FDA Knows Its Own Strength—and It Includes Concentration

February 26, 2024By Sara W. Koblitz & Kurt R. Karst

While the Biologics Price Competition and Innovation Act (“BPCIA”) is inherently distinct from the Hatch-Waxman Act, many of the fundamental concepts FDA adopted as it enacted the Hatch-Waxman Act made their way into FDA’s implementation of the BPCIA.  This of course, make sense—after decades of experience implementing the Hatch-Waxman, Congress and FDA had learned a few new tricks by 2009/2010.  Amongst other things, FDA co-opted many of the same definitions for key terms for implementation of the BPCIA.  Relevant here, FDA interpreted in Guidance that a proposed injectable biosimilar must “demonstrate that its product has the same strength as the reference product by demonstrating that both products have the same total content of drug substance (in mass or units of activity) and the same concentration of drug substance.”  FDA borrowed this definition from 21 C.F.R. § 314.3, codified in 2016, which defines strength as the “total quantity of drug substance in mass or units of activity in a dosage unit or container closure” and/or “the concentration of the drug substance.”  But in 2020, a Citizen Petition came along looking to upend FDA’s approach to strength.

Boehringer Ingelheim submitted a Citizen Petition in December 2020 encouraging FDA to interpret the term “strength” under the BPCIA differently than the Agency does under the Hatch-Waxman Act.  Specifically, Boehringer asked FDA to interpret “strength” for biosimilars to mean “total drug content” to the exclusion of “concentration.”  The Petition alleged that “such action is necessary to:

(1) ensure the Food and Drug Administration’s (“FDA’s” or “the Agency’s”) interpretation is consistent with the clear meaning of the Biologics Price Competition and Innovation Act (“BPCIA”);

(2) prevent abusive “evergreening” tactics from stifling competition of affordable biosimilar and interchangeable biological products; and

(3) maintain fair and consistent treatment of all similarly situated parenteral biological products.

As FDA explains, Boehringer’s request would allow its “Cyltezo (adalimumab-adbm) injection, which contains the same total content of drug substance and same concentration as Original Concentration Humira (e.g., 40 mg/0.8 mL), to be biosimilar to or interchangeable with High Concentration Humira (e.g., 40 mg/0.4 mL) in addition to Original Concentration Humira.”

On February 23—the same day that the Agency licensed SIMLANDI (adalimumab-ryvk) Injection, the first interchangeable high-concentration, citrate-free biosimilar to HUMIRA, and that qualifies for First Interchangeable Exclusivity (“FIE”)—FDA denied the Boehringer Petition.  FDA responded to each of Boehringer’s arguments in turn.  To Boehringer’s first and most significant argument, that Congress intended the terms “strength” to match FDA’s interpretation in 2009—prior to the codification of the definition in 21 C.F.R. § 314.3—FDA replied that its definition of strength including concentration was clear even in 2009.  Notwithstanding some language in the Orange Book Preface that may be ambiguous, FDA stated that “FDA’s interpretation of ‘strength’ as applied to liquid parenteral drug products is reflected in nearly forty years of implementation of the statutory requirement that an ANDA contain information to show, among other things, that the “strength” of the proposed generic drug product is the same as that of the RLD…”  (emphasis added).  Even more definitively, FDA wrote:

Thus, when the BPCI Act was passed by Congress in 2009 and signed into law on March 23, 2010, the statutory term “strength” in section 505(j)(2)(A)(iii) of the FD&C Act had an existing, well-established administrative meaning that reflected both the total drug content (e.g., mg) and the concentration (e.g., mg/mL) for liquid parenteral drug products.

FDA provided detailed support, going through almost every instance that Boehringer cites as evidence that FDA interpreted “strength” differently in 2009, to show that FDA has consistently applied the same definition of “strength” since the enactment of the Hatch-Waxman Act.

