Biological drugs and biosimilars

A biological drug(1) is a drug that contains one or more active principles synthesised or derived from a biological source. The active principles of biological drugs are larger and more complex than non-biological drugs. This complexity, along with specific variable characteristics (which are sometimes undetectable) in respect of their raw material and their production methods, can cause a significant degree of variability between molecules from the same active ingredient.

When patents for innovative biological products of pharmacological interest and their periods for exclusivity of data expire, a second product range is introduced onto the market. They are similar to the original products and so are known as 'biosimilar' products. A biosimilar drug(2) is a type of biological medicine that is developed to be similar (but not identical) to a pre-existing biological medicinal product (the reference product) when its period of market exclusivity has ended.

A biosimilar drug is not a generic drug.(3) A biological drug is the result not of a chemical synthesis, but of biological activity, which is changeable, thus affecting the final product. It follows that biosimilars are much harder to copy because their molecular structures are 'entangled' and their production requires complex and difficult processes.(4) On the other hand, as generics have smaller structures and are chemically synthesised (a chemical structure is reproducible), exact copies of the reference product can be produced.

Thus, biosimilars are 'special' drugs(5) which are subject to the general regime for drugs and medical devices, but which are subject to legal and regulatory specifications.

Since the variability of biosimilars can create different security profiles, the pharmacovigilance and traceability requirements are higher than for generic products. The European Medicines Agency (EMEA) – the scientific body of the European Commission responsible for evaluating medicinal products – tries to find a balance between ensuring the safety of patients and establishing an abbreviated regulatory approval process for biosimilars. It has established mechanisms for the registration, post-authorisation surveillance and monitoring of safety and the verification of effectiveness. Thus, the EMEA requires clinical trials for biosimilars that are not required, for example, for generics, increasing the cost of developing biosimilars.

Putting biosimilars on pharmaceutical markets

The introduction of biosimilars onto the pharmaceutical markets follows the same rationale as the introduction of generics: by reducing the costs involved, biosimilars are intended to contribute to the sustainability of national health systems and to ensure patients' access to medicines.

The approval of a biosimilar rests on the knowledge obtained from the reference product. The main part of the evaluation is a comparison of the biosimilar medicine with its reference product to show that there are no significant differences between them. This demonstration of similarity must include studies related to quality and pre-clinical and clinical trials – unlike generics, for which it is sufficient to prove bioequivalence in fast-track proceedings.(6)

Thanks to the centralised EU registration procedure, biosimilars have identical medicine data sheets and their marketing authorisations are valid in all EU countries.

All biosimilars approved in the European Union must undergo the EMEA's rigorous scientific evaluation before obtaining marketing authorisation. The complexity of biological drugs, and the advances in and limitations of the techniques and procedures available for the characterisation of these drugs, have led the EMEA Committee for Medicinal Products for Human Use to develop specific guidelines on both quality and the non-clinical and clinical aspects that must be taken into account when developing biosimilars.(7)

After passing the examination, the medicine is ready to be commercialised. Although replacing a reference product with a generic product is possible – and even mandatory in some cases – Community legislation, and specifically Spanish law, does not allow a reference drug to be substituted with a biosimilar when prescribing or dispensing.

In Spain, exclusion from the replacement regime of biological products is established in Article 86.4 of the Law on Guarantees and Rational Use of Medicines and Medical Devices (29/2006),(8) developed by Order SCO/2874/2007. The order provides as follows:

"1. In accordance with article 86.4 of Act 29/2006 of July 26 on Guarantees and Rational Use of Medicines and Health Products, the following medicines cannot be replaced in the act of dispensing, without the express permission of the prescribing healthcare professional:

1. The biological medicines (insulin, blood products, vaccines and biotechnology drugs)."

This allows the identification and reporting of adverse reactions to biological drugs, ensuring product traceability and controlling the safe use of medicines. In addition, biological medicines must be prescribed by their trademark, as provided under Royal Decree 81/2014 establishing the rules to ensure cross-border healthcare and amending Royal Decree 1718/2010 on prescription and dispensing orders, which specifies the information that must be included in a medical prescription. The trademark must be indicated because, by definition, biosimilars are different from the originals and therefore there can be no interchangeability between the products.


Given the complex nature of these products – the profile of which should be carefully evaluated and monitored – it is necessary to have a well-defined and transparent legislative framework covering development procedures, evaluation, registration and monitoring after they have been placed on the market. In addition, healthcare professionals should know the legal and guarantee requirements to which biosimilars are subject, and should promote their use in treatments through a rigourous, secure, transparent and smooth transition for the benefit of the national health system, the pharmaceutical industry and especially patients. The real success of biosimilars depends on their quality, efficacy and medical safety gaining credibility.

Claudia Vargas Villanueva

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