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?
- Unlocking Reference Product Exclusivity: What Biologics Sponsors Need to Know
- Biosimilars 101
- Pre-licensure inspection for monoclonal antibodies
For sponsors developing biological products, one of the earliest considerations is determining the appropriate Food and Drug Administration (FDA) regulatory pathway. Unlike small-molecule drugs, which are typically approved under Section 505 of the Federal Food, Drug, and Cosmetic Act, biological products are licensed under the Public Health Service Act (PHSA). Because these statutory and regulatory frameworks differ significantly, identifying the correct pathway from the outset is critical.
Biological products fall under two approval pathways:
- 351(a) BLA, a stand-alone biologics license application (BLA) under Section 351(a) of the PHSA.
- 351(k) BLA, an abbreviated BLA under Section 351(k) of the PHSA.
A 351(a) BLA must include all data and information necessary to demonstrate the product’s safety, purity, and potency. By contrast, a 351(k) BLA is designed for biosimilars and allows a sponsor to rely on the FDA’s prior findings for a reference product approved under a 351(a) BLA.
To seek the 351(k) BLA pathway, the sponsor must demonstrate that the proposed product is “highly similar” to the reference product and that “no clinically meaningful differences” exist under Section 351(i)(2) of the PHSA. Increasingly, 351(k) BLA sponsors rely on advanced analytical characterization and pharmacokinetic or pharmacodynamic (PK/PD) data to support biosimilarity. The FDA’s recent draft guidance underscores that comparative efficacy studies—historically the most resource-intensive component of a 351(k) BLA program—are no longer presumed necessary in all cases.
Importantly, there is no 505(b)(2)-like pathway for biological products. A 505(b)(2) new drug application (NDA) is a hybrid approval pathway for small molecules that allows reliance, in part, on published literature or the FDA’s prior findings of safety and effectiveness for an approved drug while providing new data to support changes such as dosage form, route of administration, or strength. Because biological products are regulated under the PHSA, this hybrid pathway is not available. Sponsors must therefore determine whether their product qualifies for the abbreviated 351(k) BLA pathway or requires a stand-alone 351(a) BLA.
For example, a sponsor seeking to develop a subcutaneous version of an approved monoclonal antibody currently administered intravenously cannot use the 351(k) BLA pathway because the statute requires the same route of administration when using this pathway. Instead, the sponsor must pursue a 351(a) BLA and conduct clinical studies to support the proposed product. Without a right of reference, the sponsor cannot rely on the FDA’s findings of the intravenous product in its 351(a) BLA submission.
Within the 351(k) BLA framework, sponsors may want to consider the statutory distinction between a biosimilar and an interchangeable biosimilar. An interchangeable product may be substituted for the reference product without the prescribing health care provider’s intervention, subject to state pharmacy laws. This pharmacy-level substitution is similar to how generic drugs are routinely substituted for brand-name drugs. In addition to meeting the requirements for biosimilarity, a sponsor seeking licensure of an interchangeable biosimilar must demonstrate that the product can be expected to produce the same clinical result as the reference product in any given patient and, for products administered more than once, that the risk of alternating or switching between the biosimilar and the reference product is not greater than the risk of using the reference product alone. The FDA’s interchangeability guidance clarifies that additional clinical studies are generally not required to meet these standards, but sponsors must provide robust scientific justification and extrapolation to support their conclusions.
Selecting the proper regulatory pathway for biological products is important because it shapes development strategy, timelines, and resource allocation. Sponsors should carefully evaluate whether their product qualifies for the abbreviated 351(k) BLA pathway or requires a stand-alone 351(a) BLA. Early engagement with the FDA and proactive planning can help mitigate regulatory risks. For tailored guidance on navigating these pathways, sponsors should consult experienced regulatory advisors.
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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