Congress Passes Legislation Codifying FDA’s “Active Moiety” Approach to Exclusivity Determinations

On April 23, 2021, President Biden signed into law the “Ensuring Innovation Act,” which modifies section 505 of the Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. § 355, by codifying the regulatory approach used by the U.S. Food and Drug Administration for awarding exclusivity to drug products that introduce a new chemical entity as its active ingredient. Although the legislation endorses the regulatory status quo, it is nonetheless important because a judicial decision had questioned whether, in the case of drug products that are mixtures, FDA’s approach conflicted with the text of the statute and improperly narrowed when exclusivity is available. By codifying FDA’s approach, Congress has now resolved that objection, shutting down a potential argument for exclusivity by sponsors of new drug applications.

Prior to these amendments, the FDCA provided for a five-year exclusivity period for a newly-approved drug that did not contain an “active ingredient” that had been previously approved. The FDA, however, has long implemented this statutory exclusivity — commonly referred to as new-chemical entity exclusivity, or “NCE” — using different terms than the statute. Under FDA’s approach, NCE exclusivity is available for “new chemical entities” that contain an “active moiety” not previously approved by the agency. Under FDA regulations, the “active moiety” refers to the molecule or ion (excluding those appended portions that cause the drug to be an ester, salt, or other noncovalent derivative) that is responsible for the physiological or pharmacological action of the drug substance.

In many cases, there is no relevant difference between the “active ingredient” and the “active moiety” for purposes of exclusivity. See, e.g., Otsuka Pharm. Co. v. Price, 869 F.3d 987, (D.C. Cir. 2017) (describing “active moieties” as meaning “roughly, active ingredients”). That is because for single-molecule drugs, there is both only one active ingredient and one active moiety. But in cases involving products that are mixtures, the distinction could matter. Specifically, in the context of certain well-characterized mixtures, FDA has taken the position that the entire mixture is the “active ingredient” for the drug, but that each component molecule that contributes to the drug’s effect is an “active moiety.” FDA will not grant exclusivity if one active moiety in a mixture was previously approved by the agency — even if the “active ingredient” (i.e., the mixture as a whole) had not been previously approved.

In a case involving the drug Vascepa, a district court rejected FDA’s approach to mixtures as contrary to the plain text of the statute, with the court criticizing the FDA for making exclusivity determinations based on its own “active moiety” concept rather than following the statute’s focus on whether an “active ingredient” had been previously approved. See Amarin Pharmaceuticals Ireland Limited v. FDA, 106 F. Supp. 3d 196, 204 (D.D.C. 2015). The reasoning of that decision opened the door for mixtures that contained a previously approved activity moiety to seek a five-year exclusivity award for developing a new chemical entity.

But Congress’ newly enacted legislation now closes that door, as the legislation expressly adopts FDA’s regulatory definition, providing that a drug that contains an adequate moiety previously approved by the FDA is not eligible for NCE. The new legislation thus endorses FDA’s effort to narrow the scope of exclusivity available for new chemical entities.

Readers may wonder if this legislation will impact FDA’s policy on NCE exclusivity determinations for certain fixed-combination drug products (i.e., products in which two or more active moieties are combined in a single dosage form). Historically, a fixed-combination was ineligible for five-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that the Agency had not previously approved). Acknowledging the increasing importance of fixed-combinations, in 2014 FDA amended its policy to provide that “an application for a fixed-combination submitted under section 505(b) of the FD&C Act will be eligible for five-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).” The policy change was grounded in a revised interpretation of the term “drug” in the five-year NCE exclusivity provisions to mean “drug substance” (as opposed to “drug product”). Thus, replacing “active ingredient” with “active moiety” in the NCE eligibility clause does not appear to impact FDA’s policy for fixed-combinations.