|Footnotes for this article are available at the end of this page.
In a colorful nod to one of Georgia’s most famous and respected musical bands, R.E.M., and its 1988 hit, “Orange Crush” (from the album Green — coincidence?), in July 2022, the Food and Drug Administration issued a guidance for industry titled, “Orange Book Questions and Answers.”1 The agency intends that the guidance should help the drug industry more efficiently utilize the Approved Drug Products With Therapeutic Equivalence Evaluations publication (commonly referred to as “the Orange Book”).2 This Bulletin highlights some of the key questions and answers raised in the guidance.
The Orange Book includes, among other things: (1) drug products approved by FDA under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”); and (2) patent and non-patent market exclusivity information related to approved drug products. The focal criteria for the inclusion of a drug product in the Orange Book are that it is the subject of an approved application (e.g., a New Drug Application or an Abbreviated New Drug Application) and FDA has not determined the drug product to have been withdrawn from the market due to safety or effectiveness reasons.
The Orange Book contains four main sections:
- The Prescription Drug Product List, which is a list of approved marketed prescription drug products with therapeutic equivalence evaluations (which, along with the Over-the-Counter (OTC) Drug Product List, is referred to as the “Active Section”);
- The OTC Drug Product List, which is a list of marketed OTC products that have approved NDAs or ANDAs (which, along with the Prescription Drug Product List, is referred to as the “Active Section”);
- The Drug Products With Approval Under Section 505 of the FD&C Act Administered by the Center for Biologics Evaluation and Research List; and
- The Discontinued Drug Product List, which is a cumulative list of approved drug products that have never been marketed, are only marketed outside the U.S., are for military use, are not commercially distributed by a U.S. federal or state government entity, have been discontinued from marketing and FDA has not determined that they were withdrawn from sale for reasons of safety or effectiveness, or have had their approvals withdrawn for reasons other than safety or effectiveness subsequent to being discontinued from marketing (referred to as the “Discontinued Section”).
In addition, the Orange Book contains three appendices and two addenda related to patents and market exclusivity, and therapeutic equivalence evaluations for approved multisource prescription drug products, which are reflected for drug products in the Active Section.
Highlights of the Q&A Guidance
- The Orange Book does not include:
- approved drug products that were discontinued either before the Orange Book’s first edition issued in October 1980 or discontinued between 1980 and 1987 (prior to the identification of discontinued products);
- drug products that have a tentative approval;3
- drug products marketed before 1962 for which a Drug Efficacy Study Implementation review has not been completed;
- biological products licensed by FDA under the Public Health Service Act;
- marketed drug products that are not the subject of an approved NDA or an ANDA (e.g., under an OTC monograph);
- drug products compounded by a pharmacy or outsourcing facility according to specific provisions in the FD&C Act;
- authorized generic drug products (e.g., where an NDA drug holder allows another product to be sold under the NDA); and
- re-launched drug products.
- FDA updates
- The Orange Book is updated on its website daily, semimonthly, monthly, and annually; print publication updates occur on a monthly and annual basis.
- Typically, FDA will list a new approved NDA drug product in the Active Section of the Orange Book the month after its approval, and will remain there unless the NDA holder notifies FDA that the drug product will not be available for sale within 180 days of approval; if the NDA holder provides such notification, the NDA drug product will appear in the Discontinued Section the month after its approval.
- In a case where FDA has allowed the submission of an ANDA that is not the sale of a Reference Listed Drug (“RLD”) (e.g., FDA has approved a Suitability Petition), the agency said the RLD should be the drug identified in the Suitability Petition.
- The ANDA will not obtain a therapeutic equivalence code (because it is not pharmaceutically equivalent to the RLD)
- However, once FDA has approved that “petitioned ANDA” (the one accepted under a Suitability Petition), the agency will likely give therapeutic equivalence codes to all ANDAs that contain the same petitioned differences from the RLD (e.g., dosage form, route of administration) as the first petitioned ANDA “to reflect whether these petitioned ANDAs are therapeutically equivalent to one another.”
