FDA’s Orange Book Preface Gets a Facelift: What’s New?

By Kurt R. Karst –

Those folks who have been following this blog for several years have a good sense about the depths of this blogger’s passion for the Orange Book. There’s the license plate (“ORNGBUK”), the trip to the summit of Mt. Kilimanjaro with the publication (yes, we got a few odd stares from other climbers), the new chapter in the book this blogger authors – Generic and Innovator Drugs: A Guide to FDA Approval Requirements – exploring nearly all of the Orange Book minutiae you can imagine, the various posts about Orange Book firsts and developments (here, here, and here for example), and, of course, the Hatch-Waxman/Orange Book trivia.  So it should come as no surprise that around this time each year, anticipation for FDA’s release of the annual edition of the Orange Book is at its highest.  (We’d call it a “Code Orange,” but we used that line in a another post about the Orange Book a couple of years ago – see here.)  

Why is the anticipation so high? We like perusing the Orange Book Preface each year to see what (if anything) has changed from the previous year.  Most years it’s merely a fun “where’s Waldo” type exercise (Hatch-Waxman style) looking for minor word changes or the Office of Generic Drugs’ sense of humor.  (For that sense of humor, take a look at Section 2.2 [DRUG PRODUCT ILLUSTRATION] of the Preface.  Applicants identified in the illustrations are – or were – members of FDA’s Orange Book Staff – e.g., GREENBERG PHARM; TIMOKIM LLC; JOHNSON MED; KENDRA PHARM.).  But sometimes we’ve seen new FDA policies announced in the Orange Book Preface (see our previous post here).  

The Preface to the 2016 and 36th Annual Edition of the Orange Book includes a lot of changes. Clearly, someone took a close look at the Preface to clean it up.  Many of the changes are just nips and tucks.  They start on the cover page, which now identifies the recently-established Office of Generic Drug Policy as the office housing the Orange Book Staff.  Other minor updates include corrections to grammar, word choice changes (e.g., “When the Citizen Petition is approved” to “If the citizen petition is approved”), and greater use of more contemporary terms (e.g., “authorized generic”).  

There are also a few moderate changes that have been made to the Preface. In a largely revised Section 1.12, titled “Changes to the Orange Book,” FDA reminds manufacturers that the Agency must be notified when the marketing status of a product changes.  Previously, FDA was more passive on this requirement, merely stating: “Applicant holders are requested to inform the FDA Orange Book Staff (OBS) of any changes or corrections.  Please inform the OBS when products are no longer marketed.”  In more active language, the Preface now states:

Applicants are requested to inform the FDA Orange Book staff of any changes or corrections, including any change in a product’s marketing status that would result in the product being moved to the Discontinued Drug Product List. FDA notes that 21 CFR 314.81(b)(3)(iv) requires an applicant to submit a notice to the Agency within fifteen working days of the withdrawal from sale of a drug product. 

Section 1.12 has also been updated to express FDA’s policy that the Agency does not intend to update listings with the evolution of product description conventions: 

To the extent that conventions for describing product identification information (i.e., active ingredients, dosage forms, routes of administration, product names, applicants, strengths) evolve over time, the Agency generally does not intend to revise such information for drug products already included in the List, but rather intends to apply the change prospectively to drug products added to the List.

This policy is also relayed in an addition to Section 1.2 discussed below. 

The 2015 Preface (as well as previous editions) included Section 1.3, titled “Statistical Criteria for Bioequivalence,” that went on for about two pages. That section, renamed “Further Guidance on Bioequivalence,” in the 2016 Preface is now significantly shorter, and merely states: “FDA’s regulations and guidance documents provide additional information regarding bioequivalence and bioavailability, including methodologies and statistical criteria used to establish the bioequivalence of drug products.”  In a footnote, FDA notes the revision and includes links to the Agency’s regulations and guidance documents for additional information regarding bioequivalence and bioavailability requirements.

