The draft guidance on clinical immunogenicity testing for insulin products is indeed a historic event: a bold step by the FDA that shows a determination that there is a need to bring into market lower-cost alternates to the reference products if the clinical studies that contribute to the majority of cost and time are not required.
The Section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) requires that on March 23, 2020, an approved application for a biological product under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) will be deemed to be a license for the biological product under section 351 of the PHS Act (42 U.S.C. 262).
In anticipation of the licensing of insulin products under the BPCIA in 2020, the FDA has recently issued draft guidance on the clinical immunogenicity testing as part of the biosimilarity determination for biosimilars. To be licensed as a biosimilar, an application submitted under section 351(k) must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies demonstrating that the proposed biosimilar is highly similar to the reference product, animal studies, and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics); the FDA has the discretion to determine that an element described in section 351(k)(2)(A)(i)(I) is unnecessary.
The FDA has concluded that, because insulins are relatively smaller-sized biologics that are structurally uncomplicated and have few post-translational modifications, they can be well-characterized analytically to leave little residual uncertainty regarding the risk of clinical impact from immunogenicity.
The FDA further states that there is minimal or no clinical relevance of immunogenicity with insulin product use. The FDA determination comes from:
Based on the premise presented above, the FDA determined that the current analytical tools used to evaluate quality attributes for insulin products can support a comprehensive analytical comparison that leaves little residual uncertainty regarding immunogenicity and that has minimal or no risk of clinical impact from immunogenicity. In such cases, a comparative clinical immunogenicity study would generally not be necessary to support the licensure of a proposed biosimilar or interchangeable product.
The FDA now recommends that, to secure licensing under the 351(k), the developers will need to provide:
Of greatest significance is a clear direction to developers that a comparative clinical immunogenicity and efficacy study is not required if the analytical assessment supports high similarity. Further, the design of clinical pharmacology study need not be complicated if the duration of action is determined based on reliable measures of systemic exposure and glucose response.
The draft guidance on clinical immunogenicity testing for insulin products is indeed a historic event: a bold step by the FDA that shows a determination that there is a need to bring into market lower-cost alternates to the reference products if the clinical studies that contribute to the majority of cost and time are not required.
I anticipate FDA issuing similar assessments of other biological products like the cytokine inhibitors that too fall in a similar category of highly characterizable products, and particularly the products that have little immunogenicity risk, like the filgrastim.
An ending thought remains: Why did it take the FDA 4 years to accept the thesis that is already practiced in European Union? Perhaps it was the inevitable pressure to make insulins more affordable. The fact is that, unless we have this level of clarity, it will be difficult to make biosimilars more accessible.
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