Actavis Elizabeth LLC v. FDA

Affirming an appeal from the D.C. District Court, the Court of Appeals for the D.C. Circuit ruled on November 9 in favor of the FDA’s position on drug molecules containing previously-approved active ingredients covalently bonded to further chemical components. The FDA position, before and after this ruling, is that a molecule held together by non-ester covalent bonds is itself an active ingredient, even if the molecule consists of another active ingredient covalently bonded to other molecules.

The case, Actavis Elizabeth LLC v. FDA, No 10-5066, involved the drug lisdexamfetamine dimesylate, known by the brand name Vyvanse, a treatment for ADHD. Lisdexamfetamine dimesylate is a salt of lisdexamfetamine, which in turn consists of a portion of the amino acid lysine covalently bonded to dextroamphetamine via an amine bond. After lisdexamfetamine enters the body, it breaks apart to produce dextroamphetamine. New River Pharmaceuticals, the predecessor in interest to Shire Pharmaceuticals, applied for FDA approval for Vyvanse in 2005 and received approval in 2007 with a five-year period of exclusivity under 21 U.S.C. § 355(j)(5)(F)(ii). The FDA had previously approved at least one application for dextroamphetamine, but not for lisdexamfetamine. Actavis submitted an ANDA for lisdexamfetamine dimesylate in January 2009, but the FDA returned the application because Vyvanse’s exclusivity period had not run. Actavis brought suit against the FDA alleging that Vyvanse should have only had a three year exclusivity period under 21 U.S.C. § 355(j)(5)(F)(iii), and after an FDA internal review affirming the original determination, the district court granted summary judgment in favor of the FDA.

The relevant statute in 21 U.S.C. § 355(j)(5)(F)(ii) provides that an applicant for approval of a drug with a previously-unapproved “active ingredient (including any ester or salt of the active ingredient)” is entitled to exclusivity in FDA approval for five years, starting on the approval date of the application. However, 21 U.S.C. § 355(j)(5)(F)(iii) grants only three years of exclusivity for FDA approval for drugs with previously-approved active ingredients and with applications containing new, essential clinical investigation reports sponsored by the applicant. Thus, the ability of Actavis to apply for approval for its lisdexamfetamine salt depended on whether the lisdexamfetamine salt was the same “active ingredient” as the previously-approved dextroamphetamine.

The D.C. Circuit agreed with the district court and the FDA that lisdexamfetamine, in salt form or not, was a single active ingredient, independent of previously-approved dextroamphetamine. In ruling with the FDA, the court stated that the FDA’s interpretation of its regulations was entitled to judicial deference and that Congress gave no indication in the statute or legislative history as to its position on what molecules or portions thereof constitute distinct “active ingredients.” The court also noted previous FDA statements that “even minor covalent structural changes are capable of producing not only major changes in the activity of a drug but changes that are not readily predicted.” The court found that the FDA’s approach was reasonable and ruled in the FDA’s favor.

This decision could encourage development of new drugs deriving from previously-approved drugs. Covalent, non-ester additions to an active ingredient molecule produce a new active ingredient entitled to a five-year FDA exclusivity period. Developers of new drugs may therefore engage more readily in researching derivative drugs. Other drug manufacturers, on the other hand, have to wait five years after approval of a derivative drug to submit an ANDA to the FDA for that active ingredient.