FDA Orange Book Overview
What is the FDA Orange Book?
The Orange Book is the FDA's list of drug products approved for safety and effectiveness. Its official title is Approved Drug Products with Therapeutic Equivalence Evaluations, and it carries the patent and exclusivity information linked to those products (FDA Orange Book page). It is the reference list that the US generic-drug (ANDA) approval system under 21 CFR Part 314 is built around.
Approach: I read the definitions and related sections of 21 CFR Part 314 (eCFR), a sample of current Orange Book product entries, and FDA's Orange Book web page.
Its legal role under 21 CFR Part 314
- It defines the reference list. In § 314.3, "the list" means the approved drug products published in FDA's current Approved Drug Products With Therapeutic Equivalence Evaluations [1].
- It decides whether a drug is a "listed drug". Listed-drug status "is evidenced by the drug product's identification in the current edition" of the list as an approved drug [1].
- It names the products generics rely on. These are the reference listed drug, which an ANDA applicant relies on, and the reference standard, which FDA selects for in vivo bioequivalence testing [1].
- It records therapeutic equivalence. Therapeutic equivalents are pharmaceutical equivalents with demonstrated bioequivalence that can be expected to have the same clinical effect and safety profile under labelled conditions [1].
- It anchors patent challenges. Notice of a paragraph IV certification is invalid if sent before the first working day after the patent is published in the list. The ANDA amendment documenting the notice must include a dated printout of the reference listed drug's Orange Book entry showing the challenged patent. NDA holder contact details come from the "Orange Book Staff" at CDER [2].
- It is updated monthly. § 314.430(e) says the list is updated monthly [3]. FDA's page says the same of its downloadable data files.
What an entry contains
Each approved product (one strength of one application) gets its own entry. For example, UCERIS (budesonide) 9 mg extended-release tablets, NDA N203634, shows:
- active ingredient, dosage form and route, strength, and applicant
- TE code AB
- approval date of Jan 14, 2013
- marketing status RX
- whether it is the reference listed drug and the reference standard
- five listed patents expiring Sep 7, 2031, one with use code U-1325
Entries cover both innovator NDA products and generic ANDA products. Marketing status is prescription, OTC or discontinued.
Licensed biological products are listed separately, in FDA's Purple Book.
How do I search it by drug or application number?
You can search FDA's Orange Book online from one box that takes a proprietary (brand) name, active ingredient or application number. Separate searches cover the applicant (company), dosage form, route of administration and patent number (FDA Orange Book search). I can also run the same lookups for you here and return cited entries, as in the examples below.
Approach: I opened FDA's Orange Book search page and ran test lookups in the current Orange Book product file. The FDA page doesn't say what format to use for application numbers.
Search options on FDA's Orange Book page
- Proprietary name, active ingredient or application number: all three go in the same search box.
- Applicant (company): pick from a dropdown list of manufacturers.
- Dosage form (for example TABLET) and route of administration (for example ORAL).
- Patent number. There are also links to lists of newly added patents and delisted patents.
What each kind of search returns (worked examples)
- By brand name (UCERIS): one brand can sit under more than one application, so you get every match:
- By application number (NDA 203634): returns every product number under that application, here only product 001 [4]. A product is identified by three parts: application type (N for an NDA, A for an ANDA), application number, and product number. In the Orange Book data the numbers are zero-padded, so NDA 19630 is stored as 019630 and the product number as 001.
- By active ingredient (budesonide): returns innovator and generic products together. Filtering to prescription ANDAs gives generics such as:
Ways to narrow a search
- marketing status (prescription, OTC or discontinued)
- application type (NDA or ANDA)
- TE code
- approval-date range
- applicant
If you send me a drug name or application number, I can pull its full entry, including patents and exclusivities, or list every generic rated as equivalent to a given reference listed drug.
What's a reference listed drug?
A reference listed drug (RLD) is the approved drug that a generic company relies on when it files an Abbreviated New Drug Application (ANDA). Under 21 CFR 314.3 it is "the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA" [1]. In practice, the RLD is the benchmark the generic must match and be shown to be bioequivalent to.
Approach: I read the definitions in 21 CFR 314.3 and the ANDA content requirements in § 314.94.
Related terms in § 314.3
- Listed drug: a drug approved under FD&C Act section 505(c) or 505(j) that has not been withdrawn or suspended, and has not been withdrawn from sale for safety or effectiveness reasons. Its status is shown by its listing as an approved drug in the current Orange Book [1]. An RLD is a listed drug that FDA has picked out as the product an ANDA relies on.
- Reference standard: a separate designation. It is the product FDA selects that an ANDA applicant must use in the in vivo bioequivalence study [1]. The RLD and reference standard are usually the same product, but not always. § 314.94(a)(3) says the listed drug an ANDA refers to will "ordinarily" be the reference standard [10]. That is why the Orange Book flags both separately, as in the UCERIS entry shown earlier.
What an ANDA must show against the RLD (§ 314.94(a)) [10]
- Basis of submission:
- the RLD's name, dosage form and strength
- a statement on whether, according to the Orange Book, the RLD has marketing exclusivity under section 505(j)(5)(F)
- Conditions of use: the proposed labelling's conditions of use must already be approved for the RLD.
- Active ingredient(s): the same as the RLD's.
- Route, dosage form and strength: the same as the RLD's.
- Bioequivalence: data showing the product is bioequivalent to the RLD, with a complete report of the pivotal study.
An exception applies to all three "same as" requirements (ingredient, route/dosage form/strength). A difference from the RLD is allowed if it is covered by an FDA-approved suitability petition under § 314.93. In that case, the RLD must be the listed drug named in the approved petition.
How it links to the Orange Book
Generics that show equivalence to the RLD get a therapeutic-equivalence (TE) code in the Orange Book, such as AB. § 314.3 defines therapeutic equivalents as pharmaceutical equivalents with demonstrated bioequivalence that can be expected to have the same clinical effect and safety profile under labelled conditions [1]. The RLD's Orange Book entry is also where its patents and exclusivities are listed. Those are what an ANDA applicant certifies against.
If you name a product, I can look up its RLD and reference-standard flags in the Orange Book, along with the generics rated equivalent to it.