FDA Law Blog: Bigger, Better, Faster, Stronger: The New Orange Book Makes Its Debut

FDA Law Blog: Bigger, Better, Faster, Stronger: The New Orange Book Makes Its Debut

Bigger, Better, Faster, Stronger: The New Orange Book Makes Its Debut

By Kurt R. Karst –

On Wednesday, January 25, 2017, a new chapter will begin in the decades-old story of FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”).  According to a note posted on the Electronic Orange Book website last week (as well as in a separate notice published on FDA’s website earlier this week): “On January 25, 2017, The Orange Book data will be updated to reflect the recent publication of the draft guidance for industry ‘Referencing Approved Drug Products in ANDA Submissions.’” This blogger, and presumably Orange Book aficionados everywhere, are pretty excited about the updates that are coming to both the electronic and print versions of the Orange Book (and presumably to the Orange Book Express app as well).

The draft guidance document FDA mentions in the note above – Referencing Approved Drug Products in ANDA Submissions (Docket No. FDA-2017-D-0114) – was one of many guidance documents FDA released in the days before the January 20, 2017 Presidential Inauguration.  And it’s a very, very welcome addition to the growing list of guidance documents in the Hatch-Waxman space.  Why?  Because in the draft guidance FDA defines and explains, for what is really the first time (with the exception of some new definitions included in FDA’s recent rules implementing the 2003 Medicare Modernization Act), terms fundamental to Hatch-Waxman and ANDA submissions that have for many years been misunderstood or misused (by FDA and the pharmaceutical industry). 

Those terms are “Reference Listed Drug” (“RLD”), “Reference Standard,” and “Basis of Submission.” Each term refers to something very specific and critical to an ANDA submission.  Way back in 2012, we attempted to highlight the differences among these terms in a post titled “Big RLD” Versus “Little rld” – What’s the Difference?  But now we have something official from FDA that provides both a full explanation of the terms, as well as FDA policies relevant to each term.  Here’s a summary of the RLD, Reference Standard, and Basis of Submission concepts FDA provides in an appendix to the draft guidance:

• The reference listed drug (RLD) for an ANDA is the drug product that the proposed generic drug is intended to duplicate and to which the ANDA applicant must refer in its ANDA. The RLD must be a listed drug approved under section 505(c) of the FD&C Act based on a demonstration of safety and effectiveness. FDA identifies in the Orange Book listed drugs that are eligible to be RLDs. Starting in 2017, FDA intends to modify the Orange Book 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. In the electronic Orange Book, there will be a column for RLDs. In the printed version of the Orange Book, the RLDs will be identified by a specific symbol.
• In vivo bioequivalence studies needed to support an ANDA must be conducted using the drug product that FDA has selected as the reference standard. The reference standard may or may not be the same listed drug as the RLD. While the reference standard is selected by FDA for the purposes of conducting any in vivo bioequivalence testing required for approval, all other comparisons of the proposed generic drug to determine whether it meets the statutory requirements for approval under section 505(j) of the FD&C Act (e.g., sameness requirements) generally must be to the RLD. The reference standard for a drug product selected by FDA generally is identified in the Orange Book. In the electronic Orange Book, there will be a column for reference standards. In the printed version of the Orange Book, the reference standards will be identified by a specific symbol.
• If you mistakenly identify the reference standard as the RLD in your ANDA, you may submit an amendment to a pending ANDA or a supplement to an approved ANDA to correct the information. FDA considers this error to be a deficiency related to identification of the appropriate listed drug as the RLD, rather than a change in the RLD itself. The cover letter for such a submission should clearly identify that the purpose of the submission is “Correction of RLD information.”
• The basis of submission statement in an ANDA (e.g., in section 1.12.11 of the ANDA) and in Form FDA 356h (field 20) should include the RLD and the RLD application number. For a petitioned ANDA, the basis of submission statement in the ANDA (e.g., in section 1.12.11 of the ANDA) also should include a reference to the FDA-assigned docket number for the suitability petition and a copy of FDA’s correspondence approving the suitability petition. The reference standard, if it is different from the RLD, should be identified in the appropriate sections of the ANDA (e.g., sections 1.12.11, 2.7.1, 5.2, and 5.3.1).

As FDA notes above, modifications to the Orange Book are on the way. And those changes will go live on January 25, 2017. But we don’t have to wait until then to get a peek at the new Orange Book. FDA recently published a 17-minute webinar explaining the changes to the Orange Book and the policies laid out in the draft guidance. In a presentation accompanying the webinar, FDA shows how the electronic and print versions of the Orange Book will be modified. In the print version of the Orange Book, RLDs will continue to be identified by the “+” symbol; however, FDA will now identify Reference Standards by the “!” symbol. Here’s an example:  The Orange Book Express app, which FDA introduced to the world on November 9, 2015 (see our previous post here), will also presumably be updated to reflect the new RLD and Reference Standard changes.We assume that other changes will also be made to the Orange Book with the introduction of the 2017 (and 37th) edition . . . and to the Preface in particular. That being said, we don’t anticipate quite the facelift that the Preface got last year (see our previous post here). At the very least, we assume that the Preface will be updated to remove any mention of LIBRAX as a drug product covered by an ongoing Drug Efficacy Study Implementation proceeding. After all, FDA only recently discovered and affirmed that LIBRAX is an approved drug . . . and has been for decades, according to the Agency (see our previous post here).

In the electronic version of the Orange Book, RLDs are now identified by “RLD” in the RLD column (instead of a “Yes” or “No”), and Reference Standards will be identified by “RS” in a new RS column. Here’s an example.

In the electronic version of the Orange Book, RLDs are now identified by “RLD” in the RLD column (instead of a “Yes” or “No”), and Reference Standards will be identified by “RS” in a new RS column. Here’s an example:

The Orange Book Express app, which FDA introduced to the world on November 9, 2015 (see our previous post here), will also presumably be updated to reflect the new RLD and Reference Standard changes.

We assume that other changes will also be made to the Orange Book with the introduction of the 2017 (and 37th) edition . . . and to the Preface in particular. That being said, we don’t anticipate quite the facelift that the Preface got last year (see our previous post here).  At the very least, we assume that the Preface will be updated to remove any mention of LIBRAX as a drug product covered by an ongoing Drug Efficacy Study Implementation proceeding.  After all, FDA only recently discovered and affirmed that LIBRAX is an approved drug . . . and has been for decades, according to the Agency (see our previous post here).