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BioRationality: A Dr Sarfaraz Niazi Column—FDA Launches Biosimilar Regulatory Science Program


Sarfaraz K. Niazi, PhD, dived into the benefits of the FDA's recently announced Biosimilar Regulatory Science Program, which is expected to help progress biosimilar development and simplify evaluations for interchangeability status.

Recently, the FDA unveiled a significant effort to streamline the approval of biosimilars. For the first time, the new website highlights how the development of biosimilar products can be advanced and how the interchangeable product evaluation can be simplified and made more practical.

The FDA has made a significant shift in its priorities, as explained below:

  • Enhancing the identification and risk assessment of the relevant product, excipient, and container closure attribute.
    • While the risk assessment of the product is well known, the FDA bringing in the issue of excipient and container closure attributes resonates with the difference in PRCA (pure red cell aplasia) from erythropoietin held in uncoated and coated stopper formulations since the biosimilars are allowed to have different formulations.[1],[2] This point is well-covered in my publications suggesting the developers not to use any excipient that has not been used before for the particular drug or other biological drugs.[3] But, of course, this also applies to interchangeable products.
  • Better define acceptable attributes and differences between the reference product and the proposed biosimilar product.
    • This has been a critical issue with previous FDA guidelines wherein the analytical similarity limits for attributes differed from the variation in the release specifications. This will substantially reduce the analytical assessment burden.
  • Advancing analytical tools to detect relevant differences;
    • The FDA has recently awarded a multimillion-dollar grant to the University of Michigan to create newer technologies for analytical assessment such as thermodynamics of secondary and tertiary structure, post-translational modification assessment, and using artificial intelligence to correlate 3D structure with the primary sequence as a measure of immunogenicity potential; I am a participant in this grant.[4] Given the significant increase in the sensitivity of analytical methodologies, it would be expected that more emphasis will go on this assessment.
  • Facilitating the comparative analytical assessment with enhanced statistical methodologies
    • The FDA had withdrawn its first guidance on the subject, replacing it with reduced statistical testing; here, the FDA wishes to expand the scope with more relevant tests, and this will undoubtedly improve the confidence in analytical assessment. However, the European Medicine Agency and World Health Organization are holding a different perspective on this application.
  • Advancing clinical trial design
    • Clinical pharmacology testing designs can be improved to consolidate the study in a shorter trial by modifying the inclusion criteria, as well as the basis of the design. In addition, the severe efficacy shortcomings of testing that have been well-recognized by the FDA need to be addressed to conclude whether such studies add any value to evaluating a biosimilar candidate.[5]
  • Leveraging in silico and in vitro methodologies in the comparative immunogenicity assessment
    • This is a follow-up of the Biosimilars Action Plan that remains to yield any substantial work.
  • Developing broadly applicable approaches for the use of pharmacodynamic markers
    • This is a remarkable opportunity to secure clinical efficacy waivers for all those products where a PD (programmed death) marker can be identified.
  • Researching approaches other than switching studies to meet the interchangeability standard (e.g., considering whether it might be possible to leverage real-world evidence, including health data derived from medical claims, electronic health records, data captured using digital tools, data from registries, and other sources)
    • This is the first time the FDA acknowledges that there are better approaches than switching and alternating testing that remain doubtful; the FDA has already approved one product without such testing and invited others to challenge it. Great improvement.
  • Researching the use of in vitro and in silico methods to evaluate immunogenicity that may support a demonstration of interchangeability between the reference product and the proposed interchangeable product
    • This approach applies to biosimilars and interchangeable products; the FDA has established several programs to promote replacing immunogenicity testing in naïve subjects to reduce the risk of exposure to healthy subjects.

I am looking forward to significant changes in the Biologics Price Competition and Innovation Act, but what the FDA has disclosed today should incentivize developers to present novel ideas that will reduce the cost and time to market—an essential paradigm shift needed to make biosimilars affordable. Great News!

Author Bio

Sarfaraz K. Niazi, PhD, is an adjunct professor of biopharmaceutical Sciences at the College of Pharmacy at the University of Illinois at Chicago and a patent law practitioner. Additionally, he is the founder and executive chairman at Pharmaceutical Scientist, Inc, the executive chairman of Karyo Biologics, and the founder of Adello Biologics, which was acquired by Kashiv Biosciences in 2019. Niazi also serves on the advisory board for The Center for Biosimilars®.

Link to Dr. Niazi’s last column: https://www.centerforbiosimilars.com/view/biorationality-a-dr-sarfaraz-niazi-column-the-ema-declares-biosimilars-interchangeable


[1]McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetin-associated pure red cell aplasia: Past, present, and future considerations. Transfusion. 2008;48:1754-1762. doi:10.1111/j.1537-2995.2008.01749.x

[2]Boven K, Knight J, Bader F, Rossert J, Eckardt KU, Casadevall N. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol Dial Transplant. 2005;20S:33-40. doi:10.1093/ndt/gfh1072

[3]Niazi SK. Biosimilars: A futuristic fast-to-market advice to developers. 2021:149-155. doi:10.1080/14712598.2022.2020241

[4] Niazi SK. Molecular biosimilarity-an AI-driven paradigm shift. Int J Mol Sci. 2022;23(18):10690. doi:10.3390/ijms231810690

[5] Niazi S. Scientific rationale for waiving clinical efficacy testing of biosimilars. Drug Des Devel Ther. 2022;16:2803-2815. doi: 10.2147/DDDT.S378813

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