The regulatory pathway for biosimilars aims to confirm the absence of clinically meaningful differences compared to the reference product in quality attributes, efficacy, immunogenicity and safety. This is achieved through studies which are carried out as a stepwise comparison with a reference product [2]. The first step consists of quality studies that involve 20-40 analytical tests [3], and compare the primary structures, post-translational modifications, variants, higher-order structures, and biological activities of the biosimilar and the reference product. The next step involves preclinical studies that, in the case of mAbs, should always include in vitro pharmacodynamic (PD) studies. In the clinical phase (next step), the biosimilar should demonstrate equivalence of pharmacokinetics (PK) and comparability in terms of efficacy, safety and immunogenicity to the reference product. If the biosimilar demonstrates PK similarity to the reference product, coupled with favourable analytical and functional data, the developer can proceed directly to comparative clinical studies at the same dose approved for the original mAb [4]. Immunogenicity studies are also required to demonstrate that a biosimilar mAb does not present significant differences in immunogenicity compared to the reference product. The last step in applying for approval of a biosimilar is the same as with originator biologicals, i.e. to present a risk management plan [2]. This includes a pharmacovigilance plan and risk minimization measures based on the experience gained with the reference product.

Once the biosimilar has shown similarity with the reference product in terms of quality, preclinical data, and PK/PD, and has demonstrated equivalent efficacy and similar safety in at least one of its approved indications, the European Medicines Agency (EMA) allows the evidence for the biosimilar to be extended to other indications approved for the reference product, on the basis of the experience gained with the product. Under EMA regulations, the following conditions must be met in order to allow extrapolation:

(a) The mechanism of action should be mediated by the same target molecule in both indications;

(b) The biosimilar must have demonstrated equivalence with the reference product in comparative studies conducted in a sufficiently sensitive population to detect differences between the two, if any;

(c) If the indications fall within different therapeutic areas, and the mechanism of action, posology and/or PK of the biosimilar differ from those of the reference product, additional studies may be necessary;

(d) The biosimilar must have demonstrated a safety profile comparable to that of the reference product in the evaluated indication; and

(e) The biosimilar should undergo additional immunogenicity studies [2, 4].

EMA does not provide recommendations on interchangeability with the originator biological, although it advises involving prescribers in the final decision by the Member States. The joint position of EMA and the European Commission (EC) is that Member States must decide whether biologicals and their respective biosimilars are interchangeable [2].

Biosimilars of mAbs available in the EU for the treatment of inflammatory diseases and cancer have fulfilled all the requirements for approval, and many of them have additional evidence available. Moreover, real-world data confirms the safety and efficacy of these drugs in the indications they are being used for. In Spain, many scientific societies endorse the regulatory pathway of biosimilars and their role in the efficiency of the healthcare system [5, 6]. Nonetheless, some barriers limit their use. The implementation of different measures at the patient, prescriber, institutional, and national levels might increase the penetration of biosimilars in the health system, freeing up resources that may be invested in other therapies and, potentially, boost innovation.

Conflict of interest
Several of the authors of the research paper [1] reported conflicts of interest, including having received financial support from pharmaceutical companies for attending meetings and/or congresses, or for educational programmes or have received speaker/advisory board honoraria. For full details of the authors’ conflicts of interest, see the research paper [1].

Abstracted by Miguel Ángel Calleja-Hernández, Pharmacy Department, Hospital Universitario Virgen Macarena, Seville, Spain.

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References
1. Calleja-Hernández MÁ, Martínez-Sesmero JM, Santiago-Josefat B. Biosimilars of monoclonal antibodies in inflammatory diseases and cancer: current situation, challenges, and opportunities. Farm Hosp. 2020;44(3):100-8.
2. European Medicines Agency, European Commission. Biosimilars in the EU. Information guide for healthcare professionals. [cited 2020 Sep 4]. 
3. O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. Eur J Clin Pharmacol. 2019;75(1):1-11.
4. Liu MRJ, Ramchandani M, Landa D, Born T, Kaur P. Developing the totality of evidence for biosimilars: regulatory considerations and building confidence for the healthcare community. BioDrugs. 2017(31):175-87.
5. GaBI Online - Generics and Biosimilars Initiative. Spanish gastroenterologists update biosimilar position statement [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Sep 4]. Available from: www.gabionline.net/Biosimilars/General/Spanish-gastroenterologists-update-biosimilar-position-statement
6. GaBI Online - Generics and Biosimilars Initiative. Spanish pharmacists publish biosimilar position statement [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Sep 4]. Available from: www.gabionline.net/Reports/Spanish-pharmacists-publish-biosimilar-position-statement 

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