The Chinese regulator calls for the proof to come “through different stages.” For drugs determined as biosimilars “with no or little difference, as proven from comparability testing, some subsequent comparability tests may be exempted; for those with great differences or uncertain factors, the effect on the products shall be evaluated, sensitive techniques and method designs shall be adopted to carry out a specific comparability test at a later stage, and the effect on the products shall also be evaluated.”
However, for biosimilar candidates determined either as “similar to the reference drugs in a comprehensive pharmacological comparative trial or as similar to the reference drugs in the non-clinical stages,” the SFDA says that “only the pharmacological comparability test may be considered in the future; for those drugs whose similarity could not be proven, a specific study or comparability test for clinical safety shall be carried out.”
This aligns with EU guidance, though the EU has most recently said that reference drugs in biosimilar trials may just be “representative” of a product already approved in the EEA, whereas the Chinese draft makes no mention of these considerations for drugs approved outside China.
The US, however, which released its draft guideline in May, seems to go further than the Chinese or EU regulators by creating four categories for the agency’s comparative analytical characterization: not similar, similar, highly similar and highly-similar with fingerprint-like similarity.
The Chinese are broader in this sense, noting that: “The amino acid sequences of candidate biosimilars shall be the same as those of the originator drugs. Candidate biosimilars with host cells and expressing systems different from the originator drugs during R&D shall be subject to a full validation.”
The Chinese regulators also call for comparability tests for at least three batches, and during the study, “validated, sensitive and advanced analysis techniques and methods shall be adopted to test the potential differences between candidate drugs and reference drugs.”
In case the differences from the pharmacological comparability test impact the products and are verified by the results of the non-clinical study, “a systematic comparability test shall be carried out in the future,” the SFDA says.
The China draft also notes that for products modified with polyethylene glycol and antibody-coupled drugs, “the R&D of these products as biosimilars requires serious consideration.”
And as far as the non-clinical comparability test, the SFDA say that it should “be carried out, especially for those with cell matrix and impurities different from the respective reference drugs. It is feasible that the comparability test is carried out only for pharmacodynamics (PD), pharmacokinetics (PK) and immunogenicity in case of no or minor differences between candidate drugs and reference drugs in the pharmaceutical comparability test.”