1.1. Concept of biosimilar drugs

According to the WHO, biosimilar bio therapeutic products are bio therapeutic products, i.e., biological drugs, similar in terms of quality, safety and efficacy to a previously authorized reference bio therapeutic product⁽¹⁾. In this regard, it should be recalled that these drugs are characterized by the fact that living organisms produce them.

Biosimilar medicines have health guarantees -quality, efficacy, safety, identification and information- analogous, similar, similar or equivalent to the original or reference biological medicines and, therefore, are sufficient to obtain a marketing authorization from the health authorities.

Given that most of the active principles of biosimilar medicines are obtained through biotechnological processes. It is in the territory of the European Union (EU) that such authorizations are granted by the European Medicines Agency, by virtue of the provisions of the Regulation of the EU 2019/5 of the European Parliament and of the Council, of 11/12/2018. This modifies the Regulation of the European Commission (EC) nº 726/2004, by which community procedures are established for the authorization and control of Medicines for human use and by which the European Medicines Agency is created, these are authorized by the EC.

In Spain, the authorization is granted by the Spanish Agency of Medicines and Health Products. This is the case of the following active ingredients: low molecular weight heparins, sodium chondroitin sulfate, and some commercial presentations of teriparatide.

Once the biosimilar medicinal products have been authorized by the centralized procedure, the laboratories holding the marketing authorization must initiate certain methods to market such medicinal products in the different EUA Member States, which are aimed, among others, at setting the conditions of financing by the public health services or setting the industrial sales price.

In this context, there are significant differences in access to biosimilar drugs in the EU, so that the purchase price varies from one Member State to another and not all of them may be available in all countries. Likewise, it can also happen that the authorized drug is not marketed, a situation that would lead to the revocation of the authorization if more than three years have elapsed, as occurred in the specific case of a certain drug authorized as a biosimilar.

Regardless of the regulatory body that decides on the authorization to place the drug on the market, a simplified or abbreviated regulatory procedure is followed, as it is unethical to demand the same requirements for the authorization of the latter as for the original or reference drugs, since such a scenario would entail a repetition of non-clinical and clinical trials. Not only would the scientific knowledge obtained during the development of reference drugs be ignored, but there would also be an unjustified abuse of experimental animals for drug development -with the corresponding bioethical repercussions-.

It should also be noted that the development of generic drugs is much more limited than that of reference drugs, which is why they can be marketed at lower prices and are of undeniable social interest. For example, clinical research is often reduced to bioequivalence studies ⁽²⁾.

1.2. Relevance

Medicines of a biological nature play a very significant role in the pharmaceutical sector. They represent a benefit to the pharmaceutical provision of the National Health System since they present novel pharmacological action mechanisms that are different from drugs obtained through chemical synthesis processes. In this scenario, their introduction in therapeutics has led to far-reaching changes in the care protocols of numerous diseases, among others, in the field of oncology and hematology ⁽³⁾.

Their use also has a significant budgetary impact for public health systems ⁽⁴⁾. In 2018, the use of biologic drugs in the EU regulatory territory accounts for thirty percent of pharmaceutical expenditure ⁽⁵⁾. In 2020, such pharmaceutical expenditure has been estimated at around eight and a half billion euros ⁽⁶⁾.

The difficulty of access to medicines especially in developing countries, is well known and constitutes a public health problem ⁽⁷⁾. In many developing countries, there is a lack of appropriate drug distribution systems, which further exacerbates the differences in patients’ access to these goods of social interest ⁽⁸⁾. This problem is aggravated for biological drugs, since many of them require special temperature conditions for their distribution, storage and custody ⁽⁹,¹⁰⁾.

In order to avoid restrictions on patients’ access to biological therapies for economic and/or geographical reasons -that is, independently of therapeutic issues- it is absolutely necessary to devise strategies to guarantee the sustainability of health insurance and, at the same time, to provide -or facilitate- patients with the pharmacological treatments they need in an equitable manner - regardless of their purchasing power.

