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BioRationality: Calling on Developers to Help Address Remaining Biosimilar Issues



Sarfaraz K. Niazi, PhD, summarized the citizen petitions he's filed to the FDA as well as changes he believes are needed to propel the biosimilar industry into the future, including calling on biosimilar manufacturers to help.

Developing biosimilars can be very expensive and time consuming, costing manufacturers hundreds of millions of dollars in development and research costs.

Developing biosimilars can be very expensive and time consuming, costing manufacturers hundreds of millions of dollars in development and research costs.

In May 2018, I filed a citizen petition to the FDA. I asked for a comprehensive review of the biosimilar guidelines to bring more rationality and scientific understanding of the testing required to approve biosimilars.The FDA responded 6 months after the filing on November 1, 2018, stating that it needed more time to review the requests made in the petition, even though a reply is expected within 120-180 days.1 The FDA did take some actions.

  1. This Petition suggested that the FDA adopt scientific principles to conclude the arguments for removing animal toxicology testing. The Biologics Price Competition and Innovation Act (BPCIA) was amended at the end of 2022, removing the term “animal toxicology” and replacing it with “nonclinical testing.” I feel that this decision was out of the FDA’s jurisdiction, and I suggested a legislative action that I had promoted working with the US Senate.2
  2. The Petition had suggested removing the flawed statistical testing models. The FDA withdrew pivotal guidance, “Statistical Approaches to Evaluate Analytical Similarity,” and issued a new guideline in May 2019, “Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry.” This guideline removed the tier 1 testing that was challenged in the citizen petition as nonscientific.The statistical issue related to testing critical quality attributes, such as protein content and potency, requires the 90% CI of biosimilar attributes to fall within 1.5 times the standard deviation in the reference product. The contradiction came because these attributes also meet the release specification that is fixed and different.3
  3. Began an extensive teaching program about biosimilars for all stakeholders. This action by the FDA has brought significant change in the perception of the safety of biosimilars.4
  4. Denied recommendations, including removing the 4-letter suffix system to identify all biologic drugs, not just biosimilars. I feel that the argument that this differentiation is needed to monitor post-market data is irrelevant because the registration numbers assigned to products should be sufficient to meet this requirement. However, having gone far, it is unlikely and perhaps unnecessary to question this ruling by the FDA.
  5. Issued a new guideline, “Labeling for Biosimilar and Interchangeable Biosimilar Products,” removing the identification if it is approved as an interchangeable biosimilar, stating that the interchangeable status is a legal description and not a quality differentiation.5 Thus, the information is only available only on the Purple Book.

To bring FDA’s attention, I filed a follow-on citizen petition on September 1, 2023 to address the following remaining issues:6

  • Allowing a non-US comparator product that is approved using essentially the same dossier as the US-licensed reference product.
  • Declaring to the public that biosimilars have “no clinically meaningful difference” from the originator product and thus, it should be acceptable for naïve patients and even substituted with reference products or other biosimilar products.

Recognizing that there are 2 quality attributes: one related to the product dependent on the expression system relatively invariable and the other to the process that can be tailored to match the reference product within limitations. The product-related attributes are critical, while the process-related attributes are part of release specification, such as the protein content and potency, they should not be made part of the analytical assessment exercise, as expected by the FDA. The release specifications should be based on reference product attributes except for the legacy attributes related to the dosage form, such as protein content, potency, particle size, subvisible particles, sterility, etc. The product-related attributes are expected to be the least variable, and these can be tested using a smaller number of lots. The release specification is then established using the number of lots required depending on the variability of the attributes. For example, more lots will be required to establish post-translational modifications but not for impurities that can be well accepted as legacy attributes if there are no unmatched impurities. Many of these suggestions will reduce the time and cost of developing biosimilars.

