**3. Conclusions**

The pharmacovigilance of biologics undoubtedly presents complexities that are not unique to "conventional drugs." It is an evolving science that will undoubtedly need to be implemented since knowledge about these drugs continues to expand. The peculiarities of these drugs make the monitoring of biologics and biosimilars a real challenge for regulatory agencies, manufacturers, and patients. Specific aspects of these drugs are immunogenicity, differences between batches from different manufacturers, and the definition of similarity and interchangeability or substitutability, all of which are undoubtedly important for the safety and the pharmacovigilance of these drugs [34]. An emblematic example is the number of cases between 1998 and 2004 of pure erythroid aplasia caused by autoantibodies due to a manufacturing modification that increased the immunogenicity of an erythropoiesis-stimulating agent [11, 35]; however, with three similar products on the market, the real challenge was to identify which specific agent was causing the problem [36]. As is well known, the development of biosimilars not only reduces the cost of healthcare by reducing drug costs by 20–30% [37] but also increases the number of marketing authorizations and consequently the access to such therapies, as demonstrated by a study on 21 European countries that showed that the average cost of erythropoietin fell by 35% from 2006 to 2013 [3]. Yet, as highlighted by a recent review [6], healthcare professionals still approach biosimilars with great caution and sometimes stigmatization, and, in particular, are generally opposed to multiple "switches" and interchangeability. Moreover, many treatment discontinuations with biosimilars seem to be linked to the nocebo effect [38]. Clinicians should, however, take into account the principle that no two biologics are identical, even if they are produced by the same manufacturer, as each biologic is different from another in itself [39]; they should also consider that regulations on biosimilars (unlike those on generics) are stringent and rigorous and this in itself is a guarantee (although not a certainty) of high-quality standards. Healthcare professionals and patients should, therefore, have a coherent, comprehensive, and unbiased view of the biosimilar. Still, to do so, their knowledge needs to be updated appropriately through effective and continuous training programs promoted by the various national regulatory agencies. Nevertheless, it is also necessary to collect more and more reassuring data on biologics in general and on interchangeability (and the possible induction of immunogenicity related to it), which is still the central dilemma among clinicians and stakeholders. It is also essential to consider that immunogenicity could be a consequence of several factors, such as the underlying disease, genetic background, age, and immune status, including immunomodulatory therapy, route of administration, dosing schedule, frequency, and duration of treatment, posttranslational modifications, formulation, and impurities. Finally, it is essential to develop educational tools regarding the ADR reporting process for biological products, including the appropriate use of the specific product name and batch number, and reflect on the possibility of making such data more easily accessible to the clinician/or pharmacist.
