Biosimilar Medicines: From Development Process to Marketing Authorization by the EMA and the FDA

Abstract

Biosimilars are a new category of medicines that have revolutionized the treatment of patients with life-threatening conditions, such as cancer and autoimmune diseases. A biosimilar is a biological product that is very similar to an already approved biological medicine that is used as its reference. These medicines go through less clinical studies than their reference product and therefore the cost of their development process is significantly lower, giving patients access to them more quickly and at a more affordable price. However, due to the structural complexity and inherent degree of variability of these products, it is very difficult to develop biosimilar medicines that are exactly the same as the reference product. Thus, it is extremely important to define strict controls to guarantee that these minor differences are not clinically significant in terms of safety and efficacy. Like any other medicine, biosimilars have to go through a complex approval process, which involves a thorough assessment by regulatory authorities to ensure these products meet the necessary standards of quality, safety, and efficacy before being placed on the market. Due to their nature and complexity, the approval process of biosimilar medicines contains some unique and specific considerations. This review aims to address the regulatory framework of biosimilar medicines, their development process and the approval requirements by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA).

1. Introduction

In recent years, biological medicines have significantly impacted the care of numerous patients with diverse medical conditions, including diabetes, autoimmune diseases and various types of cancer [1,2]. In contrast to chemically synthesized drugs, which have a well-known structure, biological medicines are complex products generated using biotechnological processes. These processes involve the identification, sequencing and manipulation of DNA, with the aim of producing therapeutic or medical diagnostic products [3,4,5].

When a biological medicine is placed on the market, it is under patent protection during a specified period of time. Once this period expires, the biological medicine is used as a “reference medicine” for the creation of a very similar product, designated as biosimilar medicine [1]. As the name suggests, these products are highly similar, but not identical, to its reference medicine and are subjected to fewer studies, reaching the market faster and at a lower price [1,2,6]. However, due to their nature and unique manufacturing process, they can contain some variations and therefore, to be placed on the market, they must demonstrate similar safety, efficacy and quality compared to their reference biological products [7,8].

This review article aims to clarify the concept of biosimilar medicines, comparing them with innovative biological medicines, intended copies, biobetters, stand-alone biologics and generic medicines. The regulatory framework for these products are presented, along with the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines specifically developed for these products. A detailed explanation about the manufacturing process of these products is provided, as well as key concepts related to the establishment of similarity between the biosimilar and its reference medicine. The data requirements set by the regulatory authorities for the approval of biosimilar medicines are presented, together with the different pathways that may be pursued to obtain such approval. Lastly, an evaluation of the current market for biosimilar medicines is performed, providing a comprehensive and up-to-date overview of this topic.

2. Overview of Biosimilar Medicines

2.1. Biological Medicines

Biological medicines appeared more than two decades ago and since the production of the first biological medicine in 1982, which was an insulin created through biotechnology, this new category of medicines has become increasingly important in healthcare around the world [3,9].

These medicines are made from compounds that exist naturally in the human body, such as polysaccharides (e.g., low molecular weight heparins) or proteins (e.g., insulin, growth hormones and monoclonal antibodies). The active pharmaceutical ingredient (API) of a biological medicine can differ significantly in size and structural complexity between them and between the API of a small-molecule drug, such as acetylsalicylic acid (ASA) in aspirin [2,8], as shown in Figure 1.

The production of biological medicines differs significantly from the production of small-molecule drugs. These products can be obtained through the extraction from a living organism but most of them are made using biotechnology. This process begins with the identification of a genetic code of the desired protein, followed by a complete synthesis of the DNA sequence. Then, the genetic code is inserted into a host cell line modified through recombinant DNA technology to express the desired protein, which will subsequently be harvested, purified and formulated into the final medicine [10,11].

The pharmaceutical company that produces the biological medicine holds a patent that allows for it to protect its innovation for a period of 20 years from the date of patent registration. In addition, the company also possesses market exclusivity for a specific period of time, usually 10 years from the date of market authorization [2]. In recent years, the exclusivity rights for many biological medicines have expired, opening the door for the introduction and approval of a new class of medicines called biosimilars [1].

2.2. Biosimilar Medicines

So far, there is no agreement among regulatory authorities on a universal definition for biosimilar medicine; however, they all emphasize that the main characteristic of these products is their high similarity to a certain previously approved biological product that served as a reference.

Table 1. Definition of biosimilar medicine by the EMA and the FDA.

Regulatory Authority	Biosimilar Medicine Definition
EMA	“Biological medicine highly similar to another biological medicine already approved in the EU” [2].
FDA	“Biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product” [12].

presents the definition of biosimilar medicine according to two of the main regulatory authorities, the EMA and the FDA.

As the name implies, biosimilars are not an exact copy of their reference medicine, but they have a high degree of similarity in terms of physicochemical properties, safety and efficacy profile [13,14]. When the API is a protein, the biosimilar medicine must contain exactly the same amino acid sequence and the same protein folding (3D structure) as the reference medicine [2]. However, considering that these products are made by living organisms that can carry some intrinsic degree of variability due to post-translational structural modifications they may be subjected to, this variability must be within acceptable limits to guarantee the safety and efficacy of the product [6].

The quality of these products depends mainly on their manufacturing process. The process used to produce the biological medicine is privately owned by the pharmaceutical company that developed it, so the biosimilar producer must develop its own manufacturing process. Given that each manufacturer uses a unique cell line, with a different growth medium and culture conditions to produce the biosimilar, some differences can be observed in comparison to its reference product [15]. These small differences can lead to unexpected adverse reactions, so the manufacturer must guarantee that the biosimilar meets the same requirements of safety, efficacy and quality that the reference product [2].

In relation to the final product, the biosimilar must have the same posology and route of administration of the reference medicine [14]. There may be some differences in the formulation (e.g., excipients), presentation (e.g., powder to be reconstituted/solution ready for injection) and administration device (e.g., type of delivery pen); however, they cannot affect the safety and efficacy of the final product [2].

The development of biosimilar medicines is quite different from the reference biological medicine, as shown in Figure 2. To develop a biological medicine, an extensive research and development (R&D) phase is required to find a molecule with the ideal characteristics. Non-clinical studies and phase I, II and III clinical studies are mandatory to guarantee the safety and efficacy of the new medicine. From discovery to phase III clinical studies, the process takes approximately twelve years. In the case of biosimilar medicines, they are approved by a shortened process since they are copies of products already on the market and with well-established characteristics so there is no need to carry out the research phase and initial efficacy studies (phase II clinical studies), which reduces the process time to approximately eight years and the development costs by 10–20% [16]. As a result, these medicines reach the market faster and at a more affordable price compared to the reference product. This improves patient access to these treatments and may lead to a reduction in the price of the reference biological medicine, due to the competition between the off-patent biological products and biosimilar medicines market [5].

