“Date of approval” refers only to a final approval and not to a tentative approval that may become effective at a later date. [(Emphasis added)]Eisai alleged in its Complaint that FDA violated the FDC Act and the Administrative Procedure Act (“APA”) in multiple respects by using the BELVIQ and FYCOMPANDA approval dates as the triggering events to start the NCE exclusivity periods, thereby possibly accelerating the timing of future generic competition for BELVIQ and FYCOMPA. According to Eisai:[C]onsistent with FDA’s regulation—21 C.F.R. §314.108(a)—the governing statute, and clear congressional intent, market exclusivity for BELVIQ® and FYCOMPA® should have been triggered when labeling incorporating the final CSA schedule permitted legal marketing of the products. FDA’s letters approving the products as safe and effective reinforce this requirement.

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 moietyis 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 entitymeans 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.

Endnotes1 See http://investor.amarincorp.com/releasedetail.cfm?ReleaseID=973501.2Amarin Pharms Ireland Ltd. v. FDA, 14-cv-00324 (Dist. Court, Dist. of Columbia, 2015).3 Id.4 21 CFR 314.108(b)(4). This article does not address other available exclusivities such as e.g., orphan drug exclusivity, pediatric exclusivity, or GAIN Act exclusivity, because these exclusivities are not directly relevant to procuring NCE exclusivity.

In a Federal Register Notice dated February 24, 2014, the U.S. FDA announced a draft guidance for industry that will provide a 5 year NCE exclusivity period to fixed-combination drug products that include at least one new drug substance.The Statute and Regulations at Issue Sections 505(c)(3)(E)(ii) and (j)(5)(F)(ii) of the Food, Drug, and Cosmetic Act and 21 CFR § 314.108 provide for a 5 year period of regulatory exclusivity for drug products that include a new chemical entity (NCE). In particular, 21 CFR § 314.

Under the FDC Act, FDA grants 5-year exclusivity for NCEs. An NCE is a drug that contains no “active moiety” that has been approved by FDA in another NDA. An “active moiety” is defined in FDA’s regulations at 21 C.F.R. § 314.108(a) to mean “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.” In addition, FDA stated in the preamble to the Agency’s 1989 proposed regulations implementing the Hatch-Waxman Amendments that “[a] compound (other than an ester) that requires metabolic conversion to produce an already approved active moiety is considered a ‘new molecular entity,’ . . . and will be considered a new chemical entity entitled to 5 years of exclusivity.

EndnotesBraeburn Inc. v. U.S. Food & Drug Admin., No.19-cv-982 (D.D.C. July 22, 2019). 21 C.F.R. § 314.108(b)(4)(iii). The 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.”

ARISTADA is a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole) that FDA approved for the treatment of schizophrenia – the same use for which ABILIFY is approved – and for which a period of 5-year New Chemical Entity Exclusivity was awarded. In ruling for FDA (and intervenor Alkermes), Judge Jackson granted Motions for Summary Judgment filed by FDA and Alkermes (here and here), and denied Otsuka’s Motion for Summary Judgment (here).As we previously reported (see our previous posts here and here), Otsuka alleged in its Complaint that FDA violated the FDC Act’s 3-year exclusivity provisions (FDC Act § 505(c)(3)(E)(iii) and (iv), and referred to as “romanette iii” and “romanette iv” in the court’s ruling), the Agency’s regulation governing 3-year exclusivity (21 C.F.R. §§ 314.108(b)(4) and (5)), and the Administrative Procedure Act (“APA”) in approving ARISTADA. All three allegations boil down to a single issue, as the court noted:What is at issue in the instant case is the scope of the exclusivities that were conferred to Abilify Maintena and its supplement by statute. . . .

ys out the various NDA Classification Codes FDA uses, but the new MAPP has new and refined codes: Type 1 — New Molecular EntityType 2 — New Active IngredientType 3 — New Dosage FormType 4 — New CombinationType 5 — New Formulation or Other Differences (e.g., new indication, new applicant, new manufacturer)Type 6 — New Indication or Claim, Same ApplicantType 7 — Previously Marketed But Without an Approved NDAType 8 — Rx to OTCType 9 — New Indication or Claim, Drug Not to be Marketed Under Type 9 NDA After ApprovalType 10 — New Indication or Claim, Drug to be Marketed Under Type 10 NDA After ApprovalMedical Gas — A Designated Medical Gas Certification Request Submitted Under Section 576 of the FD&C Act The new MAPP also gives us a ready-made answer when we’re asked: “What’s the difference between an NCE and a New Molecular Entity (‘NME’)”:The terms New Molecular Entity (NME) and New Chemical Entity (NCE) are sometimes used interchangeably; however, they are distinct. An NCE is defined in 21 CFR 314.108(a) as “a drug that contains no active moiety that has been approved by the FDA in any other application submitted under 505(b) of the Act.” The term NME is not defined in the statute or regulations.

But FDA says that this committment, which, to the Agency’s knowledge, has never been broken by an NDA sponsor, applies only after (and can only be broken after) NDA approval.Finally, Eisai had argued that because FDA’s regulations at 21 C.F.R. § 314.108 (implementing the FDC Act’s NCE exclusivity provisions) define the term “date of approval” to mean, in relevant part, “the date on the letter from FDA stating that the [NDA] is approved, whether or not final printed labeling or other materials must yet be submitted as long as approval of such labeling or materials is not expressly required” (emphasis added), “the regulation is written to ensure that the effective approval date for purposes of exclusivity is tied to the date that the drug can actually be commercially marketed” (i.e., marketed in interstate commerce) (emphasis in original). And in the case of BELVIQ and FYCOMPA, says Eisai, because of the need to submit and obtain approval for revised labeling, their situation falls within the emphasized text at 21 C.F.R. § 314.108 above.

Under the “bar clause,” the submission of any ANDA (or 505(b)(2) application) that “refers to the drug for which the [505(b)] application was submitted” is prevented for 5 years (absent a Paragraph IV certification). Under FDA’s revised interpretation as described in the Consolidated Response, the term “drug” in the “eligibility clause” of the statute (and in the regulatory definition of NCE at 21 C.F.R. § 314.108) refers to drug substance, not drug product. But what about the statutory “bar clause”?According to Gilead, FDA agreed in the Consolidated Response that under the “bar clause” the term “the drug” has historically been interpreted under FDA’s so-called “umbrella policy” to mean a particular active moiety rather than a drug product.