The challenging definition of naïve patient for biological drug use

Biosimilar is defined by The European Medical Agency as a biological medicinal product, which is similar but not identical to the biological drug already authorized. The biosimilar and its reference product are expected to display the same safety and efficacy profile and are generally used to treat the same conditions. The Italian Medicines Agency considers biosimilars as a valid therapeutic option with an economic advantage, especially in primary naïve patients with no previous exposure to the originator or with a sufficiently long wash-out period ("secondary naïve"). The identification of "secondary naïve" is not well defined and can be subjected to different variables, mainly the drug biologic effect and its immunogenicity. The first one depends on the type of biologics and on their mechanism of action. The second one is related to the fact that biologicals may be immunogenic and can trigger an anti-drug antibody response (ADA). ADA may behave as neutralizing antibodies blocking the active site of the biological but can also recognize other epitopes favoring the formation of immune-complexes that eventually affect the pharmacodynamics. Moreover, the concomitant immune-suppressive treatment can affect the immunogenicity, even if the exact mechanism remains unknown. In conclusion, the development and use of biosimilars represent a tool for increasing health system sustainability. However it is of paramount importance to distinguish between the pharmacodynamics of a given drug and its immunogenicity being the two aspects unrelated. Thus a detailed definition of "secondary naïve" patients is challenging, and may be related to both the two parameters.