The emergence of biosimilars offers several advantages to patients and healthcare systems, including expanded patient access to biological treatments, allowing for these products to be used as one of the first lines of treatment and at an early stage of the disease, potentially leading to better outcomes. The cost savings from biosimilars could be used to expand patient access to innovative therapies or reinvested in hiring more healthcare providers. The competition among pharmaceutical companies producing off-patent biological medicines and biosimilars can generate innovation in crucial product aspects, namely, in formulation and administration device, creating new strategies to increase patient adherence to the treatment [17,18].

2.3. Intended Copies, Biobetters and Stand-Alone Biologics

Biosimilars should not be confused with other product classes such as intended copies, biobetters and standalone biologics. Intended copies are replicas of a reference medicine that do not comply with the guidelines established by the competent regulatory authorities. Thus, they are not accessible in heavily regulated markets such as the United States (US) and Europe but are promoted in less regulated ones [19]. Regarding biobetters, they have a similar manufacturing process to their reference biological product; however, they are purposefully modified in certain attributes (e.g., posology) to improve their properties compared to their original medicine [19,20]. Lastly, standalone biologics are a recent class of medicines whose efficacy and safety are evaluated by comparing them with a placebo or a suitable comparator medicine [19].

2.4. Biosimilars vs. Generics

There is a common misconception that biosimilar medicines are the same as generic drugs. Both are copies of products already on the market; however, unlike innovative medicines (small-molecule drugs and biologics), which must go through an extensive phase of research, non-clinical and clinical studies and post-authorization evaluations, the development and approval processes of generics and biosimilars follow shortened pathways, based on the data that already exist from their reference medicines [6]. Consequently, they cost less to develop and take less time to reach the market, making them very valuable alternatives for patients, as they can access treatments with the same quality as the original products at a more affordable price.

Generic medicines are developed through an easily replicable process that uses a series of predictive chemical reactions, and their APIs are small molecules whose characterization, safety and efficacy are well-established [21]. The manufacturing process of generics takes around 2–3 years and the costs involved are relatively low [22]. On the other hand, the development of biosimilar medicines is much more complex since they use large molecules derived from living organisms as the active substance that carry some inherent variability [2]. Therefore, there may be some differences due to the nature of these products and their manufacturing process. These small variations are acceptable as long as they do not affect the safety, efficacy and quality of the biosimilar [22]. The development process of biosimilars is longer than that of generics, taking 5–9 years and the associated costs are higher [6,13].

Generic medicines must demonstrate through bioequivalence studies, that their behavior in the body is the same as the reference medicine.

Owing to the complexity of biosimilars, demonstration of bioequivalence is not enough to prove their similarity. Comparability studies directly compare a biosimilar to its respective reference and must include a comprehensive evaluation of structural and functional attributes, along with confirming similarity in efficacy and safety [14]. For biosimilars undergoing manufacturing process changes, analytical and functional comparability studies are typically enough to prove similarity. However, sometimes it is necessary to evaluate the impact of certain changes in the production process [23,24].

3. Biosimilar Medicines Regulatory Framework

The emergence of biosimilar medicines revolutionized the pharmaceutical market by offering biological products at a much more affordable price. To guarantee the safety, efficacy and quality of these medicines, regulations and procedures for the development and approval of these products were established [25]. The EMA and the FDA are the world’s largest regulatory entities, which are responsible for this assessment in the European Union (EU) and in the US, respectively. These two agencies have a great global influence and are recognized for the rigor of their regulatory and approval processes.

The EMA pioneered in the regulation of biosimilar medicines and created several guidelines, presented in

Table 2. European scientific guidelines for biosimilar medicines [28].

Topic	Title
Tailored clinical approach for biosimilars	Concept paper for the development of a reflection paper on a tailored clinical approach in biosimilar development.
Overarching biosimilar guidelines	Similar biological medicinal products. Similar biological medicinal products containing biotecnology-derived proteins as active substance: non-clinical and clinical issues. Similar biological medicinal products containing biotecnology-derived proteins as active substance: quality issues.
Product-specific biosimilar guidelines	Biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor. Non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight heparins. Non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. Similar biological medicinal products containing interferon beta. Similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues. Similar biological medicinal products containing recombinant erythropoietins. Similar biological medicinal products containing recombinant follicle-stimulating hormone. Similar medicinal products containing somatropin. Reflection paper: Non-clinical and clinical development of similar medicinal products containing recombinant Interferon Alfa.
Other guidelines relevant for biosimilars	Comparability of biotechnology-derived medicinal products after a change in the manufacturing process—non-clinical and clinical issues. Immunogenicity assessment of biotechnology-derived therapeutic proteins. Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. Biosimilars—What are the key pharmacokinetic considerations in the assessment of biosimilarity?

, related to the development and approval of these products to clarify certain aspects and to ensure that they were produced in accordance with the required safety, quality and efficacy criteria. Some guidelines are more general and compile all the relevant information about these medicines and others are more specific for each type of biosimilar [26,27].

A few years later, the FDA started to create a set of guidance documents, presented in

Table 3. FDA Guidance documents for biosimilar medicines [30].

Year	Title
2014	Reference Product Exclusivity for Biological Products Filed Under; Draft Guidance for Industry.
2015	Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product; Guidance for Industry. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; Guidance for Industry.
2016	Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product; Guidance for Industry.
2018	Labelling for Biosimilar Products; Guidance for Industry.
2019	Considerations in Demonstrating Interchangeability with a Reference Product; Guidance for Industry. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations; Draft Guidance for Industry.
2020	Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed; Draft Guidance for Industry. Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act; Draft Guidance for Industry.
2021	New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3); Draft Guidance for Industry. Questions and Answers on Biosimilar Development and the BPCI Act; Guidance for Industry.
2022	Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics; Guidance for Industry.
2023	Classification Categories for Certain Supplements Under BsUFA III; Draft Guidance for Industry. Labeling for Biosimilar and Interchangeable Biosimilar Products; Draft Guidance for Industry. Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act (Revision 1); Draft Guidance for Industry.
2024	Considerations in Demonstrating Interchangeability with a Reference Product: Update; Draft Guidance for Industry. Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Questions and Answers; Draft Guidance for Industry.

, for the development, approval and marketing of biosimilar medicines, in order to provide regulatory clarity and guidance to manufacturers. However, unlike the EMA, the FDA has developed general guidance documents that allow for a tailored approach to each product [29].

In 2018, the FDA published the Biosimilar Action Plan (BAP), whose main objective was to provide regulatory clarity to improve the development and approval procedures for biosimilar medicines and simplify the concept for patients and healthcare professionals by providing educational assistance and consequently increase their trust in this type of product [31].

