The Biologics Price Competition and Innovation Act (“BPCIA”) created an abbreviated pathway for the licensure of biosimilar and interchangeable biological products by adding Section 351(k) to the PHS Act (“351(k) pathway”). Under the BPCIA, FDA cannot approve a biological product under the 351(k) pathway unless the route of administration, the dosage form and the strength of the biological product are the same as those of the reference product.

In the context of injectable solutions, which is the form for most licensed biologics since the enactment of BPCIA, FDA has interpreted the term “strength” under BPCIA to mean total drug content and concentration.

In a recent decision denying a citizen petition, FDA has reaffirmed this interpretation. Under this interpretation, to get its biologic product licensed, a 351(k) applicant has to demonstrate that its biologic product has the same concentration and the same total drug content as the reference product. Competition for Humira^® highlights the importance of this interpretation.

Humira^® and Its Biosimilars and Interchangables

Humira^®, a liquid, injectable formulation of the monoclonal antibody adalimumab, is one of the best-selling biologics. It was originally approved in 2012 in the form of a single-use, pre-filled glass syringe of 40mg drug content at a concentration of 50mg/ml. In 2015, FDA approved a new formulation at a concentration of 100mg/ml which was designed to reduce injection pain. 

By 2020, FDA had approved four biosimilars (Amjevit™, Hyrimoz^®, Hadlima™ and Hulio^®) and two interchangeables (Cyltezo^® and Abrilada™) to Humira^® under the 351(k) pathway, all at the 50mg/ml concentration. Under settlement agreements between AbbVie (Humira^® sponsor) and 351(k) applicants, no Humira^® biosimilar or interchangeable could launch in the U.S. before 2023. Yet, when those 351(k) products launched in 2023, a majority of Humira^® prescriptions were for the 100mg/ml formulations, potentially rendering those 351(k) products obsolete. 

BI’s Citizen Petition to Change the Interpretation of “Strength” for Biologics

In December 2020, Boehringer Ingelheim (“BI”), one of the Humira^® 351(k) applicants, filed a citizen petition (“Petition”), asking FDA to change its interpretation of the term “strength” as used in Section 351(k) of the PHS Act (42 U.S.C. § 262 (k)) to mean the “total drug content” without regard to concentration or total volume. It also requested that FDA revise applicable guidance documents to be consistent with this interpretation and apply this interpretation to all pending and approved 351(k) applications, amendments and supplements. 

BI argued that FDA’s interpretation “is incorrect as a matter of both law and policy” on four grounds:

First, it conflicts with the clear meaning of “strength”—an unambiguous term of art—which Congress adopted when it passed the BPCIA in 2009. Second, FDA’s interpretation is unreasonable because it encourages, or at least permits, brand sponsors to use minor concentration changes as an anticompetitive tactic to prevent competition from biosimilar and interchangeable biological products, thereby depriving patients from accessing more affordable biological products, contrary to the goals of the BPCIA. Third, it is arbitrary and capricious because it treats parenteral solutions differently than other similarly situated parenteral products, such as lyophilized powders, without adequate justification. Finally, even assuming Boehringer Ingelheim’s other arguments do not compel an interpretation of “strength” to mean only “total drug content,” FDA should still exercise discretion to change its policy because that definition better promotes the goals of the BPCIA, and there are no countervailing regulatory interests that outweigh this important benefit.

Petition, at 1-2.

FDA Denied BI’s Petition

On February 23, 2024, more than three years after the filing of BI’s Petition, FDA issued its decision (“Decision”) on the Petition. FDA ruled that its interpretation of “strength”  is scientifically justified and that adopting BI’s proposed interpretation would raise regulatory problems. Accordingly, FDA denied BI’s Petition.

In rejecting BI’s first argument, FDA explained that it is the Agency’s long-standing interpretation of “strength” under Section 505(j) of the FD&C Act to require that a generic liquid drug product have the same total drug content and the same concentration as that of the reference product. Decision, at 10, 12-16. 

Differences in concentration between a reference product and a biosimilar, FDA noted, “could result in medication errors, potential differences in certain quality attributes, and potential differences in the PK and, where applicable, pharmacodynamic (PD) profile.” Id. at 11-12, 23-25.

The agency acknowledged that, in the single-use context, differences in concentration “may have little to no impact on usability. . . . However, FDA’s definition of strength for liquid parenteral drug products accounts for its use in all scenarios[.]” Id. at 11. 

FDA also rejected BI’s argument that “strength” and “concentration” had distinct, non-overlapping meanings when the BPCIA was enacted. It cited various rules and regulations as evidence that “concentration” is one element of “strength.” Id. at 17-19. 

In rejecting BI’s third argument, FDA explained that a drug product in an “injection” dosage form (e.g., a solution) inherently involves two components—a solute and a solvent, while a drug product in a “for injection” dosage form (e.g., a lyophilized powder) is generally solid not liquid. Thus, “injection” and “for injection” dosage forms are not similarly situated for purposed of strength determination under the BPCIA. Id. at 20.

FDA acknowledged that a BLA holder could inhibit competition by obtaining a new strength of its biologic product and discontinuing a previously approved strength. But a 351(k) applicant “could receive licensure for a discontinued strength of the reference product” and “may be able to leverage certain existing data developed with another strength” to support its application. Id. at 26.

FDA concluded that adopting BI’s proposed interpretation would raise additional concerns. For example, medication errors could occur if a biologic is approved with a weight-based dosing or multiple-dose presentation.

In addition, adopting BI’s proposed interpretation could block products from receiving the “first interchangeable exclusivity” under 351(k)(6). This is because the eligibility for exclusivity for the first interchangeable biologic is tied to the reference product and FDA generally considers “different ‘strengths’ of a product to be different reference products.” Id. at 27. Had different concentrations with the same total drug content been considered the same strength and therefore the same reference product, “first interchangeable exclusivity for one concentration would block FDA from approving as interchangeable another product with a different concentration but the same total drug content.” Id. 

Finally, given FDA’s longstanding practice in interpreting “strength” to encompass “concentration” for drugs regulated under the FD&C Act, adopting BI’s proposed interpretation “would have potentially disruptive implications for drug products regulated under the FD&C Act.” Id. at 27-28.

Based on all the scientific and regulatory justifications, FDA declined to adopt BI’s proposed interpretation of “strength” and denied its Petition.

Key Takeaways

Although the 100mg/ml Humira^® was approved in 2015, AbbVie decided not to launch it in the U.S. until 2018. Some have criticized AbbVie for that decision, accusing it of seeking to create hurdles for 351(k) applicants who had already developed or were developing the original concentration and must match the higher concentration to stay competitive.

Despite the criticism, AbbVie’s practice is not uncommon. And under the current FDA interpretation of “strength,” a 351(k) applicant has to show that its biosimilar or interchangeable products have the same concentration as the referenced product, or it will face other hurdles as acknowledged by FDA in its decision. Thus, 351(k) applicants should closely monitor the reference product, including tracking relevant clinical trials, patent filings, press releases, databases of regulatory bodies (i.e., FDA and its international counterparts such as the European Medicines Agency) and financial reports, to stay up to date.