When Can’t a “Listed Drug” Serve as a Reference Product for a 505(b)(2) Application?

By Kurt R. Karst –      

Over the past year or so, we’ve seen a change in FDA policy concerning what approvals the sponsor of a 505(b)(2) NDA can cite in an application; that is, what previous FDA approvals a 505(b)(2) sponsor can rely on for the aproval of its drug product.  This change has not come about by rulemaking or by formal FDA guidance, but rather, has been communicated to potential 505(b)(2) applicants in general FDA correspondence.  As such, we thought the larger food and drug community would benefit from bringing this issue to light. 

FDC Act § 505(b)(2) describes a 505(b)(2) NDA as “[a]n application submitted under [FDC Act § 505(b)(1)] for a drug for which the investigations described in clause (A) of [FDC Act § 505(b)(1)] and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. . . .”  Draft FDA guidance distills this statutory description down to “an application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.” 

FDA’s regulations implementing FDC Act § 505(b)(2) provide that one component of a 505(b)(2) application is the “[i]dentification of the listed drug for which FDA has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product by established name, if any, proprietary name, dosage form, strength, route of administration, name of listed drug's application holder, and listed drug’s approved application number.”  21 C.F.R. § 314.54(a)(1)(iii) (emphasis added).  FDA’s regulations (21 C.F.R. § 314.3) further define the term “listed drug” to mean:

a new drug product that has an effective approval under [FDC Act § 505(c)] for safety and effectiveness or under [FDA Act § 505(j)], which has not been withdrawn or suspended under [FDC Act §§ 505(e)(1) through (e)(5) or FDC Act § 505(j)(5)], and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness.  Listed drug status is evidenced by the drug product’s identification as a drug with an effective approval in the current edition of FDA’s [Orange Book] or any current supplement thereto, as a drug with an effective approval.  A drug product is deemed to be a listed drug on the date of effective approval of the application or abbreviated application for that drug product.

For years, FDA has permitted sponsors of 505(b)(2) applications to cite products approved under an ANDA as a “listed drug” in their application.  In most cases, this occurred when the brand name drug product was discontinued and FDA designated a therapeutic equivalent approved under an ANDA as the Reference Listed Drug (“RLD”).  In other cases, FDA approved an ANDA under a suitability petition, or approved an ANDA pre-Hatch-Waxman pursuant to a finding under the Drug Efficacy Study Implementaion (“DESI”) program, and designated the ANDA product as the RLD. 

Under FDA’s evolving thinking around 505(b)(2) applications, however, an ANDA can no longer be cited as a listed drug in a 505(b)(2) application.  According to recent guidance from FDA on this issue to would-be 505(b)(2) applicants:

If you intend to rely on the Agency’s finding of safety and/or effectiveness for a listed drug(s) or published literature describing a listed drug(s) (which we consider to be reliance on FDA’s finding of safety and/or effectiveness for the listed drug(s)), you should identify the listed drug(s) in accordance with the Agency’s regulations at 21 CFR 314.54.  It should be noted that 21 CFR 314.54 requires identification of the “listed drug for which FDA has made a finding of safety and effectiveness,” and thus an applicant may only rely upon a listed drug that is the subject of an NDA approved under section 505(c) of the FD&C Act (in other words, an application approved under section 505(j) of the Act (i.e., ANDA, generic drug) may not be cited as a listed drug).  The regulatory requirements for a 505(b)(2) application (including, but not limited to, an appropriate patent certification or statement) apply to each listed drug upon which a sponsor relies.

If you choose to rely on FDA’s finding of safety and/or effectiveness for a listed drug(s) and you intend to use your proposed comparative clinical trial to establish a bridge between your proposed drug product and the specified listed drug(s), then you should use the specified listed drug(s) (rather than a bioequivalent ANDA product) as the comparator.

In other words, the 505(b)(2) pathway, according to FDA, contemplates a 505(b)(2) applicant’s reliance on the Agency’s finding of safety and effectiveness that is contained in an NDA; and because an ANDA does not contain this finding, it cannot serve as a “listed drug for which FDA has made a finding of safety and effectiveness.” 

It is unclear whether FDA’s new policy is a one-size-fits-all policy, or whether there are exceptions.  For example, there might be some unique cases where FDA would permit a 505(b)(2) sponsor to cite an ANDA approved pursuant to a DESI proceeding as as a listed drug.  And what about an ANDA approved pursuant to a suitability petition that FDA has designated as a RLD – can a 505(b)(2) sponsor cite such a drug as a listed drug?  Perhaps FDA’s long-awaited proposed regulations implementing the Medicare Modernization Act will address these issues in greater detail.