The World Health Organization (WHO) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are crucial entities whose mission is trying to harmonize the regulatory and approval processes of medicines around the world, facilitating global access and acceptance of biosimilars. In 2009, the WHO created its own guidelines on evaluation of similar biotherapeutic products [32,33]. The ICH works consistently to create a harmonized and efficient regulatory environment between the main global pharmaceutical markets (i.e., EU, US and Japan), aiming to reduce barriers to international trade in medicines, allowing for biosimilars approved in one region to be more easily recognized and accepted in other regions [34,35]. The ICH created guidelines for development and approval of medicines in general, but some are specific to biological and biosimilar medicines, such as ICH Q5E, which helps ensure the consistency of biological products before and after changes to the manufacturing process [23].

At present, the regulatory framework for biosimilar medicines is well-established. Figure 3 presents a timeline of the principal milestones that have shaped this evolution, starting with the implementation of Directive 2001/83/EC and its subsequent amendments, followed by the introduction of the first guideline on biosimilars in 2005 and the subsequent approval of the first biosimilar by the EMA the following year. In 2009, the US initiated the establishment of a regulatory system for biosimilars, coinciding with the publication of the first guideline on these products by the WHO. In 2014, the FDA created its first guidance documents and approved its first biosimilar a year later. In 2020, the FDA issued an opinion on the interchangeability of these products, and the following year approved the first biosimilar with an interchangeable designation. Meanwhile, the EMA only addressed the issue of interchangeability in 2022. These events have collectively contributed to the formation of the current regulatory framework for biosimilar medicines, facilitating the streamlining and efficiency of the evaluation and approval processes.

4. Development of Biosimilar Medicines

The development of biosimilar medicines aims to produce a biological product without clinically significant differences from its reference medicine. However, due to the high complexity of these products, there is no “one size fits all” approach, which means that each biosimilar has a unique and specific development process [36,37].

When a pharmaceutical company develops a new biological medicine, the manufacturing process is confidential. To develop a biosimilar medicine, a new manufacturing process should be established based on a quality by design (QbD) approach. This systematic methodology starts with the prior definition of objectives and focuses on the manufacturing process optimization to develop a product whose safety, efficacy and, above all, quality meet the initial standards [38,39]. This approach requires a profound comprehension on the critical quality attributes (CQA) of the reference medicine, which are the measurable characteristics that determine its performance. It is also important to define the quality target product profile (QTPP) of the reference medicine, which are quality characteristics that must be present in the biosimilar medicine [38]. It is important to mention that the use of a QbD approach is not compulsory, but it does facilitate the process of product approval by regulatory agencies.

4.1. Selection and Characterization of the Reference Product

The first step in biosimilar development is the selection of an appropriate reference product. This should be a biological medicine with a well-known safety and efficacy profile that has already been approved by the regulatory authorities [38]. An in-depth characterization of the chosen reference medicine is performed through extensive analytical studies to identify the products’ key structural and functional characteristics using sophisticated laboratory techniques. This step is crucial because it provides valuable data for setting up acceptance criteria through the definition of ranges for crucial parameters such as potency, purity, impurities and structural characteristics [37,38,39,40,41].

Table 4. Examples of analytical methods for characterizing structural and functional attributes of a reference biological medicine [7].

Attribute	Methods
Primary structure	Peptide mapping: liquid chromatography (LC) and mass spectrometry (MS). Peptide mass fingerprint: matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS).
Higher order structure	Nuclear magnetic resonance (NMR). Surface plasmon resonance (SPR).
Post-translational modifications	Normal-phase high-performance liquid chromatography coupled with mass spectrometry (NP-HPLC–MS). Gas chromatography–mass spectrometry (GC–MS).
Size, detection of aggregates	Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE). High-performance size exclusion chromatography (HP-SEC).
Binding	Surface plasmon resonance (SPR). Enzyme-linked immunosorbent assay (ELISA).
Biological activity	Cell assays. In vivo assays.

presents some examples of the relevant attributes of the reference product and the techniques used to evaluate each one.

After characterizing the product that will serve as a reference, a manufacturing process that allows for the final biosimilar to have the same CQAs as the reference product must be developed in order to achieve the established QTPP. This process is divided into four stages, as shown in Figure 4, namely, cell line creation, cultivation and production; isolation and purification; and finally formulation, filling and finishing, and requires the use of very complex and advanced techniques [42,43].

4.2. Cell Line Creation

The first step is to create an appropriate cell line containing the gene that expresses the desired protein in enough quantity and with the intended post-translational modifications [38]. The desired gene is cloned into a complementary DNA vector and transferred into an animal or microbial host cell line engineered to express the protein of interest [38,44]. The chosen cell line must have favorable characteristics, such as high growth rate, simple medium requirements and high cost-effectiveness. Usually, pharmaceutical industries use Chinese hamster ovary cells, since this type of cell has reliable protein folding and post-translational modifications [37,38]. To finish this step, one of the clones previously obtained must be selected, through screening of hundreds to thousands of clones, to find the ideal candidate that falls within the acceptable CQAs parameter range [38].

4.3. Cultivation and Production

A master cell bank is created from the candidate clones that fall within the acceptable CQAs parameter range [42]. From this master cell bank, a working cell bank is produced and subjected to inoculation under agitation to increase cell density [38]. Then, the cells are cultured and produced in high volumes (over thousands of liters) in a large-scale fermentation bioreactor until the target production scale is reached [33,44]. To ensure cell viability, it is crucial to guarantee the quality of cell culture conditions to minimize the risk of contamination and possible glycosylation variations, as these factors can significantly influence the CQA of the final product [38]. For this, the cells are inserted into a culture medium supplemented with nutrients and maintained under controlled conditions, particularly in terms of temperature, pH, oxygen amount, osmolarity and lactate production [37].

4.4. Isolation and Purification

The protein of interest is secreted into the culture medium and to isolate it, the protein must be recovered from the cell culture by separating it from cells and debris through filtration or centrifugation [38,39]. Once the protein has been isolated, it needs to be purified using techniques such as chromatography and filtration to remove any impurities, including host cell proteins, DNA, viruses, endotoxins or aggregates. Additionally, impurities generated during this process and cellular metabolites must be eliminated to prevent an immune response [37,45].

4.5. Formulation, Filling and Finishing

Product formulation involves combining and mixing the purified protein with other components to create a stable, safe and effective formulation [46]. The final presentation of the medicine may take one of three forms: liquid, frozen or lyophilized. The preferred form is liquid; however, the addiction of viscosity lowering excipients to liquid products with a high viscosity is crucial. If the frozen presentation is chosen, excipients that can act as cryoprotectants (e.g., sucrose) should be added, to minimize the cryoprecipitation or cryoaggregation. Lastly, if the lyophilized form is chosen, sugars and surfactants must be added to protect the protein from stress caused during typical drying techniques. This pharmaceutical form requires some additional costs, namely, the use of diluents for reconstitution [37]. The formulation is transferred into its final packaging, such as vials or syringes. The filling process should be precise and meet the dosage requirements. Lastly, the finishing process refers to labeling that provides essential information about the product and packaging, which must protect the product from environmental factors and maintain its stability [38].