Aside from the minor and moderate changes, there are a couple of more significant changes FDA made to the Orange Book Preface in 2016.

First, in Section 1.2, titled “Therapeutic Equivalence-Related Terms,” FDA adds the term “Strength” and a definition:

Strength. Strength refers to the amount of drug substance (active ingredient) contained in, delivered, or deliverable from a drug product.  Note that if the criteria the Agency establishes for determining and expressing the amount of drug substance in a product evolves over time, the Agency generally does not intend to revise the expressions of strength for drug products already included in the List, but rather intends to apply the criteria prospectively to drug products added to the List.

The strength of drug products in the List is generally expressed in terms of the amount of drug substance (active ingredient) in the drug product, but is sometimes expressed in terms of the amount of the active moiety. For example, certain drug products included in the List include a designation of “EQ” next to their expression of strength.  This “EQ” designation generally is used in connection with salt drug products to indicate that the strength of such drug product is being expressed in terms of the equivalent strength of the active moiety (e.g., “EQ 200MG BASE”), rather than in terms of the strength of the active ingredient.

The description of salt drug products reflects the 2013 adoption of the USP Salt Policy, which is discussed in an FDA guidance.  FDA also cleans up the description of an “AP” therapeutic equivalence rating insofar as how the strength of parenteral drug products is expressed.

The most significant change to the 2016 Orange Book Preface appears to be in Section 1.10, titled “Change of the Therapeutic Equivalence Evaluation for a Single Product.” The change concerns the assignment of therapeutic equivalence ratings to drug products approved under 505(b)(2) NDAs.  At the end of Section 1.10, FDA adds a new paragraph:

We recognize that certain drug products approved in 505(b)(2) applications may not have therapeutic equivalence codes, and that FDA may undertake therapeutic equivalence evaluations with respect to such drug products. A person seeking to have a therapeutic equivalence rating for a drug product approved in a 505(b)(2) application may petition the Agency through the citizen petition procedure (see 21 CFR 10.25(a) and CFR 10.30).

You may recall that in recent years there’s been a decent amount of controversy over the issue of therapeutic equivalence rating assignment to 505(b)(2)-approved drug products, from citizen petitions (see our previous post here), to a lawsuit against FDA that was later dropped (see our previous post here).  In addition to substitutability, the assignment of therapeutic equivalence ratings to drug products approved under 505(b)(2) NDAs has an effect on whether or not a manufacturer is subject to annual PDUFA user fees.  

Is FDA’s pronouncement that the citizen petition process may be utilized for therapeutic equivalence rating assignment purposes an indication that FDA will no longer make therapeutic equivalence rating decisions for 505(b)(2)-approved drug products on its own initiative? Or maybe it’s that FDA will not make such determinations in non-obvious and difficult cases absent a citizen petition.  (Of course, what constitutes non-obvious or difficult will differ from one person to another.)  We’ll see.  

In the past, FDA has made the calls in complicated 505(b)(2) situations. . . . sometimes leading to inconsistencies in how (or if) 505(b)(2) drug products are rated. For example, FDA rated as “BX” three strengths of SEROSTIM (NDA 020604) with respect to corresponding strengths of other Somatropin Recombinant Injection drug products notwithstanding differences in labeled indications between the drug products. In other cases, however, products one would think might have a “B” therapeutic equivalence rating are not rated at all. For example, VELETRI (epoprostenol sodium) 1.5 mg Injection (NDA 022260) is not rated to the listed drug relied on for approval, FLOLAN Flolan (epoprostenol sodium) 1.5 mg Injection (NDA 020444). VELETRI is a 505(b)(2) by virtue of a formulation with a so-called non-exception excipient – arginine – that makes the product more stable upon reconstitution and administration. The improved stability of the product led to different labeled storage conditions, and apparently to FDA’s decision not to assign a “B” rating among the two drug products, notwithstanding pharmaceutical equivalence and bioequivalence.