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Adoption of Biosimilars—Why the Delay?

January 2023 Vol 16, No 1
Scott A. Soefje, PharmD, MBA, BCOP, FCCP, FHOPA
Director, Pharmacy Cancer Care, and Assistant Professor of Pharmacy, Mayo Clinic, Rochester, MN; HOPA Past President, 2016-2017
Reprinted from Soefje S. Adoption of Biosimilars—Why the Delay? J Hematol Oncol Pharm. 2022;12(3):117-118. Copyright © The Lynx Group. Reprinted with Permission.

Biosimilars have been available in the United States for more than 5 years, and in Europe for more than 15 years, yet we still see reluctance in the adoption of these drugs.1 The question is, why? It has clearly been shown that biosimilars reduce healthcare costs.2 Yet, a recent survey has shown that oncologists still have many misconceptions about biosimilars.3

The US Food and Drug Administration (FDA) defines a biosimilar as a drug with no clinically meaningful differences in safety, purity, and potency from the reference drug.4 Nevertheless, the barriers to the adoption of biosimilars that providers often mention are the concerns about the safety and efficacy of biosimilars.5

Providers often say to me that they cannot recommend a biosimilar drug for a particular disease state, because there is no clinical trial to support its use, which suggests that they want head-to-head clinical trials that compare biosimilars and their reference drugs.

I have even known providers who suggest that they could not use a biosimilar for the treatment of a rare disease, because there were no comparative data between the biosimilar and the reference drug. Once I reminded them that there were no clear data to support the use of the reference drug either, they relented, and we have successfully used the biosimilar.

This reluctance to use biosimilars clearly shows a lack of understanding of the concept of extrapolation. “The purpose of a biosimilar development program is to support a demonstration of biosimilarity between a proposed product and a reference product, including an assessment of the effects of any observed differences between the products, but not to independently establish the safety and effectiveness of the proposed product.”4

Thus, the idea of extrapolation is at the heart of the FDA’s abbreviated pathway for the approval of biosimilars. As described by Nabhan and colleagues, the FDA defines extrapolation this way: “If the total evidence in the biosimilar application supports a demonstration of biosimilarity for at least one of the reference product’s indications, then it is possible for the biosimilar manufacturer to use data and information to scientifically justify approval for other indications that were not directly studied by the biosimilar manufacturer.”6

When deciding if an indication can be included in the biosimilar’s extrapolated indications, the FDA reviews the biosimilar’s mechanism of action to determine several criteria, including if its proposed mechanism is what leads to a response or to adverse events; if its pharmacokinetics and pharmacodynamics are similar to the reference drug; if there is no difference in immunogenicity; and if no unexpected adverse events have been observed.4 If the biosimilar meets these criteria, the biosimilar’s indications can be extrapolated to all indications, except orphan drug and other regulatory-protected indications.4

Because generic drugs are approved based on bioequivalence data7—and we have been using extrapolation with generic drugs for years without incident—why do we hesitate to do so with biosimilars? I am familiar with all the arguments, such as that biosimilars are more complex than small-molecule generics, yet the FDA testing that is required to show no clinically meaningful differences between a biosimilar and its reference drug4 should be sufficient. In addition, those of us who are old enough to remember when generic drugs were first released into the marketplace may recall that the same argument was made then; nevertheless, generic drugs currently make up nearly 90% of the market, and they have saved billions of dollars for the US healthcare system.8

We also have to remember that all biologics are subtly different from lot to lot, because of the manufacturing processes.9,10 The FDA allows variations even within the reference drug’s lots; therefore, if the biosimilar is within the variation range, which is required to be demonstrated for approval, then we should be more than confident that the biosimilar will not have meaningful clinical differences from the reference drug.4,9,10

In the June 2022 issue of the Journal of Hematology Oncology Pharmacy, Bartels and colleagues analyze real-world data of the clinical outcomes between a granulocyte colony-stimulating factor (G-CSF) biosimilar and the 2 reference drugs used in patients who have undergone autologous stem-cell transplantation for stem-cell mobilization.11

