Some Noteworthy Changes to the 2017 Orange Book Preface & Patent and Exclusivity Information Addendum

Last week, just before the new Orange Book (print and electronic versions) made its debut, we opined (see our previous post here) that changes to the Orange Book Preface would likely be made. Now that the print version of the Orange Book is available (here), we’ve had a chance to peruse those Preface (and Patent and Exclusivity Information Addendum) revisions.  Although the changes made to the 2017 Orange Book Preface are not nearly as substantial as the 2016 facelift (see our previous post here), there are some noteworthy changes, which we highlight below.  For ease of use and reference, we put together a redline of the 2017 Orange Book Preface and Patent and Exclusivity Information Addendum showing the additions and deletions compared to the 2016 versions.

Orange Book Preface

• Right off the bat, FDA deletes from the 2017 Preface any specific reference to drug products subject to pending DESI proceedings. Now gone is the text stating “Drugs on the market approved only on the basis of safety (covered by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g., Donnatal® Tablets and Librax® Capsules] or pre-1938 drugs [e.g., Phenobarbital Tablets]) are not included in this publication.” We anticipated that FDA would remove any reference to Librax, given the recent discovery that the drug was approved in the mid-1960s (see our previous post here); however, we didn’t expect the deletion of all that DESI-related and grandfather drug information. Now such products truly “are not included in this publication.”
• In Section 1.2 (Therapeutic Equivalence-Related Terms) of the Preface, FDA clarifies certain common terms, such as “pharmaceutical equivalents” and, in particular, “strength” to comport with definitions (at 21 C.F.R. § 314.3) that became effective on December 5, 2016 with the implementation of certain provisions of the 2003 Medicare Modernization Act (“MMA”).
• Curiously, FDA, in a discussion of the term “therapeutic equivalents” in Section 1.2, deletes the following sentence:“Therapeutic equivalence determinations are not made for unapproved, off-label uses.” This sentence has appeared in the Preface since the 17th (1997) edition of the publication, and was likely added to the Orange Book Preface as a result of the U.S. Court of Appeals for the District of Columbia Circuit’s August 1996 decision in Bristol-Myers Squibb v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996) (here). That decision affirmed an ANDA applicant’s ability to omit patent- or exclusivity- protected labeling information in a manner consistent with the FDC Act’s “same labeling” requirement. In reaching its decision, the D.C. Circuit ruled that the FDC Act “expresses the legislature’s concern that the new generic be safe and effective for each indication that will appear on its label; whether the label for the new generic lists every indication approved for the use of the pioneer is a matter of indifference.”
• In Section 1.4 (Reference Listed Drug and Reference Standard) of the Preface, FDA elucidates the terms “Reference Listed Drug” and “Reference Standard” and the process for their designation, as discussed in recent guidance issued by the Agency (see our previous post here).
• Fast-forwarding to Section 1.8 (Description of Certain Special Circumstances) of the Preface, FDA includes some added discussion around Levothyroxine Sodium and therapeutic equivalence ratings. In particular, FDA explains the rating of ANDA 076187 vis-à-vis other approved drug products and in light of a recent Citizen Petition decision (Docket No. FDA-2015-P-0403).

Orange Book Patent and Exclusivity Information Addendum

• FDA makes several noteworthy revisions to the Patent and Exclusivity Information Addendum, which precedes the Prescription and OTC Drug Product Patent and Exclusivity List. The changes reflect FDA’s new regulations implementing the MMA (e.g., patent information listings, and, in particular, method-of-use patent information), as well as new law, policy and court decisions.
• FDA’s descriptions of 5-year new chemical entity exclusivity and 3-year new clinical investigation exclusivity have been refined to reflect the Agency’s current interpretations of the law. For example, FDA’s revised description of 3-year exclusivity now states that if 3-year exclusivity is granted, then “a subsequent ANDA or a 505(b)(2) application may not be approved for the exclusivity-protected ‘conditions of approval of such drug’ before the expiration of three years from the date of approval of the original application. If a NDA or 505(b)(2) applicant has exclusivity only for a new indication or use, this exclusivity generally does not preclude the approval of an ANDA or 505(b)(2) application for indications and uses not covered by the exclusivity, assuming the proposed drug product will be safe and effective as labeled.” This revised description appears to be intended to more clearly convey FDA’s focus on the scope of 3-year exclusivity (see our previous posts here and here).
• FDA includes a note around the end of the Addendum stating: “Please note that the date of approval for an NDA for which FDA recommends controls under the Controlled Substances Act is the later of the date on the approval letter for the NDA or the date of issuance of the interim final rule controlling the drug (see section 505(x)(1) and (2) of the FD&C Act).” This note is consistent with changes FDA recently implemented in the Agency’s regulations defining the term “date of approval” (21 C.F.R. § 314.3). Those changes were necessary after the statute was amended in November 2015 by the IRTNMTA (Improving Regulatory Transparency for New Medical Therapies Act) to add FDC Act § 505(x) (see our previous post here). For an example of the IRTNMTA in action, check out NDA 205525 for SYNDROS (dronabinol oral solution), 5 mg/mL. FDA “approved” NDA 205525 on July 1, 2016; however, the drug product is not yet listed in the Orange Book as an approved drug.  Why?  Because SYNDROS is not yet truly approved for Orange Book listing purposes, as the scheduling of the product under the Controlled Substances Act is pending.

Well, there you have it: the 2017 Orange Book notes for junkies. We’ll surely revisit this post in 2018 when the 38th edition of the Orange Book is published.