The development of an efficient and consistent manufacturing process is essential to guarantee product quality. However, there may be a need to change this process for various reasons, including to meet regulatory requirements or improve product quality and yield. According to the ICH guideline Q5E, which addresses comparability of biotechnological/biological products subject to changes in their manufacturing process, the manufacturer should study the CQAs of the product before and after the change, to demonstrate that the modifications have no impact on the final product [23,47].

5. Demonstration of Biosimilarity

After creating an appropriate manufacturing process and obtaining the biosimilar medicinal product with the desired CQAs and which fulfils the pre-established QTPP, it is necessary to carry out studies to demonstrate that the medicinal product is similar to its reference biological medicinal product. The demonstration of biosimilarity can be achieved through a comparative exercise, which consists of a robust head-to-head comparison of the biosimilar medicine and the reference product performed at the levels of quality, safety and efficacy [48,49]. This process is specially designed for each product and involves several stages, namely, quality, non-clinical and clinical comparability studies, evaluating several aspects such as the pharmacokinetic/pharmacodynamic (PK/PD) profile of the medicine, as well as its immunogenicity and toxicity [2]. Figure 5 summarizes all the stages of the comparability studies carried out, as well as the product characteristics that are evaluated in each one [48,49,50,51].

5.1. Quality Comparability Studies

Quality comparability studies assess whether there are significant differences between the biosimilar and the reference medicine in terms of CQAs, such as structure, purity, biological activity and impurity profile [2]. This involves extensive laboratory tests and the use of sensitive techniques, such as SPR, ELISA and MS [7]. These studies are much more sensitive to detecting differences than clinical trials because of the high variability between the individuals who participate in them [2]. This step determines the need and type of non-clinical and clinical studies that should be carried out. In most cases, quality comparability studies are enough and there is no need to conduct non-clinical and clinical studies. However, if any variations that may impact the efficacy, safety or immunogenicity of the medicine are found, further studies are required [48,52].

Statistical Approaches to Evaluate Analytical Similarity

The evaluation of analytical similarity in biosimilar medicines is founded on statistical methods, which permit objective assessment of whether the observed differences between the biosimilar product and the reference product are within the previously established limits considered as acceptable.

The most frequently statistical tools used in this process are equivalence testing and confidence intervals. In most cases, they go together in the statistical analysis of biosimilar similarity, as a confidence interval is considered one of the critical elements in equivalence testing, helping ensure that the biosimilar CQAs fall within the appropriate range of values [38].

However, the approaches between the EMA and FDA over this issue have a great discrepancy. Generally, the EMA is the more conservative, using narrower equivalence margins that reflect lesser tolerance for differences, even small ones. Consequently, the EMA will generally require supplemental and more reassuring data, such as additional clinical studies, to provide sufficient proof that difference between the biosimilar and reference product does not matter for safety and efficacy and thus establishes similarity. In contrast, the FDA has adopted a relatively more flexible approach, as it adjusts the equivalence margins based on the variability of the reference product. This way, the FDA is more willing to accept small differences because of their focus on the totality of evidence available for the product [48,49].

5.2. Non-Clinical Comparability Studies

Non-clinical comparability studies, including pharmacodynamic studies, are carried out to observe physiological target binding, activation/inhibition and the immediate physiological effects in cells. These studies are only performed on animal models (i.e., in vivo) if there is no suitable in vitro model. Toxicological studies are also performed and only use in vivo models when the biosimilar is manufactured in a different cell or organism or when the formulation contains a new excipient that has never been used before [53]. According to the 3 R’s rule (replacement, refinement, reduction) the choice of an animal model study should be duly justified [54].

5.3. Clinical Comparability Studies

Clinical comparability studies are performed to evaluate the safety, efficacy and immunogenicity of the new medicine in humans and to answer any remaining doubts from previous analytical or non-clinical studies [2]. Typically, clinical studies are randomized, controlled and blinded; however, since they are not as sensitive as analytical studies in detecting potential differences between the two medicines, they require unique designs to be able to identify those differences. An appropriate margin of equivalence must be established in accordance with the knowledge acquired with the reference biological product. Finally, these studies must follow a set of internationally recognized ethical and scientific quality standards called Good Clinical Practice (GCP) [55,56,57].

5.3.1. Clinical Pharmacology Studies (PK/PD)

Clinical pharmacology studies are necessary to demonstrate biosimilarity to the reference medicine. PK studies evaluate the bioavailability of the medicine, including its absorption, distribution, metabolism and excretion (ADME), while PD studies ensure that the mechanism of action of the biosimilar is identical to the reference product and the target is also equivalent. To carry out these studies, a population of healthy volunteers must be chosen in order to generate a homogeneous cohort. However, if this is not possible, the study must be conducted in a representative population of patients [41,58]. Conducting these studies is crucial for the abbreviated biosimilar development program. When combined with the demonstration of very similar analytical and functional activity, it allows for clinical studies to use the same therapeutic dose as the reference medicine. This eliminates the need for phase II clinical studies [58].

5.3.2. Efficacy Studies

One of the main purposes of clinical comparability studies is to prove that the new biosimilar product is equally effective as its reference medicine. Considering the available regulatory guidelines, comparative clinical efficacy studies are not always necessary. They are only needed when clinically significant differences exist after functional and structural characterization, non-clinical and clinical studies and immunogenicity assessment. In such cases, efficacy studies are needed to confirm that the clinical performance of the two products is comparable [59,60]. To perform these studies, it is crucial to choose a suitable endpoint, which can differ from the one used for the approval of the reference product. The population used must be similar to the one used to carry out the studies on the reference product, in order to guarantee the study’s high sensitivity [58].

5.3.3. Safety Evaluation

Safety must be assessed through the entire clinical program, i.e., during phase I, PK/PD studies and phase III direct comparison studies. To establish similarity between a biosimilar medicine and its reference, it is necessary to assess and compare the type, severity and frequency of any adverse events (AEs) that may occur [2,59]. It is important to note that these events can be predicted from the pharmacological action and are not exclusive to biosimilars, as they can also occur with the use of the reference product. Additionally, there is no specific requirement just for biosimilars, as their safety is monitored in compliance with the specifications applicable to all biological medicines [61,62,63].

When applying for marketing authorization for a new medicine, pharmaceutical companies must present a risk management plan (RMP) specially designed for each product, containing a pharmacovigilance (PV) plan and risk minimization measures to identify, characterize and minimize possible risks of the medicine. For biosimilars, the RMP is designed considering the knowledge acquired with the reference product. Regulatory authorities can also compel the company to perform a post-authorization safety study (PASS) after the medicine is on the market. It is important to monitor the known risks, but also to identify rare adverse reactions that can only be observed when the medicine is used by a larger number of patients and over a longer period of time. A periodic safety update report (PSUR) containing all statements of suspected adverse reactions must be provided to the authorities and, if an undesirable reaction is suspected, the needed action should be determined [2,62].