This single-center, retrospective study examined 116 unique adult patients, 52 of whom received a G-CSF biosimilar and the others received 1 of the 2 reference drugs, to analyze the stem-cell mobilization success, which was defined as the percentage of patients who achieved a target number of cells (ie, ≥2 × 106 CD34-positive cells/kg of body weight) within 7 days, regardless of plerixafor use. Treatment with plerixafor was allowed if the predetermined collection parameters were not met each day. Bartels and colleagues also examined the number of CD34 cells collected, the total dose of G-CSF, plerixafor use, and the time to the engraftment of neutrophils and platelets.11

In this study, the biosimilar was noninferior to the reference drug. The percentage of patients who met the study’s objective was slightly higher in absolute terms in the biosimilar group, but the difference was within the predefined 11% noninferiority margin. No significant differences were observed in the secondary end points between the 2 study groups.11 This study of real-world data adds to the literature, supporting the claim that the use of biosimilars produces efficacy and safety comparable to the reference drug, and that biosimilars are producing the results that were expected.

The question is—why do we even need to conduct these types of studies? The FDA’s approval pathway clearly defines clinically meaningful differences between biosimilars and their reference drugs,4 and studies such as the one by Bartels and colleagues are only proving what the FDA has already approved.

When reviewing biosimilars, the assessment of analytic similarity is the most important aspect to review: Does the biosimilar drug show the same mechanism of action as the reference drug? Are the pharmacokinetic and pharmacodynamic data similar between the biosimilar and the reference drug? And can the manufacturer reliably produce the biosimilar?12 The data from biosimilar clinical trials are only confirmatory data.

Once the data used for the FDA approval are shown by the manufacturer to be the same for the biosimilar and the reference drug, we could clearly treat biosimilar drugs as we do generic drugs for the purpose of policy and economic considerations. Given some clinicians’ reluctance to prescribe biosimilars, however, we may need to complete more of the real-world data type of studies as done by Bartels and colleagues to get to a level of acceptance finally in which biosimilars are being used without hesitation.


  1. Humphreys SZ. Real-world evidence of a successful biosimilar adoption program. Future Oncol. 2022;18:1997-2006.
  2. Jensen CJ, Tichy EM, Lempke MB, et al. Implementing and optimizing biosimilar use at Mayo Clinic. Mayo Clinic Proc. 2022;97:1086-1093.
  3. Peipert J, Kaiser K, Kircher SM, et al. Oncologists’ knowledge and perspectives on the use of biosimilars. J Clin Oncol. 2021;39(28 suppl):Abstract 35.
  4. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. April 2015. Accessed April 21, 2022.
  5. Edgar BS, Cheifetz AS, Helfgott SM, et al. Overcoming barriers to biosimilar adoption: real-world perspectives from a national payer and provider initiative. J Manag Care Spec Pharm. 2021;27:1129-1135.
  6. Nabhan C, Velley A, Feinberg BA. Barriers to oncology biosimilars update in the United States. The Oncologist. 2018;23:1261-1265.
  7. US Food and Drug Administration. What is the approval process for generic drugs? August 31, 2017. Accessed April 21, 2022.
  8. Woodcock J. Testimony: prioritizing public health: the FDA’s role in the generic drug marketplace. September 26, 2016. Accessed April 21, 2022.
  9. Ramanan S, Grampp G. Drift, evolution, and divergence in biologics and biosimilars manufacturing. BioDrugs. 2014;28:363-372.
  10. Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production? Rheumatology (Oxford). 2017;56(suppl 4):iv14-iv29.
  11. Bartels T, Klanderman M, Rogers J, et al. Comparing single-center outcomes between reference and biosimilar granulocyte colony-stimulating factor drugs used for autologous stem-cell mobilization. J Hematol Oncol Pharm. 2022;12(3):119-127.
  12. Lemery SJ. When one is a hammer, everything looks like a nail. J Oncol Pract. 2017;13(9 suppl):10s-11s.

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