What is a biosimilar?

In March 2015, the U.S. Food and Drug Administration (FDA) approved the first biosimilar in the United States. Since then, FDA biosimilar approvals have slowly increased over the years: 3 in 2016; 5 in 2017; 7 in 2018; and 7 through July 2019.

A biosimilar is a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that has no clinically meaningful differences in terms of safety, purity, or potency from an existing FDA-approved reference product.1

  • To ensure that a biosimilar is highly similar, state-of-the-art technology is used to compare characteristics of the products, such as purity, chemical identity, and bioactivity. The biosimilar manufacturer uses results from these comparative tests, along with other information, to demonstrate that the biosimilar is highly similar to the reference product2 (see Table 1)

    • Minor differences in clinically inactive components are acceptable, as well as minor within-product lot-to-lot variability inherent during the manufacturing process of any biologic, be it a biosimilar or a reference product
  • To demonstrate that no clinically meaningful difference exists in safety and efficacy, human pharmacokinetics and pharmacodynamics studies must be conducted, along with an assessment of clinical immunogenicity, and, if needed, additional clinical studies2

Table 1: Parameters Evaluated When Characterizing Biosimilars and Reference Products3
  • Aggregation
  • Amino acid sequence
  • Degradation profile for stability
  • Functional properties (bioassays, binding, enzyme kinetics)
  • Molecular weight
  • Heterogeneity
  • High order structure
  • Impurity profile
  • Posttranslational modifications
  • Secondary, tertiary, and quaternary structure

Biosimilars versus generics

While the concept of generics and biosimilars may seem comparable, and both are approved via abbreviated approval pathways, these two alternatives to brand-name medications differ greatly:

Due to the highly technical process of developing large biologic molecules (see Figure 1), biosimilars are not required to be identical, but must be proved to be highly similar to the reference product.2,4

  • Generic medicines are small molecules that use the identical active ingredient, and must demonstrate bioequivalence to the reference product2,4

    • Bioequivalence suggests that the generic drug has similar pharmacokinetic parameters, such as area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), and absorption lag time (tlag), to the reference agent

Biosimilar development and approval processes

While biosimilars are licensed (approved) by the FDA under section 351(k) of the Public Health Service Act (PHS Act) enacted in 1944, the Biologics Price Competition and Innovation Act, via the Affordable Care Act of 2010, created an abbreviated licensure pathway for biosimilar products under the PHS Act.5

There are currently 600 biosimilar trials being conducted, with at least 146 unique molecules.Biosimilars trials are primarily focused on oncology therapy, with a 36% share, and immunology treatment comprises 21% of the pipeline, which means that these two segments account for more than half of the total trials.

The abbreviated approval pathway for biosimilars focuses on different aspects of the regulatory pathway (see Figure 2).6

  • Unlike reference originator biologics, which direct most of their efforts in clinical studies to assess dosing, efficacy, and safety, the biosimilar approval process centers around characterization as the foundation of the development program

  • Animal studies (nonclinical) can aid in assessing toxicity, resolve any uncertainties remaining after the characterization, and include pharmacokinetics and pharmacodynamics studies

  • Pharmacokinetics, pharmacodynamics, and immunogenicity studies are also required in healthy people

  • Finally, comparative trials with a population diagnosed with an approved indicated disease must demonstrate clinical efficacy and safety that shows no clinically meaningful differences

Biosimilar dispensing

Unlike the typical generic agents dispensed at a pharmacy for self-administration, current FDA-approved biosimilars require infusions. These infusions usually take place at a hospital, doctor’s office, or independent infusion center, and on occasion at a patient’s home, via home health services.


The basis of biosimilar development approval for a condition is the demonstration of highly similar chemical and biological parameters to the reference product, not on efficacy. Therefore, unlike reference products, where expanding a drug’s indications requires years of testing in target disease population, testing of biosimilars can be conducted in one disease population, and if approved, results can be “extrapolated”, and based on indications of the reference drug.3,7,8

Are long-available reference products “biosimilars” of their approved versions?9-11

By nature, highly complex biologic agents, produced by living cells and developed through an intricate, multistep manufacturing process, are more sensitive to changes in any step of the manufacturing process (see Figure 3).

  • Manufacturing evolution: Known changes in the manufacturing process can lead to changes in a biologic’s attributes, and some could shift outside of established acceptable ranges. It is not uncommon for reference biologics to go through a number of manufacturing process changes, with some undergoing over 20 changes since FDA approval. Although in some cases regulators may require new clinical trials after such process changes are made, they are more likely to request recharacterization of the molecule, and often will rely on surveillance efforts to identify important clinical or safety signals

  • Manufacturing drift: Unintended or unexplained changes in manufacturing processes can also occur and may lead to deviations in product attributes, which can result in a shift in quality

  • Manufacturing divergence: Varying types of manufacturing changes may occur across facilities (different regions or countries), producing deviant forms of the same biologic

Thus, it is important to recognize that over time these changes in the reference biologic manufacturing process are essentially producing “biosimilars” of the originally approved product.


  1. Biosimilars action plan: balancing innovation and competition. U. S. Food & Drug Administration website. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM613761.pdf. Updated July 2018. Accessed July 25, 2018.
  2. Biosimilars. U.S. Food & Drug Administration website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm.
    Updated November 14, 2017. Accessed February 16, 2018.
  3. Gerrard TL, Johnston G, Gaugh DR. Biosimilars: extrapolation of clinical use to other indications. GaBI J. 2015;4:118-124.
  4. Camacho LH, Frost CP, Abella E, Morrow PK, Whittaker S. Biosimilars 101: considerations for U.S. oncologists in clinical practice. Cancer Med. 2014;3:889-899.
  5. Purple Book: lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. U.S. Food & Drug Administration website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Updated February 2, 2018. Accessed February 16, 2018.
  6. Olech E. Biosimilars: rationale and current regulatory landscape. Semin Arthritis Rheum. 2016;45:S1-S10.
  7. Tesser JRP, Furst DE, Jacobs R. Biosimilars and the extrapolation of indications for inflammatory conditions. Biologics. 2017;11:5-11.
  8. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124:3191-3196.
  9. Ramanan S, Grampp G. Drift, evolution, and divergence in biologics and biosimilars manufacturing. BioDrugs. 2014;28(4):363-372.
  10. Mehr SR, Zimmerman MP. Is a biologic produced 15 years ago a biosimilar of itself today?  Am Health Drug Benefits. 2016;9(9):515–518.
  11. Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013;72(3):315-318.