The Active Ingredient Stands Alone

July 11, 2023By Sara W. Koblitz

One of the most important questions FDA has to answer is whether a given product is appropriately characterized as a drug, biologic, device, food, cosmetic, or something entirely different.  As we have explained before, that distinction is critical to assigning a particular product to the appropriate regulatory scheme.  While it is exceedingly obvious that some products, like eyeshadow for example, are cosmetics, or a pacemaker is a device, it can get thorny where the distinction is based on a very fine line—like the number of amino acids in a given active ingredient.  That line becomes even more blurred where it’s not entirely obvious what constitutes the active ingredient.  And, like it has before, the District Court of D.C. recently grappled with this very question in Ipsen v. Becerra.

To set the stage for this case, we need to go back to March 2020, when a new definition of “biological product” threw the world of protein products into a tizzy.  As a result of the Biologics Price Competition and Innovation Act (BPCIA) passed in 2010, the definition of a “biological product” expanded to include “proteins.”  FDA further defined the term “protein” so that it includes any peptide product that has an amino acid sequence greater than 40 amino acids.  FDA also published a list of products anticipated to “transition” from a drug approved under an NDA (FDCA § 505) to a biological product deemed approved under a BLA (PHS Act § 351), and, in March 2020, products meeting the definition of “protein” officially transitioned to BLAs.

But, as is inevitable, there were some disputes about whether certain products should have transitioned, including several that resulted in litigation against FDA for continuing to regulate given products as drugs rather than biologics.  In one such lawsuit, Ipsen sued FDA arguing that the Agency’s decision to regulate its Somatuline Depot (lanreotide acetate) product as a drug rather than a biological product was “arbitrary, capricious, an abuse of discretion, and contrary to law.”  More specifically, Ipsen argued that Somatuline Depot is a “protein,” and therefore, pursuant to the March 2020 transition, should be regulated a biologic rather than a small molecule drug.

Approved in 2007 for the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy, with several indications added in the subsequent years, Somatuline Depot is a synthetic octapeptide available as ready-to-use prefilled syringes for deep subcutaneous injection.  Importantly, as an octapeptide, Somatuiline Depot is a “protein” but consists of only eight amino acids linked in a polypeptide chain.  However, Ipsen argued, Somatuline still meets FDA’s definition of a protein—more than 40 amino acids—because it contains multiple copies of its active ingredient that are linked together “in a manner that occurs in nature” to form a “nanotube” greater than 40 amino acids long.  Should the nanotube not constitute a biologic, Ipsen also argued that Somatuline Depot is at least “analogous” to a protein under the statute.   Thus, Ipsen asked the Court to direct FDA to transition the NDA to a deemed BLA.

FDA, on the other hand, argued that the finished product form—i.e., the nanotube—is irrelevant, as it is the “active ingredient” that matters for purposes of classifying the product as a drug or biologic.  Thus, FDA’s position is that a drug is a “protein” only if its “active ingredient” is composed of at least 40 amino acids.  That is not Somatuline Depot, which has only eight amino acids, and thus Somatuline Depot is not a biologic.  FDA also took the position that Somatuline Depot is not “analogous” to a protein because “it would not be appropriate to interpret the statutory term . . . in a way that would include amino acid polymers that are specifically excluded by the interpretation of the term ‘protein’ set forth in FDA’s Biological Product Definition Final Rule.”

As in most cases, the Court first addressed standing.  In one of the most plainly stated declarations we’ve seen in an FDA APA case, the Court clearly stated the principle of competitor standing.  In other words, the Court found that “Ipsen has sufficiently shown that it suffered a competitive injury because the FDA’s decision to regulate Somatuline Depot as a drug, rather than a biologic, allowed InvaGen to compete with Ipsen using the Drug Act’s § 505(b)(2) pathway. That option would not have been available to InvaGen had the FDA instead determined that Somatuline Depot and InvaGen’s product were biological products.”  Because FDA’s refusal to regulate Somatuline Depot as a biologic was the “but-for” cause of Ipsen’s competitive injury, and because “that injury flowed directly and inextricably from the FDA’s decision to regulate Ipsen under the [FDCA],” the Court found a causal nexus between FDA’s action and Ipsen’s competitive injury.  Thus, the threat of competition is enough to confer standing.

While Ipsen had standing, however, the Court pretty clearly found that FDA’s determination that Somatuline Depot is not a biologic was consistent with the regulation’s plain language and reflects rational decision making.  Though Ipsen argued that FDA should look at the finished drug product—the nanotube with far more than 40 amino acids—rather than the substance with only eight amino acids to assess whether the product is a drug or a biologic, the Court explained that “[n]either the statute nor the regulatory definition of a ‘protein’ requires the FDA to consider the size of the active ingredient as it appears in the final drug product, rather than standing alone” (emphasis in the original).  Instead, FDA’s decision to discern the active ingredient based on what “confers [its] pharmacologic activity” and thus FDA’s decision to analyze just the lanreotide acetate rather than the nanotubes “was unambiguously correct”—and even if it weren’t, the Court stated it would “defer to the FDA’s interpretation as reasonable” because it falls within FDA’s area of special expertise.   Ipsen’s alternative argument—that Somatuline Depot is “analogous” to a protein—was also rejected by the Court.  Thus, as expected the Court deferred to FDA, and left the determination as to whether a product is a drug or a protein to the active ingredient rather than the finished drug product.

Ipsen recently appealed this decision to the D.C. Circuit.  No briefs have been filed yet, with the initial submissions due the end of July.  The D.C. Circuit has previously addressed questions of drug versus device, finding against the Agency based on the plain language of the statute, so this is not entirely unfamiliar territory.  We’ll be watching to see what happens next.