Boehringer’s regulatory argument got no further traction.  FDA explained that its bioequivalence regulations at 21 C.F.R. § 320.22 do not help Boehringer’s case.  Those regulations break “concentration” out from strength but only in certain contexts.  Here, FDA breaks our concentration from strength in the context of self-evident bioequivalence that would allow FDA to grant a biowaiver (requiring inactive ingredients to be present in the same concentration as the Reference Listed Drug), which is only narrowly applicable.  In contrast, a different part of that regulation uses the term “different strength” without reference to “concentration,” but that is because the term “different strength,” in that context, is drug product and dosage form dependent; thus, there is no reference to “concentration” because it would be inapplicable to most dosage forms.  FDA concluded, its “use of the terms ‘strength’ and ‘concentration’ in different places in its BE regulations reflects the Agency’s view that ‘concentration’ is an element of strength for certain products (e.g., parenteral solutions) but is not typically broken out for others (e.g., solid oral dosage forms),” which, FDA posits, suggests “that the terms have overlapping meanings.”

Citing multiple Suitability Petitions in the small molecule context in which FDA has addressed changes to strengths by way of concentration, FDA also concluded: that “the Agency’s longstanding interpretation of the ‘strength’ of a liquid parenteral drug product to include both the total drug content and the concentration of the drug product is scientifically justified and provides a consistent and predictable approach for the development and approval of generic drug products.”  FDA then explains that scientific justification for its approach by raising significant safety and scientific concerns about Boehringer’s proposal.

With respect to safety, FDA raised concerns that differences in the either the concentration or total drug content of a parenteral product can introduce risk for medication errors, like dosing errors from difficulty in switching from the Reference Product.  Differences in drug substance concentration may also affect the quality profile of a drug product.  While the risks may not be present for all parenteral products, the Agency noted that its “definition of strength for liquid parenteral drug products accounts for its use in all scenarios, not just in the lowest risk scenarios…”  But even if those potential risks can be mitigated, FDA raises concerns that differences in concentration can affect product quality attributes in biosimilars, which directly impact safety and effectiveness.  FDA thus disagrees that such differences are not clinically meaningful.

FDA next addressed Boehringer’s allegations that FDA’s interpretation of “strength” violates the Administrative Procedure Act because there is no safety or effectiveness reason to consider concentration as relevant to a parenteral product but not a lyophilized powder for injection or other product “for injection” that ultimately become parenteral.  FDA rejects the argument because, inherently, the products Boehringer cites are not liquids at approval—they are solids that are reconstituted to become liquids.  Thus, FDA explained that “injection” and “for injection” dosage forms need not be treated the same, as “it is scientifically appropriate for the strength of a ‘for injection’ dosage form to be determined based on the total content of drug substance in the container closure because the concept of concentration (mass per volume) used for a liquid does not apply to a solid.”

Finally, FDA dismantled Boehringer’s argument about “evergreening” stifling competition.  Countering the evergreening concerns and Boehringer’s assertions that there are no countervailing interests that support its proposed omission of concentration from the “strength” definition, FDA recited its concerns of proliferation of biosimilar products with different concentrations from the reference product particularly where products evolve over their lifecycle.  More to the evergreening point though, FDA raises the point that Boehringer’s interpretation “may result in broader exclusivity that blocks a wider range of products from being licensed as interchangeable….”  In other words, because each strength is a different reference product, each is associated with its own period of interchangeable exclusivity; under Boehringer’s interpretation, FIE for one concentration would block FDA approval of another interchangeable with a different concentration but with the same total drug content.

It was not too long ago that FDA punted on BI’s petition.  In a memorandum issued last Fall concerning FIE for certain interchangeable adalimumab products (see our previous post here), the Agency recited that “[Boehringer] argues that because the original and high concentrations of Humira should be considered to have the same strength under [Boehringer’s] interpretation, Cyltezo’s exclusivity ‘covers all 10 mg, 20 mg and 40 mg adalimumab products, regardless of presentation or concentration.’”  In addressing this assertion, FDA noted that it “is not consistent with the agency’s interpretation of ‘strength’ for biosimilar and interchangeable products as articulated in [2021 Guidance].  The Agency also commented, however, that “[w]e do not need to address that pending citizen petition for the purposes of determining the expiration dates for Cyltezo 40 mg/0.8 mL, 20 mg/0.4 mL, and 10 mg/0.2 mL, in part because Pfizer is seeking licensure of Abrilada as interchangeable in those same concentrations.”  FDA’s licensure of IMLANDI (adalimumab-ryvk), and in a 40 mg/0.4 mL concentration presentation, appears to have forced FDA’s hand on the issue.