Definition
Reference Listed Drug (RLD)
A Reference Listed Drug (RLD) is the approved drug product that the FDA identifies as the one a generic applicant relies on when seeking approval through an Abbreviated New Drug Application (ANDA), usually the original brand product.
1 min readReviewed September 14, 2026
Also known as: Listed drug, Reference drug, RLD product
Key facts
- Defined in
- 21 CFR 314.3
- Designated by
- FDA, flagged in the RLD column of the Orange Book
- Related term
- Reference standard (RS), the product used in bioequivalence testing
- Usually
- The brand-name product approved under the original NDA
What is a Reference Listed Drug?
Every generic drug approved through an ANDA points back to a listed drug that the FDA has already found safe and effective. The RLD is that anchor product. The generic must match it in active ingredient, strength, dosage form, route of administration, conditions of use and, with limited exceptions, labeling.
The RLD is usually the brand product approved under a New Drug Application (NDA). The Orange Book marks RLDs with a flag in each product record.
A generic that differs from its RLD in strength, dosage form, route of administration or one active ingredient of a combination needs FDA permission first, through a suitability petition under Section 505(j)(2)(C).
RLD vs reference standard
The Orange Book now separates two roles. The RLD is the listed drug an ANDA relies on for approval. The reference standard (RS) is the specific product the FDA selects for applicants to use in in vivo bioequivalence studies.
Usually the two are the same product. They can diverge when the brand is discontinued: the FDA may then select a marketed generic as the reference standard so new applicants have a product to test against. Before approving generics that rely on a discontinued RLD, the FDA must also determine that it was not withdrawn for reasons of safety or effectiveness.
Why the RLD matters
The RLD defines a generic market. Grouping approved ANDAs by their RLD shows how many competitors each brand faces, which companies hold approvals and how that count changes over time, which feeds price erosion forecasts.
It also connects patents to generics. The patents and exclusivities listed in the Orange Book for the RLD are the ones every ANDA applicant must address, including through Paragraph IV challenges. Because RLD status can outlive the brand, generics can keep entering a market the originator has already left.