Each biosimilar will represent a distinct therapeutic choice and come to market with a unique data package, approved indications, and routes of administration.1 The patient support services offered for each and the capabilities of the specific manufacturer are also likely to differentiate which medicines healthcare providers choose.

Because of the distinct choices biosimilars represent, it is imperative for healthcare providers to understand key usage concepts and the unique aspects of each biosimilar, including functional data and/or clinical data, to ensure safe, effective prescribing and use practices.1

New patient initiation on a biosimilar

New patients requiring use of a reference product may be initiated on a prescribed biosimilar. The basis for this is the assumption that:1,2

  • The “totality of evidence,” along with scientific justification supporting extrapolation, has demonstrated that the biosimilar has matched the critical quality attributes and the function of a reference product
  • Based upon evidence supporting approval, the patient is anticipated to experience no clinically meaningful differences in the efficacy, safety, and immunogenicity of the biosimilar as compared with the reference product

Switching typically refers to a physician-guided exchange of one medicine for another with the same therapeutic intent in patients who are undergoing treatment.3,4

  • If a biosimilar has adequately demonstrated that patients can be transitioned, or switched, from a reference medicine to its biosimilar with no additional risk introduced and similar efficacy maintained, it may be appropriate to switch a patient with the consent of a treating physician
  • However, repeated switching between different biologic medicines, including biosimilars of the same product that are not designated as interchangeable (US only), should be avoided 

Substitution is a practice wherein a pharmacist may dispense an alternative biologic medicine for a prescribed biologic medicine without the prior approval of the prescriber. Certain state US law specifies that in order to be eligible for substitution, the biosimilar must be designated as “interchangeable.”5

The US biosimilars pathway offers the opportunity for a drug manufacturer to demonstrate “interchangeability,” which is a separate standard than “biosimilarity,” and requires additional evidence to achieve.1,5,6

  • An interchangeable biologic is a biosimilar that the FDA has determined is safe for a pharmacist to substitute for the reference biologic product without the intervention of the prescriber
  • To obtain an interchangeability designation, a biosimilar must be expected to produce the same clinical result as the reference product in any given patient
  • According to US regulators, obtaining a designation of interchangeability will include, among other things, successfully conducting switching studies in which patients alternate between the reference and biosimilar products with no loss in efficacy, safety, or immunogenicity versus continued use of the reference product
  • As a general rule, automatic substitution is usually permitted with generic small molecules where the FDA has determined the two products to be therapeutically equivalent 

Unlike the US, the European Medicines Agency (EMA) has the ability to approve a product as biosimilar, but does not evaluate biosimilars for interchangeability designation. In Europe, the term “interchangeable” typically refers to physician-directed changing of medicines for another medicine in the same class, also commonly referred to as switching.  Although European countries are exploring measures to facilitate pharmacy-level substitution of biologics, most European nations currently prohibit that use of biosimilars.7

Variation in Global Substitution Guidelines


  1. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411-419.
  2. Kozlowski S. US FDA Perspectives on Biosimilar Biological Products. Presented at: 2014 Biotechnology Technology Summit; June 13, 2014; Rockville, MD.
  3. Lai Z, La Noce A. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. RMD Open. 2016; 2:e000154.
  4. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed November 23, 2016.
  5. US Food and Drug Administration. Information on Biosimilars. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars. Accessed November 22, 2016.
  6. US Food and Drug Administration. Information on Biosimilars. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm. Updated August 27, 2015. Accessed November 23, 2016.
  7. Data on file, Amgen; 2015.
  8. Health Canada. Questions & Answers To Accompany the Final Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/01-2010-seb-pbu-qa-qr-eng.php. Accessed July 29, 2010.
  9. US Department of Health and Human Services. Considerations in demonstrating interchangeability with a reference product: Guidance for industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed January 25, 2017.
  10. NCSL. State laws and legislation related to biologic medications and substitution of biosimilars. http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx. Accessed December 28, 2016.
  11. Arthritis Foundation. Ohio biosimilar substitution bill signed into law by Governor Kasich. http://blog.arthritis.org/advocacy/arthritis-biosimilar-substitution-ohio. Accessed December 28, 2016.
  12. FIMEA. Interchangeability of Biosimilars – Position of Finnish Medicines Agency Fimea. https://www.fimea.fi/documents/542809/838272/29197_Biosimilaarien_vaihtokelpoisuus_EN.pdf. Accessed November 30, 2016.
  13. Niederwieser D, Schmitz S. Biosimilar agents in oncology/haematology: from approval to practice. Eur J Haematol. 2011;86:277-288.
  14. Generics and Biosimilars Initiative. Legislation on biosimilar interchangeability in the US and EU—developments far from visibility. http://www.gabionline.net/Sponsored-Articles/Legislations-on-biosimilar-interchangeability-in-the-US-and-EU-developments-far-from-visibility. Accessed January 25, 2017.
  15. Generics and Biosimilars Initiative. Australia’s PBAC recommends substitution of biosimilars. http://www.gabionline.net/Biosimilars/General/Australia-s-PBAC-recommends-substitution-of-biosimilars. Accessed January 25, 2017.
  16. Goodwin Big Molecule Watch. July 2016 PBAC meeting—positive recommendations. http://www.bigmoleculewatch.com/wp-content/uploads/2016/08/positive-recommendations-2016-07.pdf. Accessed January 25, 2017.