Biologics are medicines that contain one or more active ingredients produced or derived from a biological source of recombinant or extractive origin.6 Their chemical composition varies widely and may include proteins, carbohydrates, nucleic acids, or combinations of these substances, or even consist of complete living organisms, such as cells or tissues.6 Biological medicines can be obtained from multiple natural sources: human, animal or microorganisms.7

The main characteristics of biosimilar medicines are listed in Table 2.

According to the European Medicines Agency (EMA), a biosimilar medicine is a biologic medicine that is very similar to another biologic medicine already on the market in the European Union (EU), referred to as the “reference medicinal product”, with which it demonstrates biosimilarity.7,8 Biosimilarity is the property of a medicinal product to show similarity and lack of significant differences in terms of quality, efficacy, and safety, to a reference medicinal product against which it has been compared.

Although the basic chemical structure of the biosimilar medicine may be identical to that of the reference medicine, when a protein is “translated”, it undergoes additional modifications (glycosylation, sulphation, methylation, etc.). These modifications will be unique to each particular molecule, and therefore no two will be completely identical in a vial of any biosimilar medicine, and likewise there are differences between batches of the same reference biologic medicine. Therefore, each biological medicinal product has a certain set of critical quality attributes. These attributes are physicochemical and biological properties, some of which are more sensitive than others to variation, and include size, molecular charge, and glycosylation. All of these can be modified by changes in the process, e.g., in the type of cell used in the production process or by the culture conditions, pH temperature, etc.

Thus, during the manufacturing process of the biosimilar medicine, rigorous controls are always carried out to ensure that small differences do not affect the performance of the medicine or its safety. In other words, it is ensured that these differences are not clinically significant in terms of physico-chemistry, efficacy, or safety.9

All medicines produced by biotechnology must be authorised in the EU via the EMA through what is termed a “centralised procedure”. This means that a single registration dossier is submitted to the EMA for evaluation by the EMA's scientific Committee for Medicinal Products for Human Use (CHMP) and for safety.10

When a biosimilar is submitted to the EMA for authorisation, the CHMP, and experts on EU biological medicines (Biologics Working Party) and biosimilar specialists (Biosimilar Medicinal Products Working Party) evaluate the studies submitted to assess whether it demonstrates biosimilarity.

Biosimilarity is demonstrated through a detailed comparison (Table 3). This is a direct comparison exercise between the biosimilar medicine and its reference medicine, which verifies that minor differences in structure and function (physicochemical or biological activity) that may exist between the two do not affect the efficacy, safety, and quality of the biosimilar medicine.6 These comparison studies are not only undertaken with biosimilar medicines, but also with reference medicines when they undergo modifications to their production processes or develop new galenic formulations. This comparative assessment is done on one or more sensitive indications, i.e., on the population where differences in clinical performance related to the biosimilar medicine can best be detected.

When the CHMP issues a favourable opinion on a biosimilar medicine, the EU approves the marketing of the medicine, which is automatically authorised throughout the EU. EPAR (European Public Assessment Report) reports are published on the EMA website with a summary of the scientific evidence supporting the authorisation of the biosimilar medicine.

In addition, due to the complexity and heterogeneity of biosimilar medicines, the EU has developed a specific regulatory framework based on different and more complex principles than for generic medicines. The directives and guidelines applicable to biosimilar medicines are also available on the EMA website and are summarised in Table 4.

In Spain, in addition to approval by the EMA, prior to marketing, a favourable resolution must be issued by the Ministry of Health, Consumer Affairs, and Social Welfare for funding from the Spanish National Health System and, where appropriate, the price must be set by the Interministerial Pricing Commission.

Indication extrapolation is the extension of efficacy and safety data from a therapeutic indication for which the biosimilar medicine has been clinically tested to another therapeutic indication authorised for the reference medicine.

After successful completion of studies on the most sensitive indication(s), other indications for the reference medicinal product that the assessors consider appropriate in view of the results of the comparability study are extrapolated to the biosimilar. The extrapolation of data to other indications is always based on scientific data obtained in robust comparability studies.7

Extrapolation is a well-established scientific principle that has been used for many years in medicine, including for reference biological medicines.11 Extrapolation is performed, for example, when a biological medicinal product with several authorised indications undergoes major changes in its manufacturing process (new manufacturing site, development of new galenic formulations, etc.). The potential effect of these changes on the clinical performance of the biological medicinal product is thoroughly assessed by comparability studies (in vitro and quality studies). If clinical studies are needed, they are conducted for a relevant indication and, based on all these data, extrapolation to other indications is usually possible.

Interchangeability refers to the possibility of exchanging a medicine for another medicine that is expected to have the same clinical effect. This could mean exchanging a reference medicine for a biosimilar medicine (or vice versa), or replacing one biosimilar medicine with another.

This exchange can be done through a switch, where the change is made by decision of the prescriber, or substitution, where the change is made automatically at the pharmaceutical level without consulting the prescriber.

