Biosimilar Development Process

Biosimilarity is established by a combination of many different types of head-to-head comparisons, including structure, function (also known as activity), animal testing and human clinical testing.

Biosimilar development is a stepwise approach where the proposed biosimilar is compared head-to-head with the reference biologic. The first step is analytical characterization of structure and function, followed by animal testing and then human clinical testing. This testing ensures matching safety, purity, and potency, with no clinically meaningful differences from the reference biologic.1,2  This multi-step process is called the “Totality of Evidence.”  

Analytical characterization

  • Multiple batches of the reference biologic are procured over time.1
  • Reference biologic is analyzed and characterized with highly sophisticated and innovative analytical tools that use a variety of techniques to measure multiple parameters in multiple ways.1,3
  • These data are then used to create the acceptable range of variability or “goalpost” for the biosimilar.1

Structural and function confirmation1,5-7

  • The biosimilar is formulated with a primary amino acid sequence that is 100% identical to that of the reference biologic.
  • All structural and functional elements of the biosimilar are compared with those of the reference biologic with powerful analytical tools to show that the biosimilar is highly similar to its reference biologic.

Watch How Sandoz Engineers Biosimilars to Match the Reference Biologic

Preclinical data5

Confirms tolerability and dosing.

Clinical data

  • Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) studies demonstrate that the biosimilar is statistically indistinguishable from the reference biologic in terms of how the drug behaves in the body and how the body reacts to the drug.1,5  PK studies determine what happens to the drug in the body, while PD studies determine what happens in the body in response to the drug.
  • Phase 3 confirmatory studies are performed in patients who have conditions that can clearly show differences in safety or efficacy, if any such changes exist.1
  • Because of unavoidable differences in the manufacturing processes, a biosimilar is not likely to be entirely identical to the reference molecule.8 However, the manufacturer must prove that any differences that may exist have no impact on safety or on how the drug works.
 
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References: 1. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91:405-417. 2. Przepiorka D, Deisseroth A, Lee K, Nie L. Clinical Trial Review presented at: FDA Oncologic Drugs Advisory Committee Meeting; January 7, 2015; Silver Spring, MD. https://wayback.archive-it.org/7993/20170405222944/https://www.fda.gov/d.... Accessed October 7, 2020. 3. Tsuruta LR, Lopes dos Santos M, Moro AM. Biosimilars advancements: moving on to the future. Biotechnol Prog. 2015;31(5):1139-1149. 4. Schiestl M. A biosimilar industry view on the implementation of the WHO guidelines on evaluating similar biotherapeutic products. Biologicals. 2011;(39):297-299. 5. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015. https://www.fda.gov/download s/drugs/guidances/ucm291128.pdf. Accessed October 7, 2020. 6. Visser J, Feuerstein I, Stagnier T, et al. Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab. BioDrugs. 2013;27(5):495–507. 7. da Silva A, Kronthaler U, Koppenburg V, et al. Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013. Leuk Lymphoma. 2014;55(7):1609-1617. 8. Weise M, Bielsky M-C, De Smet K, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-5117.

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