BioRationality—The Evolution of the BPCIA and the Bright Future of Biosimilars in the US

The Biologics Price Competition and Innovation Act of 2010 (BPCIA) was approved within the approval for the Affordable Healthcare Act, yet it contained many elements that would slow the entry of biosimilars. Fourteen years later, the BPCIA and guidelines based on the BPCIA have changed significantly, reducing development costs. Here is a brief history of major events and future projections:

1998-2006: As the possibility of cheaper biologic drugs began to take shape, attempts were made by Congress to create a new class of biologic drugs, but all these attempts failed¹ during this time period. Multiple bills were presented to Congress, but they went nowhere under the intense opposition of Big Pharma companies. The legislative debate began in earnest in late 2006, when the first comprehensive bill was introduced, but this remained in limbo with solid lobbying from Big Pharma to stop it.

2006-2010: BPCIA, in its various forms, was tossed around. It was finally approved under the Affordable Healthcare Act, but it still contained many requirements that would bring the development cost to $100 million to $300 million and 5 to 8 years to get approval². The first biosimilar was approved by the FDA 6 years after the introduction of the BPCIA with great debate and concern about a filgrastim biosimilar product that had already been approved in the EU (Zarzio; Sandoz), where a significant issue was the analytical comparison. The FDA had established a guideline with tier 1 testing statistics for critical attributes that was completely irrational, but that required Sandoz to conduct dozens of studies.

2018: The FDA withdrew controversial statistical grouping in analytical testing after staunch criticism from experts in the space, including myself when I filed a Citizen Petition³. The FDA replaced the guideline, changing the terminology to “analytical assessment” rather than “comparison.”

2019: Filgrastim products were the first ones that the FDA agreed to waive efficacy testing in patients. The FDA also allowed it for other products where pharmacodynamic markers are available. Later, the FDA refined this policy, suggesting that developers find pharmacodynamic markers. Currently, developers can suggest PD markers in place of efficacy testing⁴.

2019: Immunogenicity testing was a major issue with initial biosimilars; however, all proteins are immunogenic, and it is only when an immune response alters the disposition kinetics that it matters, and that rarely happens if the primary structures are identical. FDA finally agreed and removed such testing for insulin and all other products where the PK is affected due to antidrug antibody formation⁵.

2022: Animal toxicology testing is mentioned in the BPCIA, and biosimilar applicants have conducted hundreds of such tests, but the FDA has not reviewed many. Senator Ben Ray Luján (D, New Mexico) started a mission to remove it from the BPCIA. The Bill later came out as the FDA Modernization Act of 2002 that removed the term “toxicology” and replaced it with “nonclinical.” Unfortunately, biosimilar developers continue to conduct such studies⁶.

2023: FDA published papers conducting studies on biosimilars to suggest that developers discover pharmacodynamic properties to compare with reference products when they are not known⁷; I was a reviewer of this paper and strongly opposed this non-scientific suggestion since not all PD markers will correlate with efficacy response and published a paper to advise the FDA⁸. FDA has not responded to this challenge and continues to support the idea of discovering PD markers^9,10.

2022: The classification of interchangeable biosimilars was questioned by several senators, including Senator Mike Lee (R, Utah) and now also by Senator Rand Paul, MD (R, Kentucky).

2024: While the Senators are trying to amend the BPCIA to remove interchangeability,¹¹ the FDA decided that biosimilars can receive interchangeability status without extensive switching studies¹². This FDA guideline essentially removed interchangeability yet maintained its status and complications, such as the exclusivity period. I anticipate the BPCIA will remove interchangeability in 2025, leaving an allowance for carrying over exclusivity to products with this status. It’s also recommended that the FDA allow the use of approved biosimilars as reference products; this change will significantly reduce the development cost.

2024: The FDA issued a new guideline that allows a more scientific approach to compare the glycan profiles¹³ of antibodies as biosimilars. This will significantly reduce the cost of developing products undergoing post-expression translation.

2024: The FDA issued a guideline that provides details of how biosimilars can request newer indications of their approved products when these are not included in the reference product. This has opened doors to “hybrid biosimilars” where a biologics license application (BLA) is assigned to a biosimilar without extensive testing except the claimed efficacy. This opens doors for significant return on investment for biosimilar manufacturers.

2024: The US Senate passed a bill¹⁴ to remove double patenting as the reference products reach their patent expiry to block the entry of biosimilars.

2024: The FDA has made additional changes in response to my suggestions, allowing for the addition of new indications to approved biosimilars without requiring a new BLA. The July 2024 guideline provides these opportunities, significantly boosting the development of biosimilars.

2025: The FDA is anticipated to follow the European Medicines Agency and the UK’s Medicines and Healthcare products Regulatory Agency guidelines to waive efficacy testing of biosimilars, but it will not be as a guideline but as it is advice to developers to present arguments why no additional clinical testing is not required, following the Biosimilar Action Plan.

