FDA mulls Orange Book overhaul to address patent listing, therapeutic equivalence, other issues

FDA Commissioner Scott Gottlieb, M.D. recently announced four steps FDA will be taking to ensure that the Orange Book (FDA’s publication of Approved Drug Products with Therapeutic Equivalence Evaluations) provides the greatest benefit to patients and providers, and (perhaps in particular) generic drug developers.  The Commissioner’s announcement addresses several important issues, including patent listing standards and therapeutic equivalence ratings.

Dr. Gottlieb said that in the coming year, FDA will issue draft guidance describing how the FDA evaluates therapeutic equivalence (TE) and assigns TE codes, which are published in the Orange Book.  An “A” rating indicates that products are therapeutically equivalent and signals to pharmacists and others that FDA considers the products to be substitutable for one another.  To be “A” rated, products must contain the same active ingredient, with the same dosage form, route of administration and strength, and they must be bioequivalent to each other.  These criteria are largely synonymous with the requirements for approval of generic drugs under 505(j).  Thus, drugs approved under ANDAs are assigned “A” ratings, indicating that they may be substituted for the branded pioneer product.

The agency, however, seems particularly interested in TE ratings for complex drug products, and the potential to assign TE ratings to products under 505(b)(2) NDAs.  Dr. Gottlieb said:

We believe this will be particularly beneficial for those seeking to develop generic products for harder-to-copy complex drugs that often face greater scientific and regulatory challenges and thus often have less competition.  For some of these drugs, the 505(b)(2) pathway may provide a more efficient development path and the agency is developing policy for how manufacturers can acquire a therapeutic equivalence rating to allow for full substitutability for products developed by this route.

Unlike drugs approved under ANDAs, drugs approved under 505(b)(2) need not be “the same” as the pioneer product, and FDA has less latitude to assign them “A” ratings.  FDA’s initiative seeks to maximize this latitude.

Second, Dr. Gottlieb stated that FDA will be soliciting public comment on Orange Book use and potential enhancements, including a re-examination of the types of pharmaceutical patents that must be listed in the Orange Book.  Listing patents in the Orange Book that claim the approved drug or method of using the drug is a key part of the Hatch-Waxman balancing of interests between pioneer and generic drug sponsors, affecting procedural protections and incentives for both sides.  Dr. Gottlieb indicated that FDA plans to consider novel issues associated with new technologies, such as whether an application holder for a drug product that has been approved for use in conjunction with a digital application should be required to list any patents associated with that app.  This will be a key issue in a rapidly emerging area of pharmaceutical product development.

FDA also may address other patent listing issues previously raised by stakeholders.  For example, FDA may seek to clarify the line between patents directed to “packaging” for a drug product, which are not generally listable, and patents directed to containers, closures, and other delivery-system components  considered integral to the “dosage form” of the drug product (e.g., transdermal patches, metered dose inhalers, and pre-loaded syringes), which generally are listable.

Additionally, Dr. Gottlieb announced a new draft guidance titled “Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format,” which is intended to provide approved drug application holders with clarity on the specific categories and descriptions of the information that they are required to share with FDA on the marketing status for their brand and generic drugs, as well as clarity on how to provide that information in a timely and consistent manner.

Section 506I was enacted in 2017 and requires NDA and ANDA holders alike to provide written notice to FDA within 180 days of approval if the drug will not be available for sale by that time.  It also requires 180 days written notice prior to withdrawing a drug product from sale.  Previously, the process for informing FDA that an approved product has been discontinued or withheld from sale was governed informally and there was no “advance warning” system, except in limited circumstances .  As Dr. Gottlieb notes, FDA’s intent is to provide transparency around circumstances where generic competition is lacking.

Last, Dr. Gottlieb announced plans to issue a draft guidance to provide answers to questions frequently asked by drug product applicants and approved application holders in using the Orange Book.  Overall, the Commissioner emphasized FDA’s goal to “allow generic competitors to better assess which products they choose to develop and provide greater clarity as to the path to market, [and] to make generic drug development more efficient and predictable.”

Comments will be accepted on the Marketing Status Notifications draft guidance until April 1, and there will be opportunities to comment on the forthcoming related draft guidances as well.  With much at stake, generic and pioneer drug manufacturers alike should be following these developments closely and seeking to comment.


Authored by Gary L. Veron, Jason Conaty and George O'Brien

Gary Veron
Washington D.C.
Jason Conaty
Washington D.C.
George O'Brien
Washington D.C.


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