Everything You Wanted to Know About the Orange Book But Were Too Afraid To Ask

July 26, 2022By Sara W. Koblitz

In its second Orange Book Guidance in as many days, FDA is addressing all of your burning questions about the Orange Book—and boy are we excited at the Agency’s efforts to make the Orange Book accessible for everyone!  The Guidance is a Frequently Asked Questions guidance that digs a little deeper into the Orange Book than it has in the past.  Like all Guidance documents, it starts out with background, explaining that the Orange Book is FDA’s list of drug products approved under the Federal Food, Drug, and Cosmetic Act and contains patent and exclusivity information related to such products.  For newer users, FDA explains that the Orange Book has four parts:

  • Prescription Drug List – a list of all approved marketed prescription drug products and their Therapeutic Equivalence Codes (TE Codes) (Part I of the Active Section of the Orange Book);
  • The OTC Drug Product List – a list of marketed OTC drug products approved in NDAs or ANDAs (Part II of the Active Section of the Orange Book);
  • Drug Products with Approval under FDCA § 505 Administered by CBER – a list of CBER-regulated drug products approved under NDAs (but NOT the same as the Purple Book, which is FDA’s database of licensed biological products); and
  • The Discontinued Drug Product List – a cumulative list of approved drugs that have never been marketed, have been discontinued, or have been withdrawn for reasons other than safety or effectiveness.

There are also three appendices (products listed by names and applicants and uniform terms) and two addenda (both related to patents and exclusivity).

The Guidance moves quickly into the Questions and Answers section, which is broken into four parts: Content and Format; Petitioned ANDAs; Active and Discontinued Listings; and—a crowd favorite—Patent Listings.  The Content and Format section is a bit of Orange Book 101; it addresses the basics of the Orange Book, including which applications are not in the Orange Book, how to access Orange Book Data Files, and updates of the Orange Book.

Though only one question long, the Petitioned ANDAs section packs a lot into a single paragraph.  The question essentially asks how Petitioned ANDAs—ANDAs for which FDA has granted permission to change from the reference listed drug (RLD) in route of administration, dosage form, or strength (and a few other changes)—are listed in the Orange Book.  FDA explains that the RLD, which is the drug on which the ANDA relies for FDA’s findings of safety and efficacy, is the drug that is referenced in the ANDA even though it is not pharmaceutically equivalent to the Petitioned ANDA.  And because Petitioned ANDAs are not pharmaceutically equivalent to their RLDs, they will not be assigned a TE Code (see our post about the TE Code guidance for more information about TE Codes).  Any ANDAs that have the same petitioned differences as the Petitioned ANDA will be assigned a TE Code to reflect whether the Petitioned ANDAs are equivalent to—and substitutable for—each other.

The third section, “Movement of Drug Products Between the Active and Discontinued Sections of the Orange Book,” tackles an often-confusing distinction between discontinued drug products and withdrawn.  It clarifies that a withdrawn drug product listed in the Discontinued Section does not necessarily indicate withdrawal of approval of that application; a drug product may just be withdrawn from sale, which means that the sponsor has decided to stop marketing for any reason.  Drugs withdrawn from sale for any reason other than safety or effectiveness, will be moved to the Discontinued Section of the Orange Book.  Drug products subject to a routine, temporary interruption of sale, however, are not considered withdrawn from sale or moved to the Discontinued Section.  Drugs withdrawn from sale may be moved back from the Discontinued Section to the Active Section of the Orange Book by filing the appropriate supplement.

Finally, the Patent Listing section of the Orange Book addresses some of the major issues FDA wrestled with in adopting the 2016 rules implementing the Medicare Modernization Act of 2003.  The Guidance explains that NDA holders must submit on a Form FDA 3542 within 30 days of approval of the NDA or 30 days of issuance of a patent issued after approval of the NDA information for each patent for which a claim of infringement could reasonably be asserted if another party were to reference the drug.  This patent information is then published in the Orange Book.  The Guidance also explains that Method of Use patents, which are filed with a “use code” explaining what part of the labeling the patent actually covers, are subject to the same listing requirements as other patents except that the patent is also timely filed if it is submitted on a Form FDA 3542 within 30 days of approval of a corresponding change to the drug product labeling, a change to the patent construction, or a use code change in response to a patent listing dispute.  NDA holders may also submit a reissued patent to the Orange Book but only after the original patent is withdrawn and surrendered.

The Guidance also explains how patents are withdrawn from the Orange Book.  When a patent no longer meets the statutory requirements for listing or is invalidated or canceled by a court, the NDA holder must contact FDA by submitting a letter to the NDA file to request that patent be withdrawn from the Orange Book.  The patent will be removed unless the patent is the subject of a Paragraph IV certification for which a first applicant may be eligible for 180-days of exclusivity.  A patent for which an applicant remains eligible for 180-day exclusivity will be removed after the exclusivity has been extinguished or relinquished.  Patents may also be removed from the Orange Book as a result of a patent listing dispute.

Like the TE Code Guidance, this new Orange Book guidance is helpful to Orange Book newbies.  While nothing in it is new, it—especially when read with the TE Code guidance—makes sense of FDA’s quite complicated approach to drug listing.  The two guidances should be required reading for FDA lawyers diving into the Hatch-Waxman space and IP lawyers diving into the intersection of patents and FDA law.