5.3.4. Immunogenicity Concerns

The study of immunogenicity is crucial in biological medicines since they are made of proteins that have an inherent capacity to originate unpleasant immune reactions that, on rare occasions, can provoke a reduction in product efficacy or a serious AE [2]. Many factors can cause immune responses, namely, product characteristics, such as aggregates or modifications in protein structure arising from improper storage or transportation. They can also be due to aspects related to the treatment such as route of administration (e.g., subcutaneous or intravenous) or treatment regimen (e.g., continuous or intermittent). Lastly, they can be associated with patient characteristics, including age, genetics, immune condition, concomitant treatments or the disease itself [64,65,66].

For regulatory authorities to approve a biosimilar medicine, information regarding immunogenicity is required [65]. The type and quantity of data are determined by multiple aspects, in particular, the type of biological medicine and its planned purpose. Another aspect taken into consideration is the characteristics of the product. Most of the studies aim to assess how product-related differences, such as structural alterations or presence of impurities/contaminants, can generate an undesired immune response. Lastly, in some cases, there is pre-existing information about the immunogenicity of the product, indicating that immune responses occur rarely and are unlikely to be observed before authorization. In such instances, clinical studies with a longer follow-up period and more patients are needed. Additionally, post-marketing studies may be performed [2,67].

5.4. Other Relevant Aspects

5.4.1. Extrapolation of Indication

Considering that biosimilarity between the biosimilar and its reference product has been established in one approved therapeutic indication, the extrapolation of safety and efficacy data can be made to other approved uses of the reference medicine. This allows for a significant reduction in the need to perform further or any clinical studies [68,69].

The extrapolation always relies on strong scientific evidence from rigorous comparability studies where certain aspects must be considered. The mechanism of action should be similar and involve the same receptor for the initial and the extrapolated indication. When multiple receptors or binding sites are involved, more studies might be necessary. Another aspect is the study population. Comparability studies conducted to confirm that the biosimilar’s safety, efficacy and immunogenicity data are identical to the reference medicine for a given indication must be performed in a population where potential differences can be properly identified. The data acquired from a certain indication may not directly apply to another indication in a different medical category with a distinct mode of action, dosage or pharmacokinetics [2,70].

The extrapolation of safety-related data can only be performed after a comparable safety profile has been established for the biosimilar medicine in a given indication. Thus, it is expected that adverse reactions caused by the biosimilar will be identical to its reference medicine and manifest at similar frequencies [2]. The extrapolation of immunogenicity data is more challenging because, in addition to product-related aspects, it is also determined by patient characteristics, the condition being treated and the treatment itself [2,71]. The success of the extrapolated indications for the biosimilar medicine can be ensured through the implementation of a robust post-marketing surveillance system [72].

5.4.2. Nomenclature

Due to the high complexity of biological products, the use of short and descriptive names is not possible. When it comes to biosimilar products, one question that arises is whether they should retain the same name as their reference medicine or if a new name should be considered. This reflection should take into account that biosimilars may have undergone some modifications. However, this topic is controversial, as different opinions exist. On one hand, given their unique development program, which involves the creation of a distinct manufacturing process and obtaining a new market authorization, some argue that biosimilars should be considered new medicines and therefore require new names. On the other hand, since biosimilars are considered copies of their reference products, others defend that they are similar enough to be given the same name [59,73].

In order to find a unique way to name biosimilar medicines globally, the WHO and the International Non-Proprietary Name (INN) Experts Group decided that the INN cannot be used as the only way to distinguish these medicines. While this type of identification works well for generic medicines, in the case of biosimilars, they must be distinguished from each other. It is therefore recommended to use the brand name or alternatively the INN together with a unique identifier (e.g., Greek letter). In the EU, both the reference medicine and its biosimilar share the same INN. However, they are usually prescribed by brand name to clearly distinguish between the two products and avoid any possible confusion. In contrast, in the US, biosimilars usually have a unique suffix added to their INN to distinguish them from the reference biological product [59,74].

5.4.3. Interchangeability

Interchangeability means that the original medicine may be exchanged by a biosimilar (or vice versa), or a biosimilar by another biosimilar, as long as the expected clinical outcome remains the same. This exchange can take place through two different processes, namely, switching and automatic substitution. Switching is performed when the prescriber ordered the change from one medicine to another with the same therapeutic intent. On the other hand, automatic substitution is carried out if the change is made during clinical practice without consulting the prescriber [2].

However, there are differences in the regulatory approach to interchangeability. According to the EMA, after the medicine has been approved and has demonstrated comparable efficacy, safety and immunogenicity to its reference product, it is considered interchangeable, and no further studies are necessary. Interchangeability rules are decided by individual Member States according to their legal framework [2,75,76]. In Portugal, this decision is undertaken by the National Pharmacy and Therapeutics Commission as an advisory body to INFARMED, I.P. [77,78]. The exchange process must be carried out under the supervision of the prescriber and with the patient’s consent. This way, switching is permitted, but with some restrictions, such as that it can only be performed for treatment periods of more than 6 months. Automatic substitution, on the other hand, is not currently allowed [79].

The FDA requires additional information to determine if a biosimilar is interchangeable. A switching study should be carried out, in which patients alternate between the original medicine and the interchangeable biosimilar multiple times over a defined interval of time, as shown in Figure 6, in order to prove that the switch between the two medicines does not reduce effectiveness or increase safety risks compared to using only the original product. After the interchangeable biosimilar is approved, it can replace the reference product without the intervention of the prescriber and pharmacies can change the patient’s medicines. This process is commonly called “pharmacy-level substitution” and depends on the pharmacy laws of each state [80,81].

5.4.4. Patent Protection and Market Exclusivity

Developing an innovative product is a process that requires a lot of time and cost. Therefore, after their introduction to the market, these medicines are usually under patent protection for some years. This prevents other companies from developing copies of their new product (e.g., generics or biosimilars) granting exclusive market rights to the original company. This market exclusivity allows for the company to make a profit after having invested heavily in the research and development of the innovative product [82].

For biosimilar medicines, as they are “copies” of biological products that already exist, patenting them becomes complicated, as they do not contain a novelty factor to be protected by a patent in most cases. This raises the question of what percentage of difference/similarity must exist between the biosimilar and the original product in order to satisfy the novelty criteria. Biosimilar manufacturers can obtain patent protection when the product contains some form of innovation, such as a new formulation, presentation or administration device, as long as the improvement does not result in clinically significant differences. However, when the changes performed differ substantially from the reference medicine, it cannot be approved as a biosimilar medicine [83].