Although patents “contribute to the public interest by encouraging research and innovation leading to new and better drugs” ⁽¹¹⁾. There is no doubt about the need for patents to expire after a finite period of time in order not to slow down innovation by the pharmaceutical industry, since the malicious -or abusive- use of patents leads to the establishment of monopolies that determine the high prices of drugs ⁽¹²,¹³⁾. In the 21st century, there have been numerous conflicts between intellectual property rights -patents- and human rights -the right to life, to health protection, to access to medicines- with the latter being weighted in favor of private rights ^{(13- 15)}.

It is in this context, in which economic resources are limited, there are terrible inequalities in access to drugs, and due to the need for governments to supply drugs to meet the health demands of the population, that biosimilar drugs take on great importance. These products, which are of unquestionable social interest ⁽¹³,¹⁶⁾, can be introduced on the markets once the exclusive exploitation rights of the patent of the reference or original biological drug have expired ⁽¹⁷⁾, and will then be marketed at lower prices compared to the latter.

4.1. Concept

In recent decades, the pharmaceutical industry has been marketing a broad pharmacotherapeutic arsenal in a market with an asymmetrical and atypical relationship between the different agents involved in it. Since in the case of the drugs included in the pharmaceutical provision of the National Health System, the consumer -patient and/or user- neither decides nor pays for the drug in full; the prescriber neither pays for it nor consumes it; and whoever finances it -the public administration- neither prescribes it, nor does he/she consume it ⁽³¹⁾. From the above it can be seen that, within the framework of the rational use of health resources in general, and of drugs in particular, it seems clear that it is necessary to select the drugs with the best cost-effectiveness ratio, in order to guarantee their access to the population.

According to Mahler, essential medicines constitute “one of the elements of Primary Health Care, to ensure that all people could have an economically and socially productive life” ⁽³²⁾. Unfortunately, more than one third of the world’s population is unable to access such products ⁽³³⁾.

The concept of essential medicines was coined by who in 1977 to designate those products that meet the basic health needs of most of the population. For this reason, these drugs should be available in all countries in sufficient quantities.

Although it is true that the classification of drugs as essential is criticized by some authors, who argue that there could be drugs that are necessary for the population but are not recognized as such by the WHO ⁽¹⁶⁾. It is considered appropriate for an international organization to establish, by means of a non-binding document, a list of drugs for which a continuous and sufficient supply should be guaranteed for the population, given the limited health resources. Similarly, several authors have criticized the WHO list of essential drugs because the procedure for selecting and including drugs prioritizes economic criteria over therapeutic ones ⁽³⁴⁾.

Unfortunately, universal and equitable access to medicines can be considered a utopia. There is no doubt about the difficulty of access by the population of developing countries to the drugs required to meet the demand for medicines by these societies ⁽⁷,¹⁴,¹⁸,³¹,³⁵,³⁶⁾. Medicines are essential to the lives of citizens ⁽³⁷⁾, given their link to the right to life and health protection.

Particularly significant is the traditional problem of antiretroviral drugs ⁽³⁸⁾, used in therapy for the treatment of human immunodeficiency virus infection, since, on the one hand, they are difficult to access and, on the other, a message of monogamy or sexual abstinence is conveyed to these populations ⁽³⁹⁾.

Recently, the problem related to vaccination coverage against COVID-19 can be cited ^{(40- 42)}. In Spain, the population has been stratified into groups according to priorities, and it is also worth considering whether, once a certain level of vaccination coverage has been reached, these resources could be distributed to developing countries to ensure more equitable access, or whether the maximum vaccination quota could be reached ⁽⁴³,⁴⁴⁾. The development of new formulations of these vaccines, either original drugs or biosimilar drugs that may be developed in the future, would contribute significantly to improving universal access.

Another major problem is the lack of treatments for the so-called “neglected diseases” ⁽²⁴,⁴⁵⁾, mainly due to the absence of promoters, since they mainly affect developing countries. Existing treatments for such pathologies suffer from severe problems of effectiveness, for example, the emergence of resistance, or safety, i.e., they are highly toxic.

While it is true that privately owned pharmaceutical laboratories are the main investors in the research and development of new drugs, given that this is their main economic activity, their invaluable contribution to the development of drugs for human use for the treatment and/or prevention of neglected diseases should be emphasized, so that the financing of such activities comes mainly from public institutions ⁽⁴⁵⁾.