  • Allowing developers to submit in vitro immunogenicity testing data to reduce exposure of test subjects on ethical grounds. The FDA is advancing in developing this complex science of predicting immunogenicity using in vitro methods, promoting vitro immunogenicity assays.7
  • Making pharmacokinetic study protocols more creative and in a parallel design to avoid creating immune responses.
  • Declaring that pharmacodynamic markers unrelated to clinical response need not be tested and discovered by Omics technologies.8
  • Removing the testing of clinical efficacy in patients, following the example of the United Kingdom’s Medicines and Healthcare products Regulatory Agency.
  • Removing the interchangeable status of biosimilars. This will take legislative action; however, the FDA has declared that a product approved as interchangeable cannot list this status on the label since this is not a quality issue—a significant change, but the issue remains until this status is removed. Several bills are in the Senate to amend the BPCIA.
  • Removing objections to the US Pharmacopoeia developing monographs and test methods.The FDA had issued a letter to the United States Pharmacopoeia (USP) not to create monographs for biologic drugs. “Because USP'sproposed revisions would aggravate existing concerns that a monograph could impede or delaythelicensure of biosimilars and otherbiological products, FDA strongly encourages USP to withdraw its proposal.

Enforcing the inclusion of patent information about biologics and FDA regulatory exclusivity information in the "Purple Book" database was a direct consequence of the Purple Book Continuity Act implemented by the FDA.9 The enhanced database will offer novel prospects for industry professionals to identify (1) prospective partnerships for the licensing of current intellectual property, (2) fresh strategies for the enforcement and safeguarding of intellectual property, and, potentially, (3) avenues for the advancement of new technology.

Removing the ability for companies to engage in the “patent dance” through legislative action. This will require a legislative action that is highly sought after in the US Congress.10 Still, the forces of the originator companies have successfully prevented this from happening.

I am optimistic that major regulatory agencies will harmonize the approval regulations to enable developers to secure global selling rights, making the development cost more affordable. I would welcome those with the same mission to comment on my petition or write to the FDA, particularly biosimilar developers and their associations, such as the Biosimilars Council. My proposals are not drawn from just cost-saving intentions; these are to remove any unnecessary testing of humans to enable compliance with the Helsinki Agreement and to enable broader entry of biosimilars.


  1. The FDA Docket frequently asked questions (FAQs). FDA. Accessed September 22, 2023. https://www.fda.gov/files/about%20fda/published/The-FDA-Docket-Frequently-Asked-Questions.pdf
  2. Niazi S. End animal testing for biosimilar approval. Science. 2022;377(6602):162-163. doi:10.1126/science.add4664
  3. Robers NF. Scientist invented a new pathway to approve biosimilars, and the FDA is listening. Forbes. Accessed September 22, 2023. https://www.forbes.com/sites/nicolefisher/2018/07/25/one-mans-mission-to-fix-the-fdas-biosimilar-problem/?sh=16c83e562380
  4. Biosimilars. FDA. Updated March 1, 2023. Accessed September 22, 2023. https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/biosimilars
  5. FDA. Labeling for biosimilar and interchangeable biosimilar products; Draft guidance for industry; Availability. Fed Reg. 2023;88(179):63957-63960. https://www.federalregister.gov/documents/2023/09/18/2023-20141/labeling-for-biosimilar-and-interchangeable-biosimilar-products-draft-guidance-for-industry
  6. https://www.regulations.gov/document/FDA-2023-P-3766-0001 Citizen petition from University of Illinois, College of Pharmacy. FDA. September 1, 2023. Accessed September 22, 2023.
  7. Pharmacodynamic biomarkers: Their role in biosimilar product development. FDA. Updated April 3, 2023. Accessed September 22, 2023. http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm246804.htm
  8. https://www.fda.gov/drugs/news-events-human-drugs/pharmacodynamic-biomarkers-their-role-biosimilar-product-development (accessed 22 September 2023) Medicare Advantage demographics report. FDA. February 2015. Accessed September 22, 2023.
  9. H.R. 1520, Purple Book Continuity Act of 2019. House Committee on Energy and Commerce. May 3, 2019. Updated April 3, 2019. Accessed September 22, 2023. https://www.cbo.gov/publication/55203
  10. https://www.congress.gov/bill/116th-congress/house-bill/133 H.R.133 - Consolidated Appropriations Act, 2021. Congress.gov. January 3, 2019. Updated December 21, 2020. Accessed September 22, 2023.
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