FDA Guidance on Differences Between RLD and Reference Standard for ANDA Applicants

On January 17, 2017, FDA released a nonbinding draft Guidance for Industry on “Referencing Approved Drugs Products in ANDA Submissions.”  FDA intends the Guidance to provide recommendations on how to identify a reference listed drug (RLD), a reference standard, and the basis of submission in an ANDA submission.

By way of background, an ANDA applicant relies on FDA’s finding that a previously approved drug, i.e. RLD, is safe and effective.  In obtaining approval, the ANDA applicant must demonstrate, among other things:  (1) that the proposed generic drug is the same as the RLD; (2) that the proposed generic drug is bioequivalent to the RLD; and (3) if in vivo bioequivalence studies are required for approval of the ANDA, that the proposed generic drug is bioequivalent in vivo to a reference standard selected by FDA.

ANDA applicants may obtain permission to apply for a generic drug that is not the same as the RLD by a type of citizen petition referred to as a “suitability petition.”

The Guidance defines an RLD, a reference standard, and the basis of submission as the following:

RLD:  An RLD is the specific listed drug on which an ANDA applicant relies in seeking approval for its ANDA.  The ANDA applicant must show, among other things, that its proposed generic drug is the same as to the RLD with respect to the active ingredient(s), dosage form, route of administration, strength, labeling and conditions of use.  FDA identifies listed drugs that are eligible to be RLDs in the Orange Book.  A listed drug that appears in the Discontinued Section in the Orange Book may be eligible to be an RLD, unless FDA makes a determination that the listed drug was withdrawn from the market for reasons of safety or effectiveness.  The Guidance provides ways in which a potential ANDA applicant can request FDA to designate an RLD or a different RLD.

Reference Standard:  A reference standard is a listed drug selected by FDA that an ANDA applicant must use in conducting an in vivo bioequivalence study.  FDA may require the in vivo bioequivalence study if bioequivalence is otherwise not self-evident.  As with the RLD, FDA identifies listed drugs in the Orange Book that are eligible to be reference standards.  The Guidance provides ways in which a potential ANDA applicant can request FDA to designate a reference standard or a different reference standard.

Basis of Submission:  There are three possible bases of submission for an ANDA applicant:

(1)  Basis of Submission for an ANDA for a Generic Drug that is the Same as its RLD.  The basis of submission would be the RLD.  If the reference standard is not the RLD, then the reference standard should not be identified as the basis of submission but should be identified in other relevant sections that pertain to bioequivalence.

(2)  Basis of Submission for First Petitioned ANDA.  The basis of submission is: (1) the RLD, which must be the same as the listed drug identified in the approved suitability petition; (2) a reference to the suitability petition’s FDA-assigned docket number; and a copy of FDA’s correspondence approving the suitability petition.

(3)  Basis of Submission for a Generic Drug that is the Same as a Drug Product Approved in a Petitioned ANDA.  The basis of submission is:  (1) the RLD, which must be the same as the listed drug identified in the approved suitability petition, and RLD application number; (2) a reference to the suitability petition’s FDA-assigned docket number; and (3) a copy of FDA’s correspondence approving the suitability petition.

The Guidance specifically cautions ANDA applicants not to confuse the terms RLD and reference standard.  Ordinarily, the reference standard selected by FDA will be the RLD; however, that is not always so.  If FDA has selected a reference standard for use in in vivo bioequivalence studies different from the RLD, then the ANDA applicant must compare its proposed product’s labeling and formulation to that of the RLD and not to the reference standard.

The Guidance does not address any new practice for potential ANDA applicants in submitting an ANDA.  The Guidance, however, provides that, starting in 2017, FDA intends to modify the Orange Book, both in paper and electronic form, to clarify which listed drugs are RLDs and which are reference standards, and to indicate which products in the Discontinued Section may be referred to as an RLD.