibility of the pharmaceutical sector, Access to medicines in Europe Consensus statement”.
[4] Joanna Zielińska, Włodzimierz Bialik, Changes in the biopharmaceutical market after the introduction of biosimilar G-CSF preparations – Via Medica.
[5] European Union Directive 98/44/EC of 6 July 1998.
[6] Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001.
[7] Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS), annex 1c to the Agreement Establishing the World Trade Organization, Journal of Laws 1996, No. 32, item 143.
[8] Convention on the Grant of European Patents (European Patent Convention), done at Munich on 5 October 1973, as amended by the Act amending Article 63 of the Convention of 17 December 1991 and by the decisions of the Administrative Council of the European Patent Organisation of 21 December 1978, 13 December 1994, 20 October 1995, 5 December 1996 and 10 December 1998, together with the Protocols forming an integral part thereof.