2025: The FDA is requested in a petition and through a significant publication¹⁵ to remove the restrictions on the US Pharmacopeia (USP) to create monographs of biologic drugs that will remove the need for analytical assessment of biosimilars. The FDA was concerned of the intellectual property issues and reference product modifications. However, the USP could create release specifications and provide validated test methods to remove the need for side-by-testing biosimilars with their reference product. Should the FDA consider this change, even partially, this will cut down one of the most expensive and time-consuming elements of the development of biosimilars.

What started as an expensive development has come down significantly. By 2025, the cost of developing biosimilars will be no more than what it currently costs for any 505(b)(2) development. This will mean that many companies will be able to enter the biosimilar market, bringing significant competition that will lead to a price drop of around 80% to 90%, and at this stage, Big Pharma now controlling biosimilars in the US will walk out; the history will repeat what happened when the generic drugs were introduced.

I am looking forward to it.

References

1. Carver KH, Elikan J, Lietzan E. An unofficial legislative history of the Biologics Price Competition and Innovation Act of 2009. Food Drug Law J. 2010;65(4):671-818.

2. Fontanillo M, Körs B, Monnard A, et al. Three imperatives for R&D in biosimilars. McKinsey & Company. Published August 19, 2022. Accessed October 7, 2024. https://www.mckinsey.com/industries/life-sciences/our-insights/three-imperatives-for-r-and-d-in-biosimilars

3. FDA. Citizen Petition from Pfizer Inc. Requesting the FDA to Refrain from Taking Certain Actions that Would Impair the Market for Biosimilar Products. May 14, 2018. FDA-2018-P-1876-0001. Accessed October 7, 2024. https://www.regulations.gov/document/FDA-2018-P-1876-0001

4. Niazi SK. Support for removing pharmacodynamic and clinical efficacy testing of biosimilars: a critical analysis. Clin Pharmacol Drug Dev. 2023;12(12):1134-1141. doi:10.1002/cpdd.349

5. FDA allows waiver of clinical trials for insulin biosimilars as recommended in Niazi citizen petition. Pharmaceutical Scientist. Press release; December 3, 2019. Accessed October 7, 2024. https://www.prnewswire.com/news-releases/fda-allows-waiver-of-clinical-trials-for-insulin-biosimilars-as-recommended-in-niazi-citizen-petition-300968231.html

6. Niazi SK. Analysis of FDA-licensed biosimilars: time for a paradigm shift. The Center for Biosimilars^®. July 11, 2020. Accessed October 7, 2024. https://www.centerforbiosimilars.com/view/analysis-of-fda-licensed-biosimilars-time-for-a-paradigm-shift

7. Chiu K, Racz R, Burkhart K, et al. New science, drug regulation, and emergent public health issues: the work of the FDA's division of applied regulatory science. Front Med (Lausanne). 2023;9:1109541. doi:10.3389/fmed.2022.1109541

8. Niazi, SK. A critical analysis of the FDA’s omics-driven pharmacodynamic biomarkers to establish biosimilarity. Pharmaceuticals. 2023;16(11):1556. doi:10.3390/ph16111556

9. Pharmacodynamic biomarkers in biosimilar development and approval. FDA. September 20, 2021. Updated July 20, 2021. Accessed October 7, 2024. https://www.fda.gov/drugs/news-events-human-drugs/pharmacodynamic-biomarkers-biosimilar-development-and-approval-09202021-09212021

10. Pharmacodynamic biomarkers: their role in biosimilar product development. Updated April 3, 2023. Accessed October 7, 2024. https://www.fda.gov/drugs/spotlight-cder-science/pharmacodynamic-biomarkers-their-role-biosimilar-product-development#:~:text=A%20biosimilar%20product%20(biosimilar)%20is,biological%20product%20(biologic)%20treatments

11. Lee seeks increased competition in biological drug market. Senator Mike Lee’s website. July 23, 2023. Accessed October 7, 2024. https://www.lee.senate.gov/2023/7/lee-seeks-increased-competition-in-biological-drug-market

12. Postapproval manufacturing changes to biosimilar and interchangeable biosimilar products questions and answers. FDA. Guidance document; July 23, 2024. Accessed October 7, 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postapproval-manufacturing-changes-biosimilar-and-interchangeable-biosimilar-products-questions-and

13. Niazi SK, Omarsdottir S. Lectin-based fluorescent comparison of glycan profile-fda validation to expedite approval of biosimilars. Int J Mol Sci. 2024;25(17):9240. doi:10.3390/ijms25179240

14. Niazi SK. BioRationality: Bill to Remove Double Patenting That Harms Biosimilars Heads to the House. The Center for Biosimilars. August 12, 2024. Accessed October 7, 2024. https://www.centerforbiosimilars.com/view/biorationality-bill-to-remove-double-patenting-that-harms-biosimilars-heads-to-the-house

15. Niazi, SK. Advice to the US FDA to allow US Pharmacopeia to create biological product specifications (BPS) to remove side-by-side analytical comparisons of biosimilars with reference products. Pharmaceutics. 2024;16(8):1013. doi:10.3390/pharmaceutics16081013