Essential drugs should not only be available in sufficient quantity to meet the health demands of the population. They should also meet the following requirements: a) be in the appropriate pharmaceutical form; b) satisfy adequate health guarantees, quality, efficacy, identification, information, and safety; c) be available at a price that can be afforded by the payer, e.g., the patient, the public health system, etc.

Due to the particularities of pediatric medicines, three decades later the list of essential medicines for exclusive use in humans up to twelve years of age was published independently.

The lists of essential drugs published by the who are not legally binding for the different countries, i.e. they have the character of recommendations and are therefore not valid worldwide. Their usefulness lies in the fact that they are a fundamental tool for the health planning of national territories. States must therefore draw up their own lists of essential drugs, based on the list defined by the WHO, considering the specific health needs of the population whose right to health protection must be satisfied, and ensure an adequate level of access to the drugs. The selection of biosimilar drugs by states can contribute significantly to the rationalization of the costs associated with medical treatments without reducing the quality of healthcare, and without the need to limit access to biological therapies.

Initially, the WHO list of essential medicines contained two hundred and forty-three active ingredients in twenty-seven pharmacological groups. This list has been revised every two years since then, the list of essential drugs for pediatric use only is revised at the same frequency. In 2021, five hundred and sixty-four drugs are incorporated into the general list; and three hundred and forty-eight drugs are incorporated into the list of pediatric drugs.

4.2. Classification

In turn, within the list of essential drugs, for each pharmacological group, one or two categories can be distinguished. On the one hand, a basic list, which includes only those, drugs necessary to cover the basic health needs of the population. These are, by definition, those that have demonstrated the greatest efficacy and safety, and those that present the best cost-effectiveness ratio for the priority disorders, that is, those most relevant in relation to public health, and the potential safety and cost-effectiveness of the treatment.

On the other hand, a complementary list will be established, which incorporates second-choice drugs for the treatment of priority disorders, in which any of the following circumstances are present: a) a specialized diagnosis is required, b) specific monitoring facilities, c) assistance by a specialist, d) reasons related to price cost or cost-effectiveness ratio less favorable with respect to the drugs on the main list.

4.3. Addition of biological drugs

In the latest WHO general list of essential drugs (2021), sixty of them are of a biological nature, while the number of essential drugs for the pediatric population is smaller, at forty-two.

With respect to the general list and as can be seen in Table 1, fourteen essential drugs with biological active ingredients were initially incorporated (1977). In the revisions carried out during the last decades of the 20th century, the introduction of biological drugs in these lists has been discrete: five in 1979, one in 1984, two in 1987, one in 1991, one in 1993, and three in 1999. In total, twenty-six biological drugs were designated as essential until 1999. Although in the three subsequent revisions (2001, 2003 and 2005) no biological drugs were incorporated. In the current century an important turning point is observed, since, unlike what happened at the beginning of the 21st century, thirty-five biological drugs have been incorporated: eight in 2008, one in 2009, one in 2011, one in 2011, three in 2013, seven in 2015, six in 2017, nine in 2019, and one in 2021.

Of the list of essential drugs for 2021, there are currently commercial presentations of biosimilar drugs in the EUA for ten of them, drugs containing enoxaparin are authorized at the level of each Member State, and this figure is expected to increase in the coming years, due to the expiration of the patent of the reference biological drugs. For example, the patent of the reference drug whose active ingredient is cetuximab expired in 2014; and in 2022 this will happen in the case of eculizumab ⁽⁴⁶⁾. Denosumab biosimilar drugs are currently in the clinical research phase ⁽⁴⁷⁾.

In November 2021 there were ninety commercial presentations of biosimilar drugs considered essential available in Spain. These data highlight the undoubted relevance of biosimilar drugs in therapeutics worldwide.

There is no doubt that biosimilar drugs are essential for the world’s population, since their cost-effectiveness ratio is considerably higher than that of reference biological drugs, without there having been any reduction in the health guarantees.

Biosimilar drugs provide accessibility not only from the economic point of view, but also because the laboratories responsible for the manufacture of such products also introduce improvements at the pharmacotechnical level, for example, formulation and pharmaceutical form ⁽⁴⁸⁾.