6. Biosimilar Medicines: Marketing Authorization

6.1. Data Requirements

The introduction of a biosimilar into the pharmaceutical market implies obtaining a marketing authorization from the competent regulatory authorities. This process demands that manufacturers submit an application containing relevant evidence about the product that is grouped and organized in a single document, called a Common Technical Document (CTD). The CTD is an internationally recognized standard format created by the ICH for the presentation of regulatory information on medicines, aiming to promote the harmonization and standardization of regulatory requirements in different regions of the world [84]. For many years, the CTD was exclusively a paper document, but at the moment, the use of the electronic version of the Common Technical Document (eCTD) is mandatory when applying to the EMA and strongly recommended by the FDA [85,86].

The CTD for biosimilar medicines contains some differences compared to a new biological product. Although they have the same structure, the content and focus of a biosimilar CTD heavily emphasizes the comparability between the biosimilar and the reference product across all modules [87]. Module 1 should provide a summary of the evidence used to prove that the product for which the application is submitted is a biosimilar. Details of the biosimilar such as its active substance, raw materials and manufacturing process should be included together with differences from the relevant attributes of the reference medicine. Changes during the development process that could affect the comparability exercise should be mentioned. The comparability exercise with the reference medicine in terms of quality, safety and efficacy must be described, as well as the reference medicine used throughout the entire development program. With regard to module 2, it should contain the normal mandatory requirements for all medicines, namely, a quality overall summary and a non-clinical and clinical overview [87,88].

The major differences are in modules 3, 4 and 5. In the third module, in addition to detailed information on the manufacturing process, including cell line characterization, culture conditions, purification methods and scale-up procedures, it also contains data focused on demonstrating comparability to the reference biological product, including studies conducted to establish similarity between the CQAs of both products. In addition, the analytical techniques and quality control procedures used during this evaluation should also be included in this module. Regarding modules 4 and 5, which include information on non-clinical and clinical studies, respectively, the extent to which these studies should be carried out is less for biosimilar medicines than for the biological reference medicine, since there are previous data on the original medicine. However, in addition it is necessary to carry out a comparative exercise to assess the similarity between the two products in terms of pharmacokinetic/pharmacodynamic and immunogenicity profile to guarantee the safety, efficacy and quality of the new biosimilar [87,88,89].

Table 5. Comparison of regulatory requirements for reference biological products (grey), biosimilar products (bold) and for both (black) [90,91].

Module 3 Quality	Module 4 Non-Clinical	Module 5 Clinical
Drug Substance: - Manufacture - Characterization - Control of Drug Substance - Reference standards or materials - Container closure system - Stability - Comparability Data (analytical comparison with the reference) Drug Product: - Description and composition - Pharmaceutical development (manufacture and control of excipients) - Control of drug product - Reference standards and materials - Container closure system - Stability - Comparability Data (analytical comparison with the reference)	Pharmacology: - Primary - Secondary - Safety - Interactions - Comparability Data (Primary pharmacodynamics) Pharmacokinetics: - ADME - Interactions Toxicology: - Single dose - Repeat dose - Mutagenicity - Carcinogenicity - Reproduction - Local tolerance - Comparability Data (Repeat dose)	Pharmacology Pharmacokinetics: - Single dose - Repeat dose - Special populations - Comparability Data (single dose PK) Pharmacodynamics: - Appropriate markers - Comparability Data (PD) Efficacy and safety: - Dose finding - Schedule finding - Pivotal (Indication x, y and z) - Comparability Data (Indication x) Post-marketing: - Safety - Other indications - Immunogenicity

compares in detail the general data requirements for the reference product and the biosimilar medicine in relation to modules 3, 4 and 5 of the CTD, which include information on quality, non-clinical and clinical studies, respectively.

6.2. European Medicines Agency and Food and Drug Administration Pathways

6.2.1. European Medicines Agency

Directive 2001/83/EC addressed various issues related to the establishment of a legal framework for the regulation of medicines for human use in the EU, such as labelling and packaging, marketing authorization and pharmacovigilance of medicines. Several procedures were established for the approval of medicinal products, as shown in Figure 7 [92].

The centralized procedure (CP) is one of the main strategies used for approving medicines in the EU. Regulation (EC) No. 726/2004 outlines the rules governing the marketing authorization application (MAA) through the CP managed by the EMA [94]. This procedure allows for pharmaceutical companies to submit a single MAA, which, if approved, permits the medicine to be marketed in all EU countries, as well as in Iceland, Liechtenstein and Norway [94]. The choice of the CP for the authorization of medicinal products can be mandatory or optional, depending on the type of product and its therapeutic, scientific or technical characteristics [94,95].

If a medicine does not fall within the mandatory scope of the CP or if the pharmaceutical company does not opt for this route, one of the following procedures must be chosen: A mutual recognition procedure (MRP), in which the applicant with an already authorized medicine in one EU Member State can request its recognition in other EU countries, allowing for Member States to rely on each other’s scientific assessments. A decentralized procedure (DP), where the applicant, not yet having a marketing authorization in any EU Member State, can apply for the authorization of a medicine in more than one EU Member State simultaneously. Finally, national authorization is used for medicines that will only be marketed in one Member State [93,96].

Regarding biosimilars, Directive 2001/83/EC did not initially specify the provisions for them; however, it laid the foundation for their subsequent inclusion and regulation [92]. In 2003, the directive was amended by Directive 2003/63/EC, in which the term “similar biological medicinal product” was first introduced into European legislation. The requirements that the CTD of a biosimilar should contain for its approval as well as the need to carry out comparability studies were established [97]. One year later, the directive was revised again, and Directive 2004/27/EC promoted the harmonization of authorization procedures for biosimilars across the EU, simplifying the approval process and ensuring that the same standards were applied in all Member States [98].

Almost all biosimilar medicines available in the EU were approved by the EC through the CP, overseen by the EMA. Eligibility for the approval of a biosimilar medicine under the CP can be granted in various ways, as shown in

Table 6. Eligibility of biosimilar medicines to be approved through the CP [99].

Mandatory Scope	Medicinal products developed by means of one of the following biotechnological processes: - Recombinant DNA technology; - Controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells; - Hybridoma and monoclonal antibody methods. The reference medicinal product could be a product authorized via a National/MRP or CP.
Optional Scope	Similar biological medicinal products of a centrally authorized product have automatic access to the CP.
	Similar biological medicinal products of a National/MRP/DCP product could, at the request of the applicant, be accepted for consideration under the CP, when the applicant shows that the medicinal product constitutes: - A significant therapeutic, scientific or technical innovation; - The granting of a union authorization for the medicinal product is in the interest of patients at union level.

. Some biosimilars, including certain low molecular weight heparins obtained through the porcine intestinal mucosa, can receive approval at national level [2].

