2017 Summer Newsletter- FDA Orange Book Added Identifier

FDA Orange Book Added Identifier

Prior to 2017, the FDA’s “Approved Drug Products with Therapeutic Equivalence Evaluations” (Orange Book) used the Reference Listed Drug (RLD) identifier for different uses, depending upon the market situation.  These uses included the RLD identifying the NDA or an ANDA (when the NDA was no longer marketed or other extraordinary situations) that would identify the product to compare for bioequivalence.  The RLD was also used as the standard for generics to use for pharmacokinetic testing when preparing for an ANDA submission.

In this scenario, when an ANDA was identified as the RLD, the FDA clarified which product prospective ANDA applicants should use for bioequivalence testing as the reference standard.  This change created new issues because the ANDA applicant knew which product to conduct their pharmacokinetic testing, but there was no longer a NDA to use as the basis of generic labeling.  This caused confusion for ANDA applicants because the RLD identifier was being used to determine the “reference standard” (RS), which may not have been the basis for product labeling.

In 2017, the FDA updated the Orange Book to split the RLD identifier into the two unique definitions.  The RLD now solely refers to the application and labeling aspect the ANDA applicant should reference. The RS determines the product to conduct the bioequivalence testing.  In many cases, the RLD and RS are the same product.  The separate identifiers can be used to clearly delineate the focus for the applicant’s labeling vs. the bioequivalence testing.

FDA Orange Book Examples May 2017

Januvia, a single source brand, depicts the scenario in the Orange Book where only the brand is listed and available.  Januvia is both the RLD and RS reference product.

Summer NL 1

Darifenacin (generic Enablex) demonstrates that the NDA will continue to be identified as the RLD and RS as long as it is marketed.

Summer NL 2

The RLD can identify a discontinued NDA product, while the RS can identify an active ANDA so the ANDA applicant can clearly determine the comparison application for labeling (RLD) and the comparison application for pharmacokinetic studies (RS).

This second scenario is found with Cefaclor oral suspension.  The active ANDA is the RS, and the discontinued NDA, Ceclor, is the RLD.  Prior to the FDA change in 2017, the ANDA would have been identified as the RLD instead of the discontinued NDA.

Summer NL 3

The reference standard (RS) in the FDA Orange Book is a new identifier on certain products and depicts which product the applicant should use for bioequivalence testing.  The new RS identifier is not currently found in the drug compendia, but must be referenced in the FDA Orange Book.  The RLD now is solely focused on identifying the product to reference the labeling.  ANDA applicants now have clarity from the FDA for labeling (RLD) and product source for pharmacokinetic testing (RS).


2017 Summer Newsletter- 2018 Drug Exclusion Lists