FDA denial of Vifor Velphoro petition shines new light on NCE interpretation

Overview and implications

Vifor argued in its petition that the active ingredient in Velphoro is a mixture containing a specific form of polynuclear ferric oxyhydroxide, sucrose, and starches that interact and work together to achieve Velphoro’s intended pharmacologic effect, i.e., binding to dietary phosphate in the gastrointestinal tract. Vifor’s position was that the product must be awarded NCE exclusivity because the approved active ingredient – the complex or mixture, sucroferric oxyhydroxide – had never previously been approved. Based on the 2015 federal court decision, Amarin Pharmaceuticals Ireland Ltd v. FDA, 106 F. Supp. 3d 196 (D.D.C. 2015), Vifor argued that NCE exclusivity must be applied at the statutory “active ingredient” level, and not in accordance with the agency’s longstanding “active moiety” test.

Alternatively, Vifor argued that the active moiety in Velphoro is a specific, novel form of polynuclear ferric oxyhydroxide that had never been previously approved by FDA and was, therefore, entitled to 5-year NCE exclusivity under the “active moiety standard.”

FDA denied exclusivity on both counts and used the decision to issue a major new statement on the agency’s interpretation of NCE exclusivity. This citizen petition response comes on the heels of the April enactment of the Ensuring Innovation Act, which replaces the term “active ingredient” with “active moiety” in parts of the Federal Food, Drug, and Cosmetic Act (FDCA), effectively preserving FDA’s discretion in applying NCE exclusivity. We analyzed that bill online here. The FDCA now reads in a way that is consistent with FDA’s regulations and arguably sidelines the 2015 Amarin decision relating to NCE exclusivity for successor versions of natural-source mixture products.

Active ingredient analysis

Vifor argues that the active ingredient in Velphoro is not merely its active moiety, a specific form of polynuclear iron(III)-oxyhydroxide, but is instead sucroferric oxyhydroxide, a mixture of this active moiety with carbohydrates (sucrose and starches). Vifor cited how the polynuclear ferric oxyhydroxide in Velphoro differs from polynuclear ferric oxyhydroxides in previously approved drug products (such as Venofer) in physicochemical properties such as size, iron-release characteristics, structure, and chlorine content, among others. Moreover, Vifor argued, because both the iron moiety and the carbohydrates in iron carbohydrate products play a role in the pharmacological effect of such products, the carbohydrate components cannot be excluded in any active ingredient determination.

In analyzing the components of sucroferric oxyhydroxide — polynuclear ferric oxyhydroxide, sucrose, and starches — separately, and together, FDA concluded in its response to the citizen petition that neither the carbohydrates (sucrose and starches) in Velphoro, nor the specific characteristics of the polynuclear ferric oxyhydroxide presentations of Velphoro and previously approved iron-carbohydrate products, “furnish pharmacological activity”; instead, it is the ferric oxyhydroxide that is responsible for the pharmacological activity of both Velphoro and Venofer, and is thus the active ingredient in both drug products. “Sucrose and starches are merely excipients providing stability and processing functions,” FDA asserted, and “differences in polymorphic forms (α, β, γ, and δ) of ferric oxyhydroxide have not been shown to be determinative of the inherent pharmacological activity (or activities) of ferric oxyhydroxide.”

The agency cited how it has approved numerous iron carbohydrate drug products containing ferric oxyhydroxide and one or more carbohydrates since 1974. The response to the petition recounts how, historically, FDA has not considered minor variations, such as a new ester, salt, or other noncovalent derivative, to represent important new innovations meriting exclusivity.

FDA: Fe-O bonds are covalent

Vifor’s product, Velphoro, is an oral product, but in structure it is akin to a number of parenteral iron products, like Venofer (iron sucrose) and Ferrlecit (sodium ferric gluconate complex). These structures have large polynuclear ferric cores with multiple co-linked ferric oxyhydroxide monomers polymerized via a network of Fe-O coordinate bonds. The ferric core is then tethered to a carbohydrate shell by hydrogen bonds and other weaker forces. The complexity of this structure was reflected in the existing established name (sucroferric oxyhydroxide, iron sucrose, sodium ferric gluconate complex), which acknowledges the carbohydrate shell.

Ferric oxyhydroxide, in Velphoro’s polynuclear ferric oxyhydroxide core, has the chemical formula FeO(OH). FDA said in the petition response that it considers the Fe-O bonds in monomeric ferric oxyhydroxide to be covalent bonds; under the agency’s “weight-of-evidence” test for metal-ion/ligand bonds, ferric oxyhydroxide’s covalent nature was said to be evidenced by, among other things, inter-atomic distances consistent with covalent bonds, observed geometry, and a well-defined stoichiometry, as well as differences in electronegativity of the iron and oxygen atoms.

However, FDA also asserted that the Fe-O bonds that link multiple Fe-O monomers to form the polynuclear ferric (polymeric) core do not factor into the chemical identity of the active ingredient or the active moiety. Under FDA’s rules, an active moiety is composed of things that covalently bond together, and it excludes salt bonds, ionic bonds, ester bonds, and other lesser bonds; thus, FDA rejected Vifor’s argument that “sucroferric oxyhydroxide” contains a novel active moiety. In finding the multimeric “polynuclear” Fe-O bonds to be less than “covalent,” FDA effectively relegated them to an aspect of the product’s “form” rather than its chemical structure.

Bearing on “sameness” determinations

The FDA petition response only addresses what it means to be an NCE; it does not have direct relevance to the question of ANDA drug substance “sameness.” However, it is important to note that FDA now considers the active ingredient of several polynuclear iron products (including Venofer and Ferrlecit) to be, simply, ferric oxyhydroxide – not the larger complex. Contemporaneous with the citizen petition response, FDA changed the Orange Book listings for Velphoro, Venofer, Ferrlecit and several other parenteral iron products to uniformly identify the active ingredient as “ferric oxyhydroxide.” This appears to be at odds with what FDA has previously said regarding active ingredient sameness for nanoparticle iron products, including Ferrlecit, where FDA has suggested it will consider the carbohydrates for purposes of evaluating the “sameness” of an ANDA.

Conclusion

Although much of the FDA petition response focuses on the idiosyncrasies of metal-ion complexes, and even more so in the iron replacement field, the breadth of the discussion contained within the response is noteworthy. We expect that this decision will become a seminal source of information when analyzing NCE cases well beyond metal-ion complexes.

Authored by Dave Fox and Jason Conaty