Welcome to Alston & Bird’s introduction to biological products regulation. In this five-part intro-level series, we provide answers to a number of questions drug developers may have about the regulation and regulatory pathway for their products.
The series includes:
- Is the Product a Biological Product?
- What Is the Regulatory Pathway for Biological Products?
- Biosimilars 101
- Pre-licensure inspection for monoclonal antibodies
When developing a biological product, sponsors may wonder whether the product qualifies for reference product exclusivity (RPE) under the Biologics Price Competition and Innovation Act (BPCIA). Previously, we discussed whether a product is considered a “biological product” under the BPCIA and whether the appropriate regulatory pathway is a 351(a) biologics license application (BLA) or a 351(k) BLA. For sponsors pursuing the 351(a) BLA pathway, RPE can be a critical consideration. For sponsors pursuing the 351(k) BLA pathway, it is equally important to understand whether their product will be blocked by an existing RPE period.
The FDA will not approve a biosimilar application referencing the reference product during RPE. Specifically, the FDA may not issue licensure of a biosimilar product under a 351(k) BLA until 12 years after the reference product was first licensed. In addition, a 351(k) BLA application may not be submitted for FDA review until four years after the first licensure of the reference product. This exclusivity period incentivizes innovation by granting the reference product defined market protection. The FDA issued draft guidance on RPE in August 2014, which remains an important resource for sponsors.
Not all 351(a) BLAs qualify for an RPE. For example, there is no independent RPE when the licensure is the result of:
- An application submitted as a supplement to an existing BLA.
- An application under a different BLA filed by the same sponsor as an existing BLA that involves changes not modifying the structure of the biological product.
- An application filed by the same sponsor with structural changes that do not result in a change in safety, purity, or potency.
The FDA publishes RPE determinations in the Purple Book, but the absence of a “date of first licensure” does not necessarily mean a product was ineligible for exclusivity. The FDA has not made a determination of first licensure for every 351(a) biological product listed in the Purple Book, so sponsors should not assume that missing dates indicate ineligibility. Importantly, RPE determination is not automatic at approval. It is typically initiated at the applicant’s request or when a biosimilar sponsor submits a 351(k) BLA application. To facilitate the FDA’s determination, 351(a) BLA applicants should provide:
- A list of all licensed biological products structurally related to the proposed product.
- Products for which the sponsor or affiliates are current or previous license holders.
- Detailed descriptions of structural differences, including amino acid sequence changes, glycosylation patterns, tertiary structure, and biological activity.
- Evidence showing how these structural differences impact safety, purity, and potency.
One unsettled issue is whether the concept of umbrella exclusivity, which in the Hatch–Waxman context extends protection to later-approved drugs sharing the same active moiety, applies under the BPCIA. The FDA sought public comment in 2018 on applying umbrella exclusivity to biologics, and opinions remain divided. Proponents argue that umbrella exclusivity could shield certain biologics from biosimilar competition, while opponents note that the BPCIA does not explicitly codify this concept and question whether Congress intended such protection. The FDA’s Biosimilars Action Plan indicates that developing guidance on reference product exclusivity remains a priority, but for now, the application of umbrella exclusivity to biologics is an open question.
Another open question involves fixed-dose combinations. For small molecules, the FDA clarified that new chemical entity (NCE) exclusivity applies at the drug substance level, not the drug product level. This interpretation allows fixed-dose combinations to qualify for NCE exclusivity if they contain a novel active moiety. For biologics, however, this question remains particularly relevant for reformulations that combine monoclonal antibodies with hyaluronidase to switch route of administration from intravenous to subcutaneous. Whether this combination with hyaluronidase qualifies for its own RPE is still unsettled.
The FDA has not finalized its guidance on RPE, and several interpretive questions remain. Our FDA team is closely monitoring developments. Sponsors should engage with regulatory experts early to maximize the likelihood of securing RPE for their products.
If you have any questions, or would like additional information, please contact one of the attorneys on our FDA: Drug & Device team.
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