FDARA: Single Enantiomer Exclusivity RevisitedJune 19, 2007
In chemistry, enantiomers are stereoisomers that are non-superimposable complete mirror images of one another. Enantiomers may be either “right-handed” (dextro-rotary) S(+)-isomers, or “left-handed” (levo-rotary) R(-)-isomers. A racemic mixture is one that has equal amounts of “left- and right-handed” enantiomers of a particular chiral molecule. For example, omeprazole (PRILOSEC) is a racemic mixture; esomeprazole, the “right-handed” enantiomer of the racemate, is approved under the brand name NEXIUM.
FDA has for decades treated single enantiomers of approved racemates as previously approved active moieties not eligible for 5-year new chemical entity exclusivity (but rather 3-year exclusivity). In the preamble to FDA’s July 1989 proposed regulations implementing the Hatch-Waxman Act, the Agency stated this position:
FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis. FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.
The Senate-passed version of the FDA Revitalization Act (“FDARA”), however, would provide sponsors the opportunity to elect 5-year exclusivity under certain circumstances. The FDARA provision would also apparently put to bed a 1997 FDA notice in which the Agency requested comment on whether granting a 5-year period of exclusivity to enantiomers of previously approved racemates would encourage medically significant innovation.
Specifically, FDARA § 264 would amend the FDC Act to add § 505(t) –“Certain Drugs Containing Single Enantiomers”– to provide that:
if an application is submitted under [§ 505(b)] for a non-racemic drug containing as an active ingredient a single enantiomer that is contained in a racemic drug approved in another application under [§ 505(b)], the applicant may, in the application for such non-racemic drug, elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug . . . .
Thus, if a single enantiomer is not considered to be the same active ingredient as that contained in the approved racemic drug, FDA may consider it to be a new chemical entity eligible for 5-year exclusivity. There are, however, several provisos . . . .
The election of 5-year exclusivity can only be made if:
(A)(i) the single enantiomer has not been previously approved except in the approved racemic drug; and (ii) the application submitted under [§ 505(b)] for such non-racemic drug –
(I) includes full reports of new clinical investigations (other than bioavailability studies) – (aa) necessary for the approval of the application under subsections (c) and (d); and (bb) conducted or sponsored by the applicant; and
(II) does not rely on any investigations that are part of an application submitted under [§ 505(b)] for approval of the approved racemic drug; and
(B) the application submitted under [§ 505(b)] for such non-racemic drug is not submitted for approval of a condition of use— (i) in a therapeutic category [(as identified in the list referenced at 42 U.S.C. § 1860D-4(b)(3)(C)(ii))] in which the approved racemic drug has been approved; or (ii) for which any other enantiomer of the racemic drug has been approved.
In addition to these requirements, which essentially necessitate the submission of a “full” 505(b)(1) NDA, FDARA § 264 also includes two significant limitations that may offset the incentive for electing 5-year exclusivity.
First, FDA may not approve a single enantiomer of a previously approved racemate granted 5-year exclusivity for any condition of use in the therapeutic category in which the racemic drug has been approved “[u]ntil the date that is 10 years after the date of approval of a non-racemic drug described in [proposed FDC Act § 505(t)(1)].”
Second, “the labeling of a non-racemic drug described in [proposed FDC Act § 505(t)(1)] and with respect to which the applicant has made the election provided for by such paragraph shall include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”
Whether FDARA § 264 (if enacted) will encourage the development of single enantiomers for new therapeutic uses remains to be seen. Perhaps for this reason, FDARA § 264 is a trial balloon that Congress would need to reauthorize after it sunsets in 2012 (and once Congress evaluates its costs and benefits).
- FDA policy document on stereoisomeric drugs