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"Biosimilars" Under the 505(b)(2) Pathway

Earlier this month, the FDA approved the biosimilar Zarxio (filgrastim-sndz) for sale in the United States.  This approval – the first of its kind under the so-called 351(k) pathway – comes nearly five years after the pathway was created by the Biologics Price Competition and Innovation Act (“BPCIA”).

Prior to the passage of the BPCIA and to this day, another regulatory pathway, the 505(b)(2) pathway, could be used to obtain approval of certain follow-on biologics.  Like the 351(k) pathway, the 505(b)(2) pathway allows the applicant to rely on the safety and effectiveness data of a previously-approved product.  The 505(b)(2) pathway, while largely used to obtain approval of small-molecule drugs, has been used on several occasions to obtain approval of biologics that are similar to the reference product and marketed as biosimilars in Europe.

What is the 505(b)(2) Pathway?

505(b)(2) application is an application for approval of different dosage forms, formulations, or combination products of already-approved drugs , but can also be available for approval of biologics that are similar to, and rely on information contained in, a previously-approved New Drug Application (NDA).

The 505(b)(2) pathway is available for a relatively narrow category of biologics – specifically, those that had been approved under an NDA before the BPCIA was signed into law in March 23, 2010 – and it is only available for that narrow category of biologics until March 23, 2020.  See § 7002(e) of the Affordable Care Act (ACA).

But for the biologics that fit into this category, the 505(b)(2) pathway offers a pathway for marketing approval.  Notably, any product approved under the 505(b)(2) pathway will be considered approved under the 351(k) pathway once the ten-year phase-in period is complete.  Id. at § 7002(e)(4).

What are the differences between the 505(b)(2) and 351(k) pathways?

Fundamentally, the 351(k) pathway concerns products that are regulated as biologics under the BPCIA, while the 505(b)(2) pathway concerns products that are regulated as drugs under the Food Drug & Cosmetic Act (FD&C).  The pathways involve vastly different regulatory frameworks.  The table below summarizes some of these differences.

Approval under 351(k)

Approval under 505(b)(2)

Available for

Available for
Drugs and certain biologics

Biosimilarity to a reference product (highly similar to reference product, no clinically meaningful differences)

Proof of safety and efficacy

BPCIA ( “patent dance”)

Hatch-Waxman (30-month stay)

Market Exclusivity
Limited market exclusivity for the first interchangeable biosimilar against other interchangeable biosimilars

Market Exclusivity
Likely not applicable for “biosimilars” though five years of new chemical exclusivity has been awarded for recombinant versions of previously animal-derived products

505(b)(2) Example Cases

A number of biologics have been approved under the 505(b)(2) pathway.  Examples of five 505(b)(2) products, all produced by recombinant DNA technology, are discussed in the table below.

505(b)(2) Product


(insulin glargine injection)

In August 2014, FDA granted tentative approval for Eli Lilly’s Basaglar™, a recombinantly produced insulin glargine for treating diabetes. As a 505(b)(2) product, approval relied in part on clinical studies carried out for Sanofi's Lantus (insulin glargine).  Basaglar™ does not have final approval due to Hatch-Waxman litigation involving Sanofi's patents and the associated 30-month stay.   Time to tentative approval was quick, however, coming to exactly ten months.  The same product was approved as a biosimilar in 2014 in Europe.

Omnitrope® (somatropin for injection)

In its 2006 decision to approve Sandoz’s Omnitrope, a recombinant growth hormone replacement therapy, FDA addressed and rejected citizen petitions from Pfizer, the Biotechnology Industry Organization (BIO), and Genentech opposing Omintrope’s approval.  FDA’s decision to approve Omnitrope set forth the required level of similarity between Omnitrope and the reference product, Pfizer’s Genotropin, for approval under the 505(b)(2) pathway.   Notably, Omnitrope was approved as a biosimilar in Europe in 2006.

Hylenex® (hyaluronidase human injection)

In December 2005, less than nine months after submission of the 505(b)(2) application, FDA approved Hylenex, a recombinant version of human hyaluronidase.  Hylenex is marketed by Baxter and facilitates subcutaneous fluid administration.  At the time Hylenex was approved, ovine-derived hyaluronidase was marketed as Vitrase by ISTA Pharmaceuticals, Inc.  Despite the fact that Vitrase was FDA-approved, FDA concluded that Hylenex was a new chemical entity compared to the prior versions of hyaluronidase and awarded Hylenex five years of market exclusivity

Fortical® (calcitonin-salmon)

FDA approved Unigene's Fortical® (recombinantly produced calcitonin-salmon) in August 2005 as a 505(b)(2) product.  Unigene’s application relied on the regulatory filings for Novartis's Miacalcin® (calcitonin-salmon synthetic), a treatment for osteoperosis.  Novartis submitted a citizen petition, asking FDA to deny Fortical approval because Unigene’s 505(b)(2) application did not provide both (1) two years of bone mineral density data and (2) at least the minimal fracture data that FDA required for Miacalcin.  Highlighting the lesser regulatory burden for a 505(b)(2) application compared to a NDA, the FDA denied Novartis's petition, stating that this data was not necessary for the approval of Fortical.

GlucaGen® (glucagon injection)

One of the first 505(b)(2) biologics, Novo Nordisk’s GlucaGen®, was approved in June 1998.  GlucaGen is a recombinant version of glucagon.  Novo Nordisk relied on the NDA for Glucagon USP (derived from purified beef and pork pancreas) for GlucaGen’s approval.  Years after GlucaGen was approved, FDA used GlucaGen as an example of how the 505(b)(2) route could be used to obtain approval of follow-on biologics.  Novo Nordisk objected, saying that GlucaGen was a case of “extraordinary circumstances” and that ordinarily, the 505(b)(2) route should only be used for “chemically-derived” drugs.  The FDA rejected Novo Nordisk’s position in its decision granting approval to Omnitrope® (see above).   


The 505(b)(2) pathway offers marketing approval for certain “biosimilars” – at least for the next five years. In addition to a more predictable regulatory pathway, the litigation pathway for 505(b)(2) products is more familiar and predictable as well.

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