14th June 2018

Biosimilars Approval: Opportunities and Challenges

Biosimilars (also called follow-on biologics) are biologics medicines that are “highly similar” to an FDA-approved biological product, known as a reference product.

Biosimilars Approval: Opportunities and Challenges

What are biosimilars and what makes them different from generic medicines?

Biosimilars (also called follow-on biologics) are biologics medicines that are “highly similar” to an FDA-approved biological product, known as a reference product.

Unlike most small-molecule drugs, which are chemically synthesized with highly predictable structures and functions, biologics and biosimilars are pharmaceutical compounds synthesized or extracted from a biological source, often with much more complex structures.

Thereby, unlike generic medicines in which the active ingredients are identical to the reference small-molecule drug, biosimilars, under the U.S. law, are approved based on the demonstration of a “highly similarity” to the reference products. That said, and as mentioned in our previous blog post, biosimilars are drugs that have:

  • An amino acid sequence identical or nearly identical to the reference products
  • A secondary/tertiary structure sufficiently similar to the reference products
  • No clinically meaningful differences relative to the reference products in terms of safety, purity, and potency.

As is the case for generic medicines, the availability of biosimilars is anticipated to contribute to more affordable treatment options and to increase patient access to necessary prescription medications.

Biosimilars, A Growing Market

The immense impact of biologics on patients facing serious and life threating diseases is well recognized. Millions of patients are now receiving biologics to treat various conditions such as immunological, cardiovascular, hematological, dermatological, eye, metabolic disorders, infectious diseases, or cancer. To date, more than 200 biologic products are approved for use in the U.S1 ., and the market continues to grow. Since 2011, sales of these biologics have increased by ~ 64 %.2

Since the creation of the biosimilar regulatory pathway as part of the Patient Protection and Affordable Care Act in 2010, biosimilars have slowly emerged. To date, there are 11 biosimilar products that are FDA-approved3 .

Innovative Science Solutions (ISS), as a leader in this field, played an important role in the approval of the first biosimilar, Zarxio® (Filgrastim-sndz) in 2015 and has been involved in the development of many more since. As of December 2017, The FDA reported that there are 59 biosimilar product development programs underway4 .

Based on product development programs underway and the current market trends, the global biological medicines (biologics and biosimilars) market is anticipated to surpass ~ USD 300 billion by 20225 and to reach ~$400 Billion By 20256 , with gains in market share for biosimilars.

Evaluation and Approval Processes of Biosimilars: Key Concepts

The FDA has developed clear regulatory guidelines for the evaluation and approval of biosimilars regarding their physical, chemical and clinical traits7 .

  • Assessment of analytical similarity

Important factors for consideration in assessing analytical similarity includes: expression system, manufacturing process, assessment of physicochemical properties, functional activities, receptor binding and immunochemical properties, impurities, and finished drug product stability.

The goal is to identify and evaluate the impact of differences on safety, purity, and potency.

  • Nonclinical evaluation

Nonclinical toxicity and kinetic data could be useful when uncertainties remain about the safety of the proposed product prior to initiating clinical studies

The scope and extent of animal toxicity and kinetic studies depend on publicly available information and/or data submitted in the biosimilar application related to the reference product and the proposed biosimilar product, and the extent of known similarities or differences between the two.

  • Clinical evaluation

The nature and scope of clinical studies depend on the extent of residual uncertainty about the biosimilarity to the reference product after conducting extensive structural and functional characterization and, where relevant, nonclinical studies.

The Agency expects adequate clinical PK, and PD if relevant, comparisons between the proposed biosimilar product and the reference product.

The Agency usually seeks at least 1 clinical study that includes a comparison of the immunogenicity of the proposed and reference product generally.

The Agency looks for at least one comparative clinical study to support a demonstration of biosimilarity if there are residual uncertainties about whether there are clinically meaningful differences between the proposed and reference products based on structural and functional characterization, animal testing, human PK and PD data and clinical immunogenicity assessment

Demonstrated biosimilarity is different from “stand-alone” product development.

Analytical similarity data is the foundation of biosimilar development. This first step contributes to understanding the relationship between quality attributes and the clinical safety and efficacy profile; aids to determine residual uncertainty about biosimilarity, and is essential to predict expected “clinical similarity” from the quality data.

The nature and scope of the nonclinical and clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after the analytical similarity assessment.

Overall, the totality of the evidence supports the demonstration of biosimilarity.

ISS has almost two decades of experience in developing regulatory strategies, including support for FDA Advisory Committee meetings and has been involved in several biosimilar programs including the first biosimilar FDA approval. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies.

For more information on how ISS can help you prepare for your next meeting, contact info@innovativescience.net.


1. U.S. Food and Drug Administration Biological Approvals by Year. Accessed June 1, 2018; www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicalApprovalsbyYear/
2. QuintilesIMS Institute; Medicines Use and Spending in the U.S. A Review of 2016 and Outlook to 2021; May 2017
3. U.S. Food and Drug Administration Biosimilar Product Information,  Accessed June 1, 2018; www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580432.htm
4. U.S. Food and Drug Administration, Cumulative number of biosimilar development programs in the BPD Program in the month, accessed June 1, 2018; www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cder&status=public&id=CDER-RRDS-Number-of-biosimilar-dev-programs-in-BPD-Program&fy=All
5. Global Biologics Market to Surpass 300 Billion by 2022 with accelearated new launches in Oncology; https://www.prnewswire.com/news-releases/global-biologics-market-to-surpass-300-billion-by-2022-with-accelerated-new-launches-in-oncology-300619374.html
6. www.grandviewresearch.com/press-release/global-biologics-market
7. U.S. Food and Drug Administration, FDA Webinar – FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US, accessed June 1, 2018; www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm428730.htm

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