On May 26, 2021, USFDA denied Vifor Fresenius’ petition for awarding 5-year of NCE to Velphoro®(sucroferric oxyhydroxide).

 

USFDA approved Velphoro on Nov. 27, 2013 for the the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. Structurally, Velphoro is comprised of particles in which a hydrated, poorly soluble “polynuclear ferric oxyhydroxide” core is surrounded by an immediate layer of sucrose molecules that are loosely associated with this core, along with molecules of starch. FDA has described this as “sucroferric oxyhydroxide” – nonproprietary United States Adopted Name (USAN).

 

Petitioner (Vifor Fresenius Medical Care Renal Pharma, France)  filed petition in Apr. 2016 & requested FDA to grant 5-year New Chemical Entity (NCE) exclusivity to Velphoro & immediately stay the acceptance, receipt, filing, review, and approval of any ANDA or 505(b)2 referring Velphoro. The Petitioner asserted that Velphoro is entitled to 5-year NCE exclusivity under both statutory “active ingredient standard” provided in the FD&C Act, and the Agency’s regulatory “active moiety standard.”

 

With respect to “active ingredient standard” the Petitioner asserted that active ingredient in Velphoro is “sucroferric oxyhydroxide,” a mixture containing a specific form of polynuclear ferric oxyhydroxide (the active moiety), sucrose, and starches, which interact and work together in different ways to achieve Velphoro’s intended pharmacologic effect.  FD&C Act requires that the Agency assess approved active ingredients as a whole, rather than focus narrowly on active moieties, and because this active ingredient has not previously been approved by FDA, Velphoro is entitled to 5-year NCE exclusivity under the statutory “active ingredient standard.”

 

With respect to “active moiety standard” the Petitioner asserted that “specific form of polynuclear ferric oxyhydroxide” is the active moiety in Velphoro. It is specifically designed to minimize the release of iron, has never been previously approved by FDA. Therefore, Velphoro is entitled to 5-year NCE exclusivity under the “active moiety standard.”

 

The Petitioner further argued that the term “active ingredient” in the FD&C Act should not be limited to “active moiety”. Relying on the U.S. District Court decision in Amarin Pharmaceuticals Ireland Ltd v. Food & Drug Administration, 106 F. Supp. 3d 196 (D.D.C. 2015) (Vascepa®), the Petitioner claimed that the FD&C Act requires each new active ingredient to be eligible for 5-year NCE exclusivity, even if, as in the Amarin case, an active moiety of the active ingredient can be found in a previously approved active ingredient. [In Amarin case, Eicosapentaenoic acid (EPA), was the active moiety & initially FDA denied NCE because mixture containing EPA was already approved in another product, Lovaza. But, Court reversed the decision & said that FDA’s interpretation was unreasonable because FDA could not interpret “active ingredient” differently in the generic approval context than in the exclusivity context.]

 

What is active ingredient standard?

“FD&C Act in section 505(c)(3)(E)(iii) and (j)(5)(F)(iii) provide in relevant part that “[i]f an application submitted under subsection (b) of this section for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b) . . . is approved . . . , no application may be submitted under this subsection which refers to the drug for which the subsection (b) application was submitted before the expiration of five years from the date of the approval of the application under subsection (b) of this section . . . .” (emphasis added).

 

What is active moiety standard?

Active moiety defined in the Agency’s regulations in § 314.3 (21 CFR 314.3) as “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”

 

FDA in response rejected the Petitioner’s assertions and arguments & said that ferric oxyhydroxide is both the active ingredient and the active moiety in Velphoro. And, because ferric oxyhydroxide was previously approved drug product (Venofer), Velphoro is not eligible for 5-year NCE exclusivity.

 

FDA’s Interpretation of the 5-year NCE Provision is lawful based on “active moiety” standard

Petitioner largely relied on Amarin case & asserted that statute unequivocally requires FDA to recognize 5-year NCE exclusivity for each new active ingredient as it is approved, even if such new active ingredient (here, sucroferric oxyhydroxide) contains a previously approved active moiety (here, ferric oxyhydroxide). The Petitioner thus questions the validity of the Agency’s interpretation of the 5-year NCE exclusivity.

 

FDA said that the district court’s order in Amarin applies only to the dispute in that case, and the Agency disagrees with that decision’s reasoning to the extent that it questions the validity of FDA’s active moiety interpretation. In addition, the Agency believes that the Amarin court’s Chevron step-two analysis is inconsistent with Chevron deference. Accordingly, FDA will not adopt the Amarin court’s reasoning in these and other circumstances. FDA further said that the Petitioner’s preferred interpretation reflects a fundamental misunderstanding of the relevant statutory provisions, applicable legislative history evincing Congress’s intent, and controlling D.C. Circuit precedent. FDA said that the statutory provisions that govern 5-year NCE exclusivity are ambiguous, and FDA’s interpretation reflects congressional intent.