A request for eligibility must always be submitted, whether the product falls under the mandatory or optional scope. The producer must also provide a justification of eligibility for assessment under the CP [99].

This process requires the involvement of several EMA committees, including the Committee for Medicinal Products for Human Use (CHMP), responsible for the scientific evaluation of the application, which works together with the Biosimilar Medicinal Products Working Party (BMWP), which provides recommendations on non-clinical and clinical issues directly or indirectly relating to biosimilar medicines. In addition, the Pharmacovigilance Risk Assessment Committee (PRAC) for safety-related aspects and risk management also contributes to this process. From the submission of the application to the granting of marketing authorization, it typically takes around 12 to 18 months. However, depending on several factors such as the complexity of the product in question, the quality of the data provided by the manufacturer in the application, and the availability and workload of the agency, the process can take more or less time [26].

The MAA should be submitted through the eSubmission gateway or web client in eCTD format. Once the application has been received, the EMA starts the validation process with the aim of ensuring that it contains all the essential regulatory elements. This process must be completed by the start date of the procedure. In case there is any missing information, it must be provided by the applicants in a defined time frame [99].

Once the validation process is complete, the appointed rapporteur and co-rapporteur receive the dossier and the evaluation process begins. When the application concerns a biosimilar of a biological medicine that obtained authorization through the CP, the evaluation process begins that same month. In the case of an application relating to a biosimilar of a biological product that received authorization under a national/MRP/DCP procedure, the EMA will ask the Member State where the reference product obtained a marketing authorization to send, within one month, a confirmation that the reference product is or has been authorized, along with data about the full composition of the reference product and other relevant information, if necessary. Consequently, the evaluation process will only begin once all the relevant information has been obtained [99].

Next, the committees involved carry out a scientific assessment of the application, which can take up to 210 “active” days, as it consists of alternating periods of active evaluation and periods during which the clock is stopped, in order to give the applicant time to resolve any concerns identified during the evaluation. After that, a scientific opinion on whether the medicine may be authorized or not is issued by CHMP and sent by the EMA to the authorizing body for all centrally authorized products, the EC, which issues a legally final decision based on the EMA’s recommendation [99,100,101].

After the medicine has been approved, the EMA continues to monitor its safety through the PRAC, which carries out some routine activities, such as the constant tracking of suspected side effects reported by patients and healthcare professionals. If any data suggest that the medicine is no longer safe, the necessary actions are taken immediately (e.g., restrict/suspend the use of the medicine) in order to protect patient health [26].

6.2.2. Food and Drug Administration

To be able to market their products on the US market, manufacturers must submit an application to the FDA to ensure that their product complies with the statutory requirements for approval, including meeting standards for safety, efficacy and quality. The FDA has several well-established approval pathways, depending on the characteristics of the product, as shown in Figure 8.

Biological products are regulated under section 351(a) of the Public Health Service Act (PHSA) by submitting a Biologics License Application (BLA) that contains all information and data necessary to prove that the product is safe, pure and potent. Regarding biosimilar medicines, the Biologics Price Competition and Innovation Act (BPCIA) of 2009, enacted as part of the Patient Protection and Affordable Care Act (PPACA) in 2010, amended the PHSA and introduced section 351(k). This section established an abbreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product. This section delineates the requirements for the demonstration of biosimilarity or interchangeability with the reference product and the procedures for the submission and review of these products’ applications [102,103,104].

There are some general requirements that the application must include to be approved by the 351(k) pathway, such as a demonstration that the product is biosimilar to a reference product already approved through analytical, non-clinical and clinical studies, unless the FDA decides that, in its discretion, certain studies are not necessary. Moreover, the product must use the same mechanism(s) of action for the intended condition(s) of use known for their reference. The condition(s) of use proposed in the labelling should be the ones that have been previously approved for the reference product and it must contain the same route of administration, dosage form and strength. Lastly, all details regarding the manufacturing and packaging of the product must comply with the established requirements to guarantee the safety, purity and potency of the product [105].

After ensuring that their product meets all the requirements mentioned above, the manufacturer submits a BLA to the FDA. The evaluation of biosimilar and interchangeable products involves the collaboration of several teams, namely, the Center for Drug Evaluation and Research (CDER), which regulates biological products mostly produced by biotechnology methods, with the help of the Office of Therapeutic Biologics and Biosimilars (OTBB), which coordinates and supports all biosimilar and interchangeable product-related activities. In addition, the Center for Biologics Evaluation and Research (CBER) regulates a variety of biological products, such as blood and blood components, gene therapy products and human tissue [9,106]. The contribution of all these teams in the process of reviewing the application is crucial to determine whether the product meets the regulatory requirements for approval, including demonstrating biosimilarity to the reference product and meeting standards for safety, efficacy and quality.

The review process includes a total of six major steps, namely, pre-submission activities, process submission, planning and conducting a scientific/regulatory review of the application, taking official action and finally post-action feedback to the applicant. The time from application submission until the official action is decided is usually up to 10 months. This procedure is relatively quick, as the agency is interested in speeding up the review process for biosimilars to increase access to quality biological medicines and promote competition. However, it is necessary to ensure that the product has the desired safety and efficacy, so this timeline can vary considerably depending on the complexity of the product and the availability of data for the FDA to proceed with the review process. During this time, communication is maintained with the sponsor, namely, through information requests, meetings and the end of review conference [107].

The FDA is responsible for deciding whether to approve or refuse the biosimilar/interchangeable product application. If the medicine does not present clinically meaningful differences from the reference product, it is successfully approved and can be marketed in the US. After that, the product is included in the Purple Book, which is an online database that contains information about biological products, including biosimilar and interchangeable biological products regulated by the CDER and allergenic, cellular and gene therapy, hematologic and vaccine products regulated by the CBER [108,109].

Table 7. Comparison between relevant aspects of the approval process for biosimilar medicines by the EMA and the FDA.

	EMA	FDA
Approval Process	Centralized procedure	Section 351(k) of the PHSA
Scope	Valid at regional level, covering all 27 Member States of the EU and the countries of the EEA, Norway and Iceland.	Valid nationally, only within the US.
Teams Involved	BMWP, CHMP and PRAC.	CBER, CDER and OTBB.
Main Steps of the Evaluation	Pre-submission; assessment; Preparation of responses; Assessment of responses; Preparation of responses; Final CHMP opinion; Final EC decision.	Pre-submission activities; Process submission; Plan the review of the application; Conduct scientific/regulatory review; Official action on the application; Post-decision feedback.
Steps After the Evaluation	Transmission of Opinion and Annexes in all EU languages to Applicant, Commission, members of the Standing Committee, Norway and Iceland; EMA issues press releases and updates its official website to inform about the approval.	The final decision is communicated to all team members and to the applicant; The biosimilar is included in the Purple Book.
Time	210 “active” days + periods when the clock is stopped.	About 10 months (~300 days).

provides a direct comparison of crucial aspects that are part of the approval process for biosimilar medicines by the EMA and the FDA.

