3.10 The 505(b)(2) versus 351(k) choice

The FDA regulatory guidance

Therefore, the first interchangeable biosimilar product could conceivably find itself competing not only with the reference product but also with one or more biosimilar products, a scenario which might seem to significantly diminish the value of obtaining an interchangeable designation. However, because an interchangeable biosimilar product does not require notification of the prescribing physician, it would likely be prescribed over a competitive biosimilar product that does require notification.

The pediatric exclusivity available to biosimilar applicants under the 351(k) pathway provides an additional six-month period of exclusivity beyond the period provided for any other applicable regulatory exclusivity (e.g., data, market or orphan drug). It does not attach to the end of any patent exclusivity protecting the product.

Prior to the passage of the BPCI Act 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. A 505(b)(2) application is an application for the approval of different dosage forms, formulations, or combination products of already-approved drugs, but can also be available for the approval of biologics that are similar to, and rely on the information contained in, a previously approved 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 BPCI Act was signed into law on March 23, 2010—and it is only available for that narrow category of biologics until March 23, 2020 (§ 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 10-year phase-in period is complete (ACA, § 7002(e)(4)). Fundamentally, the 351(k) pathway concerns products that are regulated as biologics under the BPCI Act, while the 505(b)(2) pathway concerns products that are regulated as drugs under the FDCA.

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. The pathways involve vastly different regulatory frameworks. Table 3.5 summarizes some of these differences. 105

Biosimilarity: The FDA Perspective

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Table 3.5 Comparison of 351(k) and 505(b)(2) Pathways

Approval under 351(k) Approval under 505(b)(2)

Available for biosimilars Evaluation: Biosimilarity to a reference product (highly similar to reference product, no clinically meaningful differences) Litigation: BPCIA (“patent dance”) Market exclusivity: Limited market exclusivity for the first interchangeable biosimilar against other interchangeable biosimilars Available for drugs and certain biologics Evaluation: Proof of safety and efficacy

Litigation: Hatch–Waxman (30-month stay) Market exclusivity: Likely not applicable for biosimilars, although five years of new chemical exclusivity has been awarded for recombinant versions of previously animal-derived products

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, include the following: • Basaglar® (Insulin glargine injection): In August 2014, the FDA granted tentative approval for Eli Lilly’s Basaglar, a recombinantly produced insulin glargine for treating diabetes. As a 505(b)(2) product, the approval relied in part on clinical studies carried out for Sanofi’s Lantus (insulin glargine). Basaglar does not have final approval due to the Hatch–Waxman litigation involving Sanofi’s patents and the associated 30-month stay. Time to tentative approval was quick, however, coming to exactly 10 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, the FDA addressed and rejected citizen petitions from Pfizer, Biotechnology Industry Organization, 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, the FDA approved Hylenex, a recombinant version of human hyaluronidase. Hylenex is marketed by Baxter and it 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, the FDA concluded that Hylenex was a new chemical entity compared to the prior versions of hyaluronidase and awarded Hylenex five years of market exclusivity.