The EMA does not include recommendations on interchangeability with the reference medicinal product. Although they advise involving prescribers in the final decision, the joint position of the EMA and the European Commission is that Member States should decide whether biologic drugs and their respective biosimilars can be interchangeable.12

In Spain, order SCO/2874/2007 allows switching but prevents automatic substitution when there is no prior consensus with the prescriber,13 in line with the position of countries’ main rheumatology, dermatology, and oncology scientific societies.9,14,15 However, this order refers to article 86 of Law 29/2006, of 26 July, on Guarantees and Rational Use of Medicines and Medical Devices, an article that falls under chapter IV, which refers to the rational use of medicines in pharmacies. Therefore, it does not apply to the hospital setting, where each Pharmacy and Therapeutics Committee (PTC) establishes whether a biosimilar can be exchanged and the criteria to be applied by consensus of all stakeholders (doctors, hospital pharmacists, primary care pharmacists, healthcare managers, and patients). Thus, exchange at the hospital level is allowed if it has been approved by the hospital PTCs, the regional committees, and the physician who is represented on these committees.16

In general, the decision on public funding of medicines goes hand in hand with their evaluation. Biosimilar medicines are no exception and follow the same economic evaluation guidelines as other biological medicines. With regard to the of funding medicines, there are multiple factors that can influence how they are priced by the authorities (incremental clinical effectiveness, cost-effectiveness and budgetary impact, burden of disease, and unmet medical need, size of the target population, domestic reference prices, international reference prices, cost of production, innovative nature of the product, ethical and equity considerations, contribution to GDP, and lobbying). These factors also apply to some extent to biosimilar medicines, although price referencing them to the reference medicines is a major element.

Traceability is defined as the ability to trace and follow a medicine through all stages of production, distribution, and use. Traceability, as a mechanism for tracking a medicine throughout its “lifetime”, has been widely recognised as a fundamental element of patient safety.

Another important requirement for biosimilar medicines to ensure correct safety monitoring is the traceability of both their prescription and their administration to patients.

The efficacy of biosimilar medicines in immune-mediated diseases has been extensively demonstrated in RCTs and reported in several systematic reviews and meta-analyses.17–21 These studies have shown that biosimilar medicines are very similar to reference drugs in terms of structure, physicochemical and biological properties, pharmacokinetics, efficacy, safety, and immunogenicity. For example, in patients with rheumatoid arthritis, no statistically significant differences have been found in ACR20, ACR50, or ACR70 at 12, 24, and 52 weeks between biosimilars and reference drugs, or in the rate of serious adverse events.17–19 Neither have they been found in spondyloarthritis, including psoriatic arthritis.20,21 However, their bioequivalence, efficacy, and safety have also been demonstrated in patients with cutaneous psoriasis.22

In inflammatory bowel disease, multiple observational studies have demonstrated the effectiveness and safety of IFX and biosimilar ADA.23,24

Similarly, data from observational studies in other immune-mediated diseases have been published with results in line with those obtained in RCTs.25,26

The impact on pharmaceutical spending as a result of biological drugs coming to the market is significant and growing.27,28 Their unquestionable clinical value is accompanied by a price that is usually higher than that of chemically synthesised drugs. The introduction of biosimilar medicines has led to significant savings. One of the most important national studies was conducted by the Weber Foundation in 2017.29 This analysis estimated a retrospective saving of 478 million euros between 2009 and 2016, which could be increased by 1,965 million euros from 2017 to 2020, according to their prospective analysis, with the use of biosimilars.

In this regard, it should be noted that the European regulatory framework is designed to promote and accelerate market access for biosimilar medicines. The aim is to promote competition in the market, contain pharmaceutical expenditure, and improve access to biological and other innovative medicines.

In relation to switching, the NOR-SWITCH non-inferiority RCT, conducted in nearly 500 patients with various immune-mediated diseases, demonstrated that switching from the original IFX to the biosimilar CT-P13 is not inferior to continued treatment with the original drug in terms of efficacy, safety, and immunogenicity.30,31 In this RCT, patients were given stable treatment with IFX for at least six months and then approximately half of them switched to the IFX biosimilar. The data show that efficacy and safety were comparable between groups, with a non-inferiority margin of 15%.

Published observational studies on switching show similar results in the different immune-mediated diseases.32,33

A nationally published survey concluded that many professionals are relatively cautious about using biosimilars in clinical practice.4 The main barriers to the use of biosimilar medicines found in this survey, as in others conducted in neighbouring countries,27,34–40 include lack of confidence, knowledge, or experience in the use of these medicines.

Furthermore, the survey showed great variability at hospital level in the management of biosimilar medicines (access, protocols, etc.).4

On the other hand, the main facilitators for their use are access to evidence (clinical trials and real-life empirical data) on availability, efficacy, safety, and interchangeability, together with the guidance provided by scientific societies, the opinion of relevant colleagues, and the development of local protocols.4

Patient information and shared decision-making are essential to promote adherence and avoid the nocebo effect with the use of biosimilar medicines.41 Studies have shown that their doctors, and other healthcare professionals, such as nurses and pharmacists, are the main source of information for patients, and that they want to be involved in decisions concerning their health.42,43

In this regard, with the use of biosimilar medicines, it is recommended that the main characteristics, safety, and suitability of the biosimilar medicine, as well as any potential changes throughout the course of treatment should be explained in detail. It is also advisable to involve patients in the pharmaceutical expenditure and the contribution of these medicines to the sustainability of the system.

There are now specific guidelines for patients,44,45 and educational material (included in patient support programmes), a home delivery service, tele-pharmacy/tele-assistance, or counselling in patient associations.

Table 5 summarises a proposal for potential future lines of work with the use of biosimilars.