7. Market Evaluation

The EMA was the first regulatory authority to approve biosimilar medicines, in 2006. Since this was the first time that legislation and guidelines were developed to ensure the safe and effective approval of biosimilars, the EMA adopted a very cautious approach. The FDA only started approving biosimilar medicines in 2015, and since then, it has approved various biosimilars every year. Compared to the EMA, the FDA has a high approval rate, possibly due to the previous implementation of an approval pathway based on the legislative and expertise established by the EMA [1]. The number of biosimilar medicines approved by the EMA and the FDA per year are shown in Chart 1 and Chart 2, respectively, from the approval of the first biosimilar medicine in 2006 to the present day.

The first biosimilar approved by the EMA was Omnitrope^® in 2006, whose reference medicine is Genotropin^®, which is a human growth hormone (hGH), that contains somatropin as active substance and belongs to the pituitary and hypothalamic hormone and analogue pharmaceutical group. The most recently approved biosimilar medicine was Wezenla^® in 2024, whose reference medicine is Stelara^®, which is a monoclonal antibody that contains ustekinumab as the active substance and belongs to the immunosuppressant pharmaceutical group [110].

In the case of the FDA, the first biosimilar approved was Zarxio^® in 2015, which is a granulocyte colony-stimulating factor (G-CSF), whose reference medicine is Neupogen^®, that contains filgrastim as the active substance and belongs to the immunostimulant pharmaceutical group. The most recently approved biosimilar medicine was Epysqli^® in 2024, which is a monoclonal antibody, whose reference medicine is Soliris^®, that contains eculizumab as the active substance and belongs to the immunosuppressant pharmaceutical group [111].

In 2021, the FDA approved the first interchangeable biosimilar, called Semglee^®, whose active substance is insulin glargine. This product can be substituted for its reference medicine, Lantus^®, at the pharmacy level without the intervention of the prescribing healthcare provider [111].

Until today, a wide variety of biosimilar medicines have already received regulatory approval and are available on the market. Chart 3 and Chart 4 present the number of biosimilars approved per pharmaceutical group by the EMA and the FDA, respectively.

In both regulatory entities, the pharmaceutical group with the most approved biosimilar medicines is immunosuppressants, which are medicines used in a variety of diseases that involve the immune system. Their purpose is to suppress or dampen cell-mediated and humoral immune responses. These products are commonly used in the treatment of autoimmune diseases, organ transplantation and certain inflammatory conditions where the immune system attacks healthy tissues or organs [112].

By way of example, Humira^® is a biological medicine that belongs to the immunosuppressant pharmaceutical group and is widely prescribed to treat autoimmune diseases, such as plaque psoriasis, rheumatoid arthritis and Crohn’s disease. This medicine is currently approved by the EMA and the FDA and has 10 alternatives available in both the EU and the US, as shown in Figure 9.

However, over the last years, there have also been many medicines whose application was refused by the EMA and FDA. The reason for this decision by the regulatory authorities may be due to concerns regarding the comparability of the biosimilar medicine and its reference, insufficient data on the stability of the active substance, a poorly detailed manufacturing process or the use of processes that have not been adequately validated. In addition, many applications have been withdrawn at the request of the marketing authorization applicant due to inability to answer the questions posed by the regulatory authorities within the time available and for commercial reasons.

8. Conclusions and Future Prospects

Biological medicines are innovative products used to treat complex and chronic diseases. These products are produced from living organisms using advanced biotechnology techniques. They are generally made of proteins, which have a complex molecular structure and some intrinsic variability associated. Their cost and production time is high, leading to a demand for more accessible alternatives equally safe and effective. Thus, with the expiry of the biological medicines’ patents, a new class of medicines has begun to emerge on the pharmaceutical market: biosimilar medicines.

These products are well known for being “copies” of an already approved biological medicine. The biosimilar producer must develop its own process, which can lead to some differences between the biosimilar and its reference biological medicine. These differences are acceptable as long as comparability studies demonstrate the biosimilar has no clinically significant differences from its reference. In the past years, the pharmaceutical market has undergone a major revolution with the appearance of biosimilar medicines. These products have increased patient access to biological products with the same safety, efficacy and quality of their reference medicine, but at a considerably reduced cost.

Due to the unique characteristics of biosimilars, specific guidelines were created by regulatory authorities to assist manufacturers developing medicines that meet strict safety, efficacy and quality criteria. Several regulatory authorities around the world have defined their own guidelines, as well as the review and approval process for this type of product, fostering the production of high-quality biosimilars, facilitating the regulatory approval process and speeding up their entry into the pharmaceutical market.

The appearance of biosimilar medicines has brought numerous benefits. Due to their lower cost, biosimilars increase patient access to biological medicines and offer doctors and patients more treatment options, being a useful alternative when the reference biological is not available or is discontinued, ensuring continuity of treatment. Furthermore, these medicines have created competition in the pharmaceutical market, which can promote price reductions and improve the consequent accessibility of treatments, stimulating innovation, as pharmaceutical companies are encouraged to develop new therapies and improve production processes to remain competitive. Finally, for healthcare systems, the savings generated using biosimilars can be redirected to other areas, such as the research and development of new treatments, improvements in health infrastructure and the creation of education programs.

However, biosimilars still have some obstacles to overcome. There is a lack of information concerning these products and many healthcare professionals and patients are still not completely familiar with these products and their advantages. This can cause hesitation when it comes to prescribing a biosimilar instead of an original biological product. Furthermore, although the approval processes for biosimilars have been well established, there are still challenges regarding harmonization of regulatory requirements. Improving and simplifying approval processes or even creating a single regulatory pathway that ensures the safety and efficacy of these complex products would accelerate and facilitate the entry of more biosimilars into the market worldwide and enhance competition.

In a near future, the pharmaceutical market will face a “biosimilar gap”, since the patents of some biological products are about to expire and no corresponding biosimilars are available. This represents a great opportunity for manufacturers, and it is therefore expected that several companies will start producing biosimilar medicines. The creation of strategic partnerships between pharmaceutical companies is also expected, to speed up the development of these products. Finally, innovations in the technologies used in the manufacture of biologics and biosimilar medicines are essential to help companies overcome challenges in terms of scalability, quality control and regulatory compliance. This could enable the development of more consistent biosimilar manufacturing processes, reducing production costs and increasing their competitiveness in the market.

Overall, this study aimed to elucidate on the regulatory framework of biosimilar medicines, as well as their development and approval process. Much remains to be explored about this subject, as the future of biosimilar medicines is promising and predicts a significant impact in the health sector, both in terms of accessibility and innovation.