Table 2.

Definitions of interchangeability across geographies

Location	Regulatory authority	Health authority position on interchangeability	Statutory/legal definition of interchangeability	Responsibility for implementation	Key takeaway
USA	FDA	FDA determines a biological product to be interchangeable with a reference product if (1) the biological product “is biosimilar to the reference product” and “can be expected to produce the same clinical result as the reference product in any given patient” and (2) “for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch” [11]	Yes, through BPCIA 2009	Individual states	Auto-substitution
European Union	EMA	“Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect…. Replacement can be done by:  Switching, which is when the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent  Substitution (automatic), which is the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber” [16]	Noa	Member states	Physician-directed switching or auto-substitution
Australia	TGA	No formal definition of interchangeability. However, “brands that can be substituted by the pharmacist are indicated in the Schedule of Pharmaceutical Benefits by an ‘a-flag’ (a small ‘a’). Only a-flagged medicines can be substituted by the pharmacist” [20]	Nob	PBAC	Auto-substitution
Canada	Health Canada	“…the term ‘interchangeability’ often refers to the ability for a patient to be changed from one drug to another equivalent drug, by a pharmacist, without the intervention of the prescriber who wrote the prescription. Health Canada's authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug” [86]	Noc	Individual provinces and territories	Auto-substitution
Brazil	Anvisa	Not defined. Interchangeability considered to be a matter of clinical practice [87]	–	Physicians	Physician-directed switching
Japan	PMDA	Not defined. Interchangeability considered to be a matter of clinical practice [88]	–	Physicians	Physician-directed switching

BPCIA Biologics Price Competition and Innovation Act, FDA Food and Drug Administration, EMA European Medicines Agency, PBAC Pharmaceutical Benefits Advisory Committee, PMDA Pharmaceuticals and Medical Devices Agency, TGA Therapeutic Goods Administration

^aDecisions regarding interchangeability fall to the governing bodies of EMA member states

^bDecisions regarding interchangeability are made by the PBAC, a government body tasked with recommending drugs for reimbursement

^cDecisions regarding interchangeability are made in accordance with the rules and regulations of individual Canadian provinces and territories