Table 1: Summary of key regulatory pathways and requirements for biosimilar approval.

Requirement Regulatory authority
WHOa-c EMA (EU)d,e FDA (US)f-i
Approval pathway/ development • Reference product (RP) must be licensed in region/ country where biosimilar approval is sought
• Biosimilar authorization is based on a stepwise comparability exercise
o Quality studies: head-to-head comparisons of quality and heterogeneity (e.g., physicochemical, biological, immunochemical properties); documented manufacturing process; stability studies
o Non-clinical studies: Pharmacokinetic (PK), Pharmacodynamic (PD), and toxicological
o Clinical studies: clinical comparability exercise (i.e., PK/PD studies followed by pivotal clinical studies to show comparable safety/effectiveness/ immunogenicity)
• Varying amounts of data may be requested by individual national regulatory authorities
• Post-marketing surveillance is required		 • Abbreviated approval pathway
  o EU-wide marketing authorization granted via centralized EMA procedures
  o Requires manufacturer submission of a Marketing Authorization Application (MAA)
  o MAA evaluated by EMA’s Committee for Medicinal Products for Human Use, Pharmacovigilance and Risk Assessment Committee, and Biologics/Biosimilar Working Parties
• Data required from stepwise comprehensive comparability studies
  o Pharmaceutical and comparative quality studies
  o Comparative non-clinical studies
  o Comparative clinical studies of safety/efficacy, PK/PD, and immunogenicity
• If biosimilarity is shown, safety/efficacy findings from clinical trials of the RP may be used to support MAA
  o Allows for shorter and less costly drug development program
• Post-marketing surveillance is required		 • Abbreviated approval pathway
  o Created by the Biologics Price Competition and Innovation Act under the Affordable Care Act in 2010 (§351[k], Public Health Service Act)j
  o Requires manufacturer submission of a Biologics License Application (BLA)
o BLA evaluated by the FDA’s Centers for Drug/Biologics Evaluation and Research
• Data required from 3 study types
  o Analytical studies (e.g., physicochemical, functional properties)
  o Non-clinical studies (e.g., toxicology)
  o Clinical studies (e.g., PK, PD, immunogenicity)
• If biosimilarity is shown, safety/efficacy findings from clinical trials of the RP may be used to support BLA
  o Allows for shorter and less costly drug development program
• Post-marketing surveillance is required
Extrapolation • If biosimilarity is shown, the biosimilar may obtain approval for other clinical indications of the RP, even if not directly assessed in clinical trials
• Scientific justification required		 • If biosimilarity is shown, the biosimilar may obtain approval for other clinical indications of the RP, even if not directly assessed in clinical trials
• Scientific justification required		 • If biosimilarity is shown, the biosimilar may obtain approval for other clinical indications of the RP, even if not directly assessed in clinical trials
• Scientific justification required
Interchangeability/
switching/ substitution		 • No guidance
• Practices to be defined by national authorities		 • No guidance
• Practices to be regulated by legislation in individual EU countries		 • Interchangeability requires data from 3 transitions from reference to biosimilar product
• Switching requires data from 1 transition from RP to biosimilar
Nomenclature • Reference and related biosimilar products share same nonproprietary name (i.e., the International Nonproprietary Name [INN])
• Reference and related biosimilar products will have unique “biological qualifier” (BQ) added to the INN (2015 proposal)
  o BQ = 4 random lower-case consonants
• Example (fictitious)
  o SBP = replicamab-jnzt
  o RBP = replicamab-kngx		 • Reference and related biosimilar products have distinct proprietary names
• Reference and related biosimilar products share same nonproprietary name (i.e., INN)
• Example (actual)
o Biosimilar = Remsima® (infliximab)
o RP = Remicade® (infliximab)
• Proprietary names and batch numbers should appear on product packaging		 • Reference and related biosimilar products have distinct proprietary names
• Reference and related biosimilar products have a non-proprietary proper name that combines a shared core name plus a unique suffix
  o Core name = the name selected by the US Pharmacopeial Convention for the active substance (same for biosimilar and RP)
  o Suffix = 4 random lower-case letters attached to the core name by a hyphen (distinct for biosimilar and RP)
• Example (fictitious)
  o Biosimilar = replicamab-jnzt
  o RP = replicamab-kngx

aReference [10]. bReference [21]. cReference [44]. dReference [11]. eReference [20]. fReference [12]. gReference [22]. hReference [23]. iReference [45]. jReference [48]. EMA: European Medicines Agency; EU: European Union; US FDA: United States Food and Drug Administration; RP: reference product; WHO: World Health Organization.