 

In particular, the term “active ingredient,” especially when read in context of the parenthetical phrase “(including any ester or salt of the active ingredient),” is ambiguous because it is undefined; it could refer to the drug’s active ingredient or its active moiety. Court also as a general matter, in Abbott (Depakote), Actavis (Vyvanse), and Otsuka (Abilify Maintena/Aristada), concluded that the meaning of the term “active ingredient” is ambiguous. Therefore, FDA’s approach of “active moiety” concept is reasonable & right. Congress also intended to provide 5 years of exclusivity only to “new chemical entities” which is evaluated as per “active moiety” standard. The term “active ingredient” appears in provisions of the FD&C Act governing exclusivity and FDA review and approval of ANDA applications. But, Congress intended the term “active ingredient” to mean “active moiety” in the context of the 5-year NCE exclusivity provisions. Since enactment, FDA has also consistently taken the position that the term NCE was meant to incorporate the same principles as FDA’s classification system, including the active moiety concept. Recently, on April 23, 2021, Congress amended the relevant statutory provisions to explicitly adopt FDA’s interpretation that the phrase “active ingredient (including any salt or ester of the active ingredient)” means “active moiety.”

 

Ferric oxyhydroxide, the active ingredient and active moiety in Velphoro, has been previously approved

The Petitioner argued that the active ingredient, “sucroferric oxyhydroxide” is novel because (a) the polynuclear iron(III)-oxyhydroxide active moiety is different from any polynuclear ferric oxyhydroxide in previously approved drug products; and (b) it contains a different combination of polynuclear ferric oxyhydroxide and carbohydrates in different ratios from other previously approved ferric oxyhydroxide iron-carbohydrate drug products. FDA, however disagreed & said that ferric oxyhydroxide is responsible for the pharmacological activity of both Velphoro and Venofer, and is thus the active ingredient in both drug products under the regulatory definition of “active ingredient.” Sucrose and starches are merely excipients providing stability and processing functions. Because ferric oxyhydroxide, the active ingredient, contains only non-ester covalent bonds, it is also the active moiety under the Agency’s 5-year NCE exclusivity regulations, which is again approved previously in Venofer.

 

Like Velphoro, Venofer consists of a mixture of ferric oxyhydroxide with a carbohydrate (sucrose in this instance). Like in Velphoro, the ferric oxyhydroxide is also presented as a polynuclear array of ferric oxyhydroxide repeat units, and while the size of these arrays may differ, there are no chemical or structural differences between the ferric oxyhydroxide repeat unit in Velphoro and that in Venofer. Moreover, Petitioner’s comparisons of the purported physicochemical properties of Velphoro and Venofer are irrelevant to the active moiety assessment.

 

The Agency intends to consider additional Regulatory Actions and/or Policy Changes to address certain issues implicated by this petition response

FDA said that the current established name for the active ingredient in Velphoro Tablets, 500 mg, sucroferric oxyhydroxide, is inconsistent with the decision in this Petition response. FDA said that our regulation recognizes the role that USAN plays in naming active ingredients. Here, USAN has adopted sucroferric oxyhydroxide as the established name for the active ingredient in Velphoro, USP has subsequently balloted and approved the USAN drug substance & the Agency has approved Velphoro with the established name of sucroferric oxyhydroxide tablets and labeling stating that sucroferric oxyhydroxide is the active ingredient. Nevertheless, the Agency has never stated in the approval or otherwise that it considers sucrose and starch to be a component of an active ingredient or an individual active ingredient in the drug. Other drug products containing an iron carbohydrate, is also inconsistent with the conclusions. FDA said that it intend to consider options by which it can address such inconsistencies. Such options may include working with appropriate naming bodies to explore how best to deal with the conclusion of this petition response that ferric oxyhydroxide is the active ingredient in Velphoro (and other affected iron carbohydrate products), and how this affects the established name of the drug product(s).

 

FDA further recognized that the expression of “strength” in the Velphoro labeling [500 mg iron (equivalent to 2,500 mg sucroferric oxyhydroxide)] also appears to be inconsistent with the determination that the active ingredient in Velphoro is ferric oxyhydroxide and not sucroferric oxyhydroxide. Accordingly, the Agency intends to consider options to draft appropriate labeling to describe the strength of Velphoro more accurately. FDA further intends to consider taking similar action for other iron carbohydrate products.