A biosimilar (or similar biological medicine) is a biological medicine equivalent in quality, efficacy and safety to an original biological medicine, called a reference product. The dosage and route of administration must be the same, and the biosimilar is authorized for all or some of the indications approved for the reference biologic.

Overlay of Fc CT-P13 (green) and RMP Fc (red) crystal structures: (A) front view; (B) Side view. Source: Physicochemical characterization of Remsima. Soon Kwan Junga, Kyoung Hoon Leea, Jae Won Jeona, Joon Won Leea, Byoung Oh Kwona, Yeon Jung Kima, Jin Soo Baea, Dong-Il Kimb, Soo Young Leea & Shin Jae Changa

The biosimilar contains a version of the active substance of the reference product. Equivalence with it must be established by means of a comprehensive “comparability exercise”. The objective of this exercise is to demonstrate that the slight physicochemical differences between the two products do not significantly affect the benefit/risk profile, which makes it possible to support that the active principle of both drugs is essentially the same. Once the equivalence is accredited and authorized, the biosimilar is one more biological medicine. Physicochemical variability without therapeutic significance is inherent to products of a biological nature, and sometimes identifiable between batches of certain biological drugs subject to changes in the production process. This may even require the execution of a custom "comparability exercise" between two or more batches of the same biological, original or biosimilar medicine, in order to verify their equivalence.

The approval of the biosimilar is based on rigorous scientific-medical evidence, and the regulatory authorities apply the same criteria to original and similar biologics (biosimilars) in relation to the degree of demand in the benefit/risk balance estimated as acceptable.

The approval, or not, of a biosimilar candidate depends on the result of the “comparability exercise”. The biological condition of the compared products requires an extensive and exhaustive exercise. Its extension and design will depend on the clinical knowledge accumulated over the years of therapeutic use of the reference medicine, and its pharmacological characteristics. The “comparability exercise” generally ranges from a detailed assessment of the degree of structural and functional similarity, to confirmatory clinical trials in patients. Which supposes between 6 and 12 years of study. Its objective is to prove with sufficient guarantees that both products share efficacy and safety profile.

Comparison between a biological monoclonal antibody and a molecule of acetylsalicylic acid. Source: Developing the Nation's Biosimilars Program. Steven Kozlowski, MD, Janet Woodcock, MD, Karen Midthun, MD, and Rachel Behrman Sherman, MD, MPH

The demonstration of equivalence between medicines that do not have a biological origin, such as a generic candidate and the original product of chemical synthesis (or «small molecule») with which it is compared, does not require such an extensive and exhaustive evaluation since it is possible to generate chemical synthesis active principles virtually identical in their structure. Although the legal basis on which they are based is comparable, the biosimilar and generic concepts should not be confused. Similarly, it is not scientifically advisable to talk about biogenerics.

The authorization of biosimilar medicines, of biotechnological origin, in the countries of the European Economic Area (EEA), such as Spain, is subject to a centralized procedure. In other words, the European Medicines Agency (EMA), located in Amsterdam, is the institution responsible for evaluating the dossier (or file) that includes the studies carried out with the biosimilar candidate, and issuing a report regarding accreditation, or not, of biosimilarity. EMA evaluators are experts belonging to the regulatory agencies of each of the member states.

The EMA was a pioneer in developing guidelines on how biosimilars should be developed; that is, about the studies required to demonstrate equivalence. The criteria of this regulatory framework were then reproduced in their practical verbatim by the World Health Organization (WHO), and collected in essence by reference regulatory agencies (the US FDA, the Canadian, the Japanese and the Australian). The team of experts that evaluates the dossiers of the original biological medicines also does so with biosimilar candidates, and necessarily applies the same criteria regarding the required guarantee of efficacy and safety. Therefore, belonging to the EEA has a special meaning in the field of biosimilars, due to the very particular leadership and recognition that is attributed to the EMA regarding the experience in the enforceable regulatory requirements, and in the pre-commercial evaluation of these products.