Would I FIE to You? FDA’s First Interchangeable Exclusivity Determination Results in Expiration

Back in late September 2023 (and corrected in October), FDA issued its first interchangeable exclusivity determination pursuant to the Biologics Price Competition and Innovation Act (“BPCIA”).  As has been explained, the BPCIA provided an abbreviated pathway to market for follow-on biologics—biosimilars and interchangeable biosimilars—and with that pathway came two types of exclusivity periods: one for the “Reference Product” to encourage continued innovation and one for the “First Interchangeable” biosimilar to encourage the development of biosimilars that could be substituted for the brand product without health care provider intervention.  Relevant here, “First Interchangeable Exclusivity” (referred to by FDA as “FIE”) provides that FDA may not license a second interchangeable biosimilar until the earlier of:

• 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product;
• 18 months after­:
  • a final court decision on all patents in a BPCIA suit against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
  • dismissal with or without prejudice of a such an action;
• 42 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has been sued under the BPCIA and the litigation is still ongoing within such 42-month period; or
• 18 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has not been sued under the BPCIA.

The FIE determination released in fall 2023 involves the Reference Product AbbVie’s Humira (adalimumab) and two interchangeable biosimilars—first approved is Cyltezo (adalimumab-adbm), filed by Boehringer Ingelheim Pharmaceuticals, Inc, which was followed by Abrilada (adalimumab-afzb), filed by Pfizer.  Important to note here is that each interchangeable biosimilar was first approved as a biosimilar and each biosimilar manufacturer had been sued under the so-called “patent dance” procedure prior to seeking licensure of the biosimilar products as interchangeable.  The question at issue for FDA was therefore: When is the expiration date of FIE for the first approved interchangeable adalimumab, Boehringer’s Cyltezo, and whether that exclusivity has expired?  In other words, FDA needed to determine whether the initial biosimilar litigation—pre-interchangeable supplemental approval—counts towards the FIE expiration date calculation.

FDA provided each Boehringer and Pfizer the opportunity to present its interpretation of FIE expiration provisions, but FDA ultimately “decline[d] to adopt either Pfizer’s or BI’s proposed interpretation.”  Congress, FDA explained, did not seem to have accounted for staggered licensure of biosimilars in which interchangeable status would be sought as a supplement and that litigation might happen between initial licensure and supplemental licensure, leaving the statutory text relatively ambiguous.  Whoops.

With the ambiguity of the statutory text, FDA looked at the plain language, context, and the structure and purpose of the statute—including both parties’ positions on those points.  Notably, the purpose of the statute seemed to govern much of FDA’s interpretation.  The Agency writes in its determination “[w]e were thus mindful of Congress’s desire to both provide a meaningful opportunity for a period of exclusivity for the first interchangeable product, without allowing the applicant of such product to have unilateral control of the start and end date for that period of exclusivity,” but cautioned against “[a]dopting an interpretation that would allow a first interchangeable product’s applicant plenary control over the entry of competing interchangeable products could enable manipulation and distortion of the market, which would undo the incentives for competition that Congress sought to put in place.”

FDA chose to read the FIE expiration period relevant to patent litigation to apply only where such litigation involved the submitted interchangeable products—litigation over the original biosimilar that later may be determined interchangeable is not relevant to the FIE expiry calculus.  Here, because the relevant patent litigation (resulting in settlements) “commenced and concluded” before Boehringer submitted its interchangeability supplement, the litigation is not relevant to Cyltezo’s FIE period.  Instead, FDA explained, “the term ‘action instituted under [PHS Act § 351(l)(6)]’ must be linked to ‘the application for the first approved interchangeable biosimilar biological product,” which means the application seeking a determination of interchangeability.  And FDA also is clear that any action that triggers the potential FIE expiration “must at the very least be limited to . . . litigation involving the same reference product as in the interchangeability application.”

FDA explained the public health benefits of this interpretation: it encourages applicants to submit aBLAs as soon as practical to increase competition and access.  If the expirations clock starts ticking before the application for the interchangeable product has been submitted, “applicants may choose to either delay submitting their BLA until they have a data package that can support licensure of their proposed product as an interchangeable, or they may submit an application for biosimilarity only, and may not seek licensure as interchangeable at all because their biological product will likely not have a chance to benefit from FIE.”  Thus, FIE expiration is triggered only upon infringement suit arising from the submission of the first interchangeable product application; this interpretation applies to both the litigation trigger and the absence of litigation trigger.

Indeed, if it were possible for neither the litigation triggers nor the absence of litigation trigger to apply to start the clock running for FIE expiry, the only possible trigger would be one year after first commercial marketing.  FDA raises concern that such an interpretation could lead to anti-competitive behavior, for example, where the applicant enters into an agreement with the reference product applicant not to start marketing its interchangeable product as part of settling the patent infringement action, which could have the result of blocking all other interchangeable products indefinitely.  Thus, the fact litigation was filed regarding the biosimilar and no litigation was filed against the interchangeable would trigger the 18-month forfeiture of FIE under FDA’s interpretation.

Because AbbVie filed no patent infringement against Boehringer for the interchangeable biosimilar (presumably because it was covered in the settlement for the previous non-interchangeable biosimilar), FDA used the date of approval to calculate FIE expiration.  Boehringer’s interchangeable Cyltezo in 40 mg/0.8 mL and 20 mg/0.4 mL for subcutaneous injection was approved on October 15, 2021; the supplement for 10 mg/0.2 mL was approved on March 18, 2022.  Thus, 18 months from approval would result in expiration of FIE on April 15, 2023, and on September 18, 2023 respectively.  The first commercial marketing of each, according to the biosimilar patent settlement agreement, was July 1, 2023, which would render the FIE expiration date July 1, 2024.  But because the statute sets FIE expiration at the earlier of the relevant conditions, the April 15, 2023 and September 28, 2023 dates were the FIE expiration dates.

This all sounds complicated, I know.  But the main takeaway from this FIE expiration determination is that it’s only interchangeable approval and litigation that count towards the FIE expiration calculations.