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The Regulation of Follow-On Biological Products via 505(b)(2)

Strike While the Iron is Hot

In December 2015, the U.S. FDA granted approval for Eli Lilly and Company’s Basaglar (insulin glargine injection), a long-acting human insulin product indicated for glycemic control in patients with diabetes mellitus. Basaglar marked the first “follow-on” insulin therapy to be approved in the U.S. through a truncated review pathway based on similar safety and efficacy findings to that of an existing drug, Lantus (insulin glargine injection). Basaglar possesses an identical amino acid sequence to Lantus, and thus Lilly successfully submitted a new drug application through the abbreviated 505(b)(2) pathway that relied, in part, on the FDA’s finding of safety and effectiveness for Lantus to support approval. Ultimately, Basaglar not only proved sufficiently similar to Lantus to scientifically justify reliance, but Basaglar-specific data (including two clinical trials enrolling 534 and 744 patients with type 1 and 2 diabetes mellitus respectively) firmly established the drug’s safety and efficacy for its approved uses.

Notably, Basaglar is considered a biosimilar of Lantus in other regions such as Europe (branded under the name Abrasia) where it received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP, a division of the European Medicines Agency) in 2014, however it was technically approved as a “follow-on” product in the United States. This may come as a surprise to many, however the reasoning behind the FDA’s decision is fairly straightforward, and is largely due to historical regulation of similar (animal- and human- derived) protein-based biopharmaceuticals (like Lantus) as drugs.

Existing Legal Basis for Regulation of Biological Products

In the U.S., two statutes currently have regulatory jurisdiction over therapeutic biological products: The Federal Food, Drug, and Cosmetic Act (21 USC § 301, FD&C), and the Public Health Services (PHS) Act (42 USC § 262; PHS). Generally, the FDA’s Center for Biologics Evaluation and Research (CBER) regulates the majority of biologics and associated biosimilar products under section 351 of the PHS Act, however a select handful of biologics that were traditionally derived from natural sources (i.e. insulin, human growth hormones,) as well as associated follow-on products are actually still regulated as drugs by the Center for Drug Evaluation and Research (CDER) under section 505 of the FD&C Act. FDA generally refers to follow-on protein products as those subsequent-generation proteins and peptides deemed to be sufficiently similar to a product already approved under the FD&C Act.

Why aren’t all biologics reviewed and regulated by CBER? At least in terms of abbreviated approval, the answer may have more to do with familiarity than anything else. Whereas the FDA asserts there already exists sufficient authority and infrastructure for follow-on protein products to be developed under section 505(b)(2) where scientifically appropriate, the infrastructure for accelerated biosimilar approval that currently exists for Section 351(k) of PHS is still somewhat nebulous. In 2010, the PHS Act was amended to create an abbreviated approval pathway for biosimilars, or biologics deemed highly similar to or interchangeable with existing approved reference biological products. This pathway, commonly referred to as the Biologics Price Competition and Innovation Act (BPCIA) of 2010, is similar in concept to that of the Hatch-Waxman Act of 1984 in that it allows reliance on previously established scientific knowledge about a drug, thereby saving time and avoiding unnecessary duplication of clinical or nonclinical testing. According to the FDA, under section 351(i) of this amendment, biological products are approved as biosimilar if a sponsor can demonstrate “high similarity” to a reference product notwithstanding minor differences in clinically inactive components and there are no “clinically meaningful” differences between the biological product and the reference product in terms of safety, purity and potency. However, many have found this concept confusing, especially what constitutes clinically meaningful, and what level of nonclinical and clinical evidence is necessary to establish “high similarity”. Consequently, the BPICA has been riddled with a host of regulatory and scientific issues, which may be why only a small handful of products have been approved since its implementation.

Choosing the Appropriate Developmental Pathway for Biologic Products

When deciding which developmental pathway to pursue for a biologic product, consider these fundamental differences that exist between the 505(b)(2) and 351(k) regulatory pathways (Table 1):


Going, Going, Gone?

The BPCIA recently changed the authority under which follow-on protein products will soon be regulated by amending the definition of a ‘biological product’ in the PHS Act to include a ‘protein (except any chemically synthesized polypeptide). On March 11, 2016, the FDA released a draft guidance on its interpretation of the “deemed to be a license” provision of the BPICA 2010. This provision (Section 7002(e)(4)) states that “An approved application for a biological product under section 505 of the Food, Drug, and Cosmetic Act (21 U.S.C. 355) shall be deemed to be a license for the biological product under such 351 [of the PHS Act] on the date that is 10 years after the date of enactment of [the BPCI Act]”. The FDA interprets this provision to mean that as of March 23, 2020, the 505(b)(2) pathway will no longer be available for biosimilar approval. Furthermore, NDA applications for biological products that have already been approved under 505(b)(2) will become Biologics License Applications (BLAs) under section 351(k). Regarding pending applications, the statute is interpreted rather conservatively: the FDA states that the BPCIA “does not provide a mechanism to transition an approved application under section 505 to an approved BLA under the PHS Act prior to March 23, 2020, or after March 23, 2020. Unfortunately, the upcoming changes will undoubtedly slow down the developmental process for new follow-on products like Basaglar that are simple enough for submission under 505(b)(2), so it may be advisable for those development programs that are 505(b)(2)-applicable to take advantage of the pathway while the opportunity is still available.

For many, the 505(b)(2) pathway may present a more streamlined regulatory option for certain follow-on protein products, but only for a limited time.  In addition to a more established and predictable regulatory pathway, 505(b)(2) offers up to 5 years of market exclusivity for products where statutory requirements are met. Premier Consulting is the global regulatory authority on 505(b)(2) submissions; for more information on how we can meet your regulatory needs, please contact us.