- FDA stated that a drug product considered “withdrawn from sale” is not limited to the withdrawal of approval of the drug product application; withdrawal from sale is not limited to a permanent withdrawal of a product.
- It can include drug products for which “any decision to discontinue marketing” has been made.
- FDA has stated previously that a drug is considered to have been “withdrawn from sale” if:
the applicant has ceased its own distribution of the drug, whether or not it has ordered recall of previously distributed lots of the drug. A temporary interruption in the supply of a drug product would not be considered a withdrawal from sale, however, unless triggered by safety or effectiveness concerns. [citation omitted].
- FDA also said a drug product can be considered withdrawn from sale if the NDA or ANDA holder has notified FDA that the drug product is not being marketed.
- If an NDA or ANDA holder is withdrawing its product from sale (or intends to), it should submit the notification in a letter to the applicable NDA or ANDA file through the electronic submissions gateway 180 days prior to the withdrawal. If that is not possible, the notice should be made “as soon as practicable,” but no later than the date of withdrawal from sale.
- A drug product’s move to or from the Discontinued Section is normally reflected in a future Orange Book monthly cumulative supplement update.
- Prior to a request that an application be moved from the Discontinued Section to the Active Section, the application holder should determine whether the submission of an NDA or ANDA supplement is required prior to, or at the time of, introduction of the drug product into the marketplace.
- If a prior approval supplement is required, the application holder should notify FDA one to two months prior to the anticipated approval supplement, through a submission to the application file, that the holder looks to sell (or resell).
- If a Changes Being Effected supplement is required, the application holder should determine the anticipated launch date (generally the date the drug product is put into the market) and notify FDA that it intends to sell (or resell) one to two months before the anticipated launch date through submission to the application file.
- If an NDA holder wants to resubmit a reissued patent for Orange Book listing (e.g., so that competitors have to certify as to any patents that cover the drug, which can delay approval of the competitor if a patent infringement lawsuit is brought), it must request that FDA remove the original patent from the Orange Book before reissuance.
- The original patent will remain listed in the Orange Book until FDA determines that no first ANDA applicant is eligible for 180-day exclusivity based on certain conditions, not discussed here.
- If an NDA holder determines that a patent or patent claim no longer meets the statutory requirements for listing, it must promptly notify FDA to amend or withdraw the patent information and request that the patent information be removed from the Orange Book.
- In a case where a claim of a listed patent has been canceled or invalidated according to a final decision issued by the Patent Trial and Appeal Board of the United States Patent and Trademark Office or by a court — from which no appeal has been, or can be, taken — if the NDA holder determines that a patent or patent information no longer meets the statutory listing requirements, it must notify FDA in writing within 14 days of the decision and request that such patent or patent information be amended or withdrawn in accordance with the decision and include information related to the patent cancelation or invalidation decision (including a copy of the decision).
- FDA will remove a patent or patent information from the Orange Book if there is no first ANDA applicant eligible for 180-day exclusivity. An NDA holder may submit a withdrawal of a patent and its removal from the Orange Book by letter to the NDA file.
- Anyone can dispute the accuracy or relevance of patent information published in the Orange Book. The dispute should be sent to the Division of Orange Book Publication and Regulatory Assessment at email@example.com, where FDA will forward the dispute to the NDA holder for a response.
- The guidance delivers industry insight as to how the agency intends to handle NDA and ANDA listing, patent and non-patent exclusivity information, and proposed changes to the Orange Book.
- The guidance provides industry with procedural recommendations that FDA expects companies to follow when seeking changes to the Orange Book.
- The guidance offers transparency to companies, which should help firms as they make regulatory- and business-strategic decisions based on the Orange Book.
 See https://www.fda.gov/media/160167/download.
 The Orange Book is available at https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm.
 A tentative approval is issued when: (1) an NDA or an ANDA is approvable, but FDA cannot grant final approval because there is an applicable period of patent or non-patent exclusivity that precludes final approval; or (2) an application is approvable but cannot be granted final approval because a court order mandates that the NDA or ANDA may not be approved until a certain time.