Contains Nonbinding Recommendations
Regarding the same labeling requirement, the generic drug must have the same labeling as the
RLD, except for differences permitted under the FD&C Act and Agency regulations.
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Accordingly, an ANDA applicant must compare its proposed product’s labeling to that of the
RLD, even if FDA has selected a new reference standard for use in in vivo bioequivalence
studies, as described in detail in section III.C. below.
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Similarly, in evaluating drug product
formulation and inactive ingredients, an ANDA applicant must compare its proposed generic
drug to the RLD’s formulation, not the formulation of the reference standard.
4. Identification of the RLD in the Orange Book
Prior to 2017, the column in the electronic Orange Book labeled “RLD,” and the symbol in the
printed version described as identifying the RLD, at times indicated the drug product FDA
selected as the reference standard and at other times indicated the RLD, contributing to
confusion about which drug is the RLD and which drug is the reference standard. In 2017, FDA
began to identify in the Orange Book which listed drugs, including some in the Discontinued
Section, FDA has designated as RLDs, and which listed drugs in the Active Section FDA has
selected as reference standards. In the electronic Orange Book, there is a column for RLDs and a
column for reference standards. In the printed version of the Orange Book, the RLDs and
reference standards are identified by distinct symbols.
5. Changing the RLD
Once an ANDA applicant chooses the RLD on which it intends to rely, the FD&C Act and FDA
regulations prohibit the applicant from amending or supplementing its ANDA to change the
RLD after the ANDA has been submitted.
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An ANDA applicant that seeks to change its RLD
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The FD&C Act and FDA’s regulations permit labeling differences because of differences approved under a
suitability petition or because the generic drug and the RLD are produced or distributed by different manufacturers.
Section 505(j)(4)(G) of the FD&C Act and 21 CFR 314.94(a)(8)(iv). In certain instances, the labeling for the
generic drug may differ from the labeling for the RLD if FDA permits the ANDA applicant to omit (carve out) an
indication or other aspect of the RLD’s labeling protected by patent, or by exclusivity, and obtain approval for the
remaining, non-protected conditions of use, provided the differences do not render the proposed product less safe or
effective than the RLD for all remaining non-protected conditions of use. See, e.g., section 505(j)(2)(A)(viii) of the
FD&C Act; 21 CFR 314.127(a)(7).
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An applicant is responsible for checking appropriate sources in order to obtain the RLD labeling. FDA posts
approved labels and labeling for most drug products on Drugs@FDA
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Other sources such as FDA’s Online Label
Repository athttps://dailymed.nlm.nih.gov/dailymed/index.cfm, and PRPLLR™ (Pragmatic Regulated Product
Labeling Listing and Registration) may not necessarily display the most recently approved labeling. In instances
where the RLD labeling cannot be located, an applicant for convenience initially may compare its proposed generic
drug’s labeling with the labeling of another ANDA that referenced the same RLD and currently is marketed. Where
FDA has withdrawn approval of the application for the RLD for reasons other than safety or effectiveness, the
ANDA applicant, before approval of the generic drug, may need to revise labeling to reflect certain updated
information that would have been necessary for the RLD had the application for the RLD not been withdrawn. See
FDA’s draft guidance for industry Updating ANDA Labeling After the Marketing Application for the Reference
Listed Drug Has Been Withdrawn (July 2016). When final, this guidance will represent FDA’s current thnking on
this topic.
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Section 505(j)(2)(D) of the FD&C Act; 21 CFR 314.96(c) and 314.97(b). We note that where an applicant has
previously mistakenly identified the reference standard (described in detail in section III.C.) as the RLD on Form