Also Codifies FDA's Longstanding "Active Moiety" Approach for New Chemical Entity Exclusivity

In April 2021, President Biden signed two bipartisan bills that aim to promote drug competition and to reduce prescription drug prices—the Ensuring Innovation Act (EIA)¹ and the Advancing Education on Biosimilars Act of 2021 (Biosimilars Act).² While the Biosimilars Act aims to increase patients' and healthcare providers' awareness and adoption of biosimilars by enabling the Department of Health and Human Services to create a website with educational materials about various aspects of biologics and biosimilars, the EIA in part amends the requirements for the New Chemical Entity (NCE) exclusivity under the Federal Food, Drug, and Cosmetics Act (FDCA). This change in the exclusivity provisions has been touted by some as foreclosing the unintended opportunity for drug developers to make certain non-pharmacological changes to previously approved molecules as a way to delay generic drug entry.

In particular, before the EIA amendments, the NCE exclusivity provisions stated that a drug having "no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application" would be eligible for the five-year NCE exclusivity. The EIA amends the statute to replace the phrase "active ingredient (including any ester or salt of the active ingredient)" with "active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations))." Although the U.S. Food and Drug Administration (FDA) has historically interpreted "active ingredient" to mean "active moiety," the courts have not always sided with the FDA in its interpretation of the statute.

The EIA thus adopts the FDA's longstanding "active moiety" approach by incorporating the regulations promulgated by the FDA and also leaving the door open for the FDA to modify the definition or its NCE approach going forward through successor regulations. Since the enactment of the EIA, the FDA has not issued any new guidance or regulation specifically on the NCE exclusivity, but it would not be surprising if the FDA issues new guidance or regulations, especially in view of ongoing litigation in this space.

21 CFR § 314.3 currently defines "active ingredient" and "active moiety" as follows:

Active ingredient is any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.

Active moiety is 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.

Further, the FDA defines a "new chemical entity" under 21 CFR § 314.108 as follows:

New chemical entity means a drug that contains no active moiety that has been approved by FDA in any other NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act.

For drugs where the active ingredient overlaps one-to-one with the active moiety, the NCE analysis is straightforward. On the whole, since the EIA adopts the FDA's longstanding "active moiety" approach, the NCE analysis under the EIA is not expected to impact most drug products going forward. That said, two types of drug products that have been the subject of various litigation are worth taking a closer look in view of the EIA—fixed-combination drug products and prodrugs.

Fixed-Combination Drug Products

Fixed-combination drug products are typically drug products that include two or more active ingredients combined in a single dosage form. In Amarin Pharm. Ireland Ltd. v. FDA,³ the court vacated the FDA's decision to limit the regulatory exclusivity for Amarin's fish oil drug Vascepa to the three-year new clinical investigation exclusivity instead of the five-year NCE exclusivity. In denying the NCE exclusivity for Vascepa, the FDA argued that Vascepa's active ingredient, icosapent ethyl, which is an ethyl ester of eicosapentaenoic acid (EPA), a type of omega-3 fatty acid, was not eligible as an NCE because the agency previously approved another drug, Lovaza, which composed a mixture of multiple omega-3 fatty acid ethyl esters that included the ester of EPA. The federal judge disagreed with the FDA and held that the FDA improperly equated "active ingredients" with "active moieties" in its evaluation of NCE eligibility for icosapent ethyl and that its "active moiety" approach was contrary to the statute.

The EIA essentially reverses the Amarin decision by siding with the FDA and echoes the agency's 2014 Guidance for Industry, titled "New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products," stating:⁴

an application for a fixed-combination submitted under section 505(b) of the FD&C Act will be eligible for 5-year NCE exclusivity if it contains a drug substance, no active moiety of which has been approved in any other application under section 505(b). For example, a fixed-combination drug product that contains a drug substance with a single, new active moiety would be eligible for 5-year NCE exclusivity, even if the fixed-combination also contained a drug substance with a previously approved active moiety.

Accordingly, in order to qualify for the five-year NCE exclusivity, the drug product will need to include at least one active moiety that has never been approved by the FDA. Since the regulatory definition of an active moiety includes "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," such modifications or derivatives of a previously approved active moiety would not be eligible for the NCE exclusivity.

Prodrugs

A prodrug typically refers to a drug product that is metabolized or converted into a pharmacologically active form, or a metabolite, in the body. The FDA considers molecules that require metabolic conversion to be active moieties eligible for NCE exclusivity and has granted NCE exclusivity to many prodrugs. For prodrugs involving non-ester covalently bonded molecules of previously approved drugs, their NCE eligibility analysis should not change significantly with the enactment of the EIA.

For example, in a 2009 FDA letter, Docket No. FDA-2009-N-0184,⁵ the FDA reaffirmed the five-year NCE exclusivity granted to Vyvanse (lisdexamfetamine dimesylate), a prodrug that consists a non-ester covalent bond between dextroamphetamine and lysine through an amide bond, which is metabolically converted to dextroamphetamine in the body. Dextroamphetamine was an active moiety in a number of previously approved drugs. In this 2009 letter, the FDA provided the following rationale:⁶

Pursuant to FDA's interpretation of 21 CFR § 314.108, a salt will not be considered an active moiety. Therefore, although lisdexamfetamine dimesylate is the active ingredient of Vyvanse, because lisdexamfetamine dimesylate is a salt, lisdexamfetamine dimesylate is not the active moiety. The exclusivity analysis then turns to the lisdexamfetamine molecule.

