Reference Listed Drug (RLD): What It Is and How to Pick One
A Reference Listed Drug is the approved drug product that a generic application relies on. File an ANDA under section 505(j) and you are not proving your product is safe and effective from scratch. You are showing it is the same as something FDA already approved, and the RLD is that something.
FDA identifies RLDs in the Orange Book, whose full name says what it is: Approved Drug Products with Therapeutic Equivalence Evaluations.
RLD and Reference Standard are not the same thing
This is the distinction that causes the most trouble, and the Orange Book lists them in separate columns.
The Reference Listed Drug is the listed drug your application relies on for approval. It is a regulatory reference point.
The Reference Standard (RS) is the product FDA has selected for you to actually buy and test against in your in vivo bioequivalence studies. It is a physical reference point.
They are usually the same product. They are not always. When the RLD has been withdrawn from sale for reasons unrelated to safety or effectiveness, FDA may designate a different product as the Reference Standard, because you cannot run a bioequivalence study against something you cannot obtain.
Running your BE study against the wrong one is expensive in the way that requires repeating the study.
Reading TE codes
The Orange Book assigns each multi-source product a therapeutic equivalence code. The first letter carries the meaning:
- A codes mean FDA considers the product therapeutically equivalent to the reference: substitutable with the expectation of the same clinical effect.
- B codes mean it is not, usually because of an unresolved bioequivalence question or a dosage form that makes equivalence hard to establish.
The second letter narrows the dosage form or the reason:
| Code | Meaning |
|---|---|
| AA | Conventional dosage form, no known bioequivalence problems |
| AB | Bioequivalence demonstrated where a potential problem exists. The most common code you will see |
| AN | Solutions and powders for aerosolisation |
| AO | Injectable oil solutions |
| AP | Injectable aqueous solutions |
| AT | Topical products |
| BX | Data insufficient to determine equivalence |
An AB rating is what most state substitution laws key on, so it is usually the commercial objective rather than a technicality.
Two products can both be AB rated to the same reference and still not be rated to each other. The rating is always against the reference, never pairwise between generics.
Choosing the RLD
Most of the work is confirming that the obvious answer is still the right one.
- Confirm it is still designated. RLD designation moves. A product withdrawn from sale may keep or lose it, and FDA can designate a new RLD.
- Match strength, dosage form and route exactly. An ANDA has to be the same as its RLD on all of them. A difference means a suitability petition or a 505(b)(2), not an ANDA.
- Check the Reference Standard separately. See above. Do not assume.
- Read the patent and exclusivity listings. These live in the Orange Book alongside the product entry and determine when you can be approved, which is a different question from whether you can be approved.
- Check for withdrawal. A drug withdrawn for safety or effectiveness reasons cannot serve as a reference.
RLD, and 505(b)(2)
A 505(b)(2) application also relies on a listed drug, but differently. An ANDA argues sameness. A 505(b)(2) allows a difference, in strength, dosage form, route or indication, and supports that difference with its own data plus FDA's prior findings for the listed drug.
Choosing between them is usually decided by one question: is your product the same as the reference on every attribute an ANDA requires? If not, the ANDA route is closed and the 505(b)(2) is the one that exists.
Where to look it up
The Orange Book is published by FDA, and much of the same product data is
available through the openFDA drugsfda endpoint, which carries the TE code,
the reference drug flag and the reference standard flag for each product.
Patent and exclusivity data is not in openFDA. It is in the Orange Book data files, and any tool that claims to give you a complete picture without them is missing the part that decides your launch date.
Frequently asked questions
What is a Reference Listed Drug?
The approved drug product that a generic application relies on for approval. An ANDA shows its product is the same as the RLD rather than establishing safety and effectiveness independently.
What is the difference between an RLD and a Reference Standard?
The RLD is the regulatory reference your application relies on. The Reference Standard is the product FDA has selected for you to test against in in vivo bioequivalence studies. They are usually the same product, but not always.
What does an AB rating mean?
FDA considers the product therapeutically equivalent to its reference where a potential bioequivalence problem exists and equivalence has been demonstrated. It is the rating most state substitution laws rely on.
Are two AB-rated generics equivalent to each other?
Not necessarily. Therapeutic equivalence is rated against the reference product, not pairwise between generics.
Can an RLD change?
Yes. Designation can move, particularly when a product is withdrawn from sale, and FDA can designate a different Reference Standard so bioequivalence testing remains possible.
What is the Orange Book?
FDA's publication *Approved Drug Products with Therapeutic Equivalence Evaluations*, which identifies RLDs, Reference Standards, therapeutic equivalence codes, and patent and exclusivity information.
When do I need a 505(b)(2) instead of an ANDA?
When your product differs from the listed drug in a way an ANDA does not permit, such as a different strength, dosage form, route or indication.