BioRationality: No More Biosimilars—Just Biogenerics

Since the 2004 European Medicines Agency (EMA) biosimilar guidelines, the world has gained 64 FDA and 92 EMA approvals, often repeated for several molecules. It is now well established that physicochemical and in vitro biological comparison of biosimilars with their reference products is sufficient to ensure their clinical safety and efficacy.¹ I have presented this proposition to EMA, FDA, and the UK’s Medicines and Healthcare products Regulatory Agency, including suggestions to engage the US Pharmacopeia to reduce the cost of development further.²

Biosimilars are required to demonstrate bioequivalence with the reference product, just as it is mandated for some generic drugs using the same protocols. This proof is more than enough to indicate that any subtle structural differences between molecules, which are inevitable between batches anyway, do not alter the disposition profile and, thus, the activity of the drug.

The EMA clearly states, "Clinical data cannot be used to justify substantial differences in quality attributes.³” So, on the one hand, according to the regulators, clinical data are not allowed to justify differences seen in physicochemical and biological comparative studies. On the other hand, the regulators have withheld clear guidance that clinical efficacy testing should not be required. It is not only a waste of financial resources, but it is also tantamount to human abuse since the greater the similarity between products, the more patients will need them, introducing a methodological paradox.

The efficacy of biological drugs in any indication is based on their affinity toward the biomolecule it binds, which can be precisely quantified in cell-free experiments that measure the binding constants when different proportions of the ligand and receptor are present in the solution. These data are more objective than any clinical response. Other in vitro tests ensure the safety of protein drugs in their injectable form. However, the zeal to demonstrate similarity results in over 1000 test results, as shown in the filings of each biosimilar, is a wasteful, redundant exercise based on a total misunderstanding of the nature of biological drugs and the fear of mismatching promoted by the reference product developers.

The misunderstanding goes further into selecting critical quality attributes comprising the release specifications, resulting in redundant testing. If the primary sequence matches, so should most of the efficacy and safety elements of the molecule, and this comparison is easier to make without having to test multiple lots of reference products. The same holds for other attributes that are not variable and dependent on the primary structure.

The time has come for the regulatory agencies to declare biosimilars as biogenerics.⁴ There is already a precedence; the FDA considers peptides smaller than 40 amino acids as a chemical drug subject to approvals through the abbreviated novel drug pathway. I think biosimilars should take the same path if the companies that make them can be rational and not get cautioned by conflict of interest. I see a day when the 299 biological drugs and 35 recombinant vaccines will have biogenerics affordable to the remaining 80% of the world deprived of them.

References

1. Doevendans E, van Meer P, Schellekens H. The devolution of biosimilars regulations. Nat Biotechnol. 2025;43:19-22. doi:10.1038/s41587-024-02497-5

2. Niazi, S.K. 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, 1013. https://doi.org/10.3390/pharmaceutics16081013

3. Guidance on the licensing of biosimilar products. Medicine & Healthcare products Regulatory Agency. Updated November 7, 2022. Accessed October 15, 2024. https://www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products/guidance-on-the-licensing-of-biosimilar-products

4. Niazi, SK. Biosimilars: Harmonizing the approval guidelines. Biologics. 2022;2:171-195. doi:10.3390/biologics2030014