Table 1.

Main differences between biosimilars and generic medicines.

	Biosimilars	Generics	Ref.
Product characteristics	- Large complex molecules (up to 270,000 Da)	- Small and simple molecules (up to 300 Da)	[5]
Production	- Produced using live organisms (highly sensitive to manufacturing changes) - 5–9 years - High production costs	- Produced by chemical synthesis - 2–3 year - Lower production costs	[5,21]
Structural comparison to reference medication	- Highly similar to the RP: same amino acid sequence; - There may be differences in minor parts of the structure	- Structurally identical to the reference medicine	[4,5,12]
Development	- Comparability studies between the biosimilar and the RP	- Bioequivalence between the generic and the RP is evaluated	[4,22]
Nomenclature	- Rules vary from country to country	- Same chemical name (active ingredient) as the reference medicine	[12,16,18,23]
Requirements for approval	- Animal and clinical studies (toxicity, PK, PD, and immunogenicity)	- No animal or clinical studies (only bioequivalence studies) - The active ingredient must be identical in strength, dosage form, and route of administration	[3,5,12,23]
Post-authorization activities	- Pharmacovigilance (PV)	- Phase IV, risk management plan including PV	[9,18,24,25,26]
Immunogenicity	- Immunogenic	- Mostly nonimmunogenic	[23,24,25,27]
Equivalence	- Data must demonstrate, in each indication, that clinically significant differences, related to safety and efficacy, are not verified - Conclusive clinical studies may not be necessary for all indications	- Demonstration of bioequivalence is enough to grant all approved indications for the RP, without requiring any additional clinical studies	[5,12,18,23,26]
Interchangeability and substitution	- EMA see biosimilars to be scientifically interchangeable (2022), but any decision on the use of biosimilars is the mandate of the EU member states - FDA can designate a biosimilar interchangeable if a sponsor applies for this (but it is up to US State Law to permit substitution at pharmacies) - Automatic substitution is generally the decision of each country	- If permitted by state law, pharmacists may automatically substitute the generic for the reference medicine	[2,18,23,27,28]