As FDA interprets and applies 21 CFR § 314.108, a non-esterified covalently bonded molecule will be considered an active moiety in a drug. FDA has determined that lisdexamfetamine is a non-esterified covalently bonded molecule and thus lisdexamfetamine is the active moiety in Vyvanse. Further, lisdexamfetamine has not been previously approved as an active moiety in a drug product under section 505(b) of the Act, and is therefore a new chemical entity entitled to 5 years of exclusivity.

Further, the FDA clarified that it "relies on a relatively straightforward analysis of the chemical structure of the drug when analyzing eligibility for exclusivity," distinguishing its current position from a 1991 NCE exclusivity decision made based on the molecule's activity before the agency finalized the applicable regulations.⁷ In the 1991 decision, the FDA granted the NCE exclusivity to an ester of a previously approved molecule on the basis that the esterified portion of the molecule was responsible for the molecule's activity while the de-esterified form was inactive. Such activity-based ester modification of a previously approved molecule would not be eligible for the NCE exclusivity under the current chemical structure analysis and regulations.

Consistent with the FDA's rationale in the Vyvanse decision, the EIA aligns the statutory language with the FDA's regulations and makes it more clear that prodrugs consisting of esters, salts, or other noncovalent derivatives of a previously approved active moiety would no longer be eligible for the NCE exclusivity.

Sandoz v. FDA—Dust Not Yet Settled

However, a recent complaint filed by Sandoz on March 5, 2021 against the FDA in the District Court for the District of Columbia, before the enactment of the EIA, challenging the FDA's grant of the NCE exclusivity for Sanofi's multiple sclerosis drug Aubagio (teriflunomide), highlights the complexity and the nuance of the NCE analysis.⁸ This complaint comes after Sandoz's previous administrative appeal of the FDA's NCE exclusivity decision on Aubagio and filing of Abbreviated New Drug Applications (ANDAs) for its generic version.

Unlike the Vyvanse case, the previously approved active moiety involved here, leflunomide, is the prodrug, and the NCE designation being challenged is the metabolite, which was present as an impurity in the previously approved prodrug. Upon oral administration of leflunomide, the isoxazole ring of leflunomide is opened to form the teriflunomide metabolite in the body.⁹

According to the complaint, Sandoz argues that the FDA had previously approved leflunomide as the active ingredient of Arava in 1998 for a different indication and that "what is highly unusual and pivotally important to this case is the fact that teriflunomide not only is the active metabolite of Arava®'s leflunomide in vivo; it also is meaningfully present in Arava® tablets ex vivo … FDA-approved Arava® tablets contain therapeutically active teriflunomide that at least in part is responsible for Arava®'s physiological and pharmacological action."¹⁰

In granting the NCE exclusivity for Aubagio, the FDA argued that teriflunomide has not been previously approved and was thus eligible for the NCE exclusivity, which is in line with the FDA's chemical structure analysis for the active moiety in the drug product. This case, however, highlights the potential ambiguity created where both the FDA and the drug sponsor were aware of the presence of the metabolite in a previously approved drug product, albeit as an impurity, even though the active ingredient previously approved by the FDA was leflunomide. The outcome of this case has the potential to muddy the waters or provide further clarity to the NCE analysis, especially with respect to the scope of the definition of active moiety in the prodrug context and known impurities that are later discovered to have physiological or pharmacological activity.

In other areas, the Biden administration has moved quickly to restore FDA oversight and independence in its regulation of various medical products, and the enactment of the EIA is no exception.

[1] Sen. Bill Cassidy, Press Release, Cassidy, Smith, Marshall Bipartisan Legislation to Lower Prescription Drug Costs Signed into Law by President (April 23, 2021), available at https://www.cassidy.senate.gov/newsroom/press-releases/cassidy-smith-marshall-bipartisan-legislation-to-lower-prescription-drug-costs-signed-into-law-by-president-; S. 415 (117th Cong.), available at https://www.congress.gov/117/bills/s415/BILLS-117s415enr.pdf.

[2] S. 164 (117th Cong.), available at https://www.cassidy.senate.gov/imo/media/doc/Advancing%20Education%20on%20Biosimilars%20Act.pdf.

[3] Amarin Pharm. Ireland Ltd. v. FDA, 106 F. Supp. 3d 196, 217-19 (D.D.C. 2015); see also Congressional Research Service, Defining Active Ingredient: The U.S. Food and Drug Administration’s Legal Interpretation of Regulatory Exclusivities (December 10, 2019), available at https://crsreports.congress.gov/product/pdf/R/R46110.

[4] FDA, Guidance for Industry, New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products (October 2014), available at https://www.fda.gov/files/drugs/published/New-Chemical-Entity-Exclusivity-Determinations-for-Certain-Fixed-Combination-Drug-Products.pdf (emphasis added).  

[5] FDA, Letter dated October 23, 2009, Docket No. FDA-2009-N-0184, available at https://www.wsgr.com/a/web/8e7awFcT8F2CVNDVVDbdeP/fda-2009-n-0184-00341.pdf.

[6] Id. at 9-10.

[7] Id. at 9.

[8] Sandoz Inc. v. Cochran et al., No. 1:21-cv-00600 (D.D.C. 2021).

[9] Aly L, Hemmer B, Korn T. From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis. Curr Neuropharmacol. 2017;15(6):874-891, available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652031/.  

[10] Complaint at ¶¶ 31-33, No. 1:21-cv-00600.