Usage Examples
- The ANDA names the RLD as the 10 mg tablet, so the 5 mg strength needs a suitability petition first.
- The RLD is withdrawn from sale, but FDA selected a marketed ANDA as the reference standard, so the BE study doses that product.
- Confirm the RLD before we lock the protocol - the comparator and the labeling both fall out of that choice.
What is RLD (Reference Listed Drug)?
An RLD is the FDA-approved listed drug an ANDA relies on as its legal basis, setting the active ingredient, dosage form, strength, route, conditions of use, and labeling the generic must match.
The RLD exists because Congress let generic sponsors skip new safety and effectiveness studies. Section 505(j) of the FD&C Act trades that evidence for a comparison: the applicant points at a drug product FDA already found safe and effective and shows its own product is the same. The RLD is that anchor, and without a designated one there is no ANDA pathway to use.
The RLD fixes what the ANDA must match: active ingredient, conditions of use, route, dosