As we move in to 2020, FDA is fastidiously preparing for the event 10 years in the making: the transition. For those of you unfamiliar with the “transition,” it refers to the “deemed to be a license” provision of the Biologics Price Competition and Innovation Act. The 2010 statute amended the statutory definition of a “biological product” to include “a protein (except any chemically synthesized polypeptide),” and this definition is officially in effect as of March 2020. As a result, almost 100 approved NDAs will automatically transition into BLAs on March 23, 2020. On the same date, FDA will no longer accept applications under section 505 of the FDCA for protein products, and any pending drug applications (other than supplements) will receive a Complete Response.
The most notable product undergoing the “transition” is insulin. Given the high costs of insulin that limit product accessibility, FDA is anxious to get more insulin products on the market. As a drug, insulin sponsors have had difficulty scientifically demonstrating the requisite “sameness” needed for generic approval. For that reason, as well as technical advances in delivery, most insulin products were approved under 505(b)(1) or 505(b)(2) NDAs (a look at the Orange Book shows that FDA has never approved an ANDA for generic insulin). But as a biologic, putative “generic” insulin manufacturers no longer have to demonstrate “sameness” – only that their insulin products are “highly similar” to the reference product. While their products are not “generic” – and not interchangeable until sameness can be demonstrated – the 351(k) biosimilar pathway makes it a little easier for new insulin products to come to market provided that analytical studies demonstrate that there are no clinically meaningful differences between biosimilar and reference product safety, purity, and potency.
To “enable a more robust route for developing lower cost copies of insulin,” a commitment the Agency undertook under the watch of Commissioner Gottlieb and appears to be continuing under Acting Commissioner Giroir, FDA issued a draft guidance last week designed to “facilitate the development of, and improve patient access to, life-saving insulin [biosimilar and interchangeable] products.” The guidance is intended to inform developers on the data an information necessary to support a demonstration of biosimilarity or interchangeability for an insulin product. Part of the Biosimilars Action Plan, the guidance is focused specifically on “Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products.”
The guidance explains that FDA has typically recommended the submission of clinical immunogenicity studies for the approval of insulin drug products under the 505(b) pathway and that FDA has previously stated that the same is expected in any 351(k) insulin applications. However, FDA has now “updated its thinking” with respect to clinical immunogenicity studies: the Agency now believes that if a comparative analytical assessment supports demonstration of “highly similar” for a proposed biosimilar or interchangeable insulin product, there should be little uncertainty regarding immunogenicity, and comparative clinical immunogenicity studies may not be required. While this isn’t the case for all biosimilar or interchangeable insulin products and FDA will analyze on a case-by-case basis for individual applications, the presumption is no longer that such studies are required. FDA attributes this shift to “the evolution in the understanding and extensive characterization of protein products” arising from technological improvements, particularly with respect to small, well-understood, well-characterized, and structurally uncomplicated proteins like insulin.
FDA also uses this guidance to explain its expectations for data to support a demonstration of biosimilarity or interchangeability in a 351(k) for insulin. In addition to “a robust and comprehensive comparative analytical assessment demonstrating that the proposed insulin product is ‘highly similar’ to its proposed reference product with very low residual uncertainty regarding immunogenicity” and an immunogenicity assessment justifying why a comparative clinical study to assess immunogenicity is not necessary, FDA expects to see adequate chemistry, manufacturing and controls information, a comparative clinical pharmacology study between the proposed insulin product and the reference product, and a comprehensive and robust comparative analytical assessment to show that the insulin product is “highly similar” to the reference product.
While, in theory, a sponsor could submit a 351(k) aBLAs for insulin before March 2020, this can only happen if an insulin reference product is approved under a BLA. Since the “transition” of the approved insulin NDAs does not officially happen until March 2020, there is no reference product on which a biosimilar insulin application can currently rely. (Though FDA could start approving insulin products under BLAs in 2010, the Purple Book does not show any approved insulin BLAs.) Upon that transition though, when insulin becomes a valid biosimilar reference product, there will likely be many insulins vying for approval. This guidance suggests that FDA will exercise some flexibility in its requirements for biosimilar insulin, helping the agency bring additional insulin products to market more quickly in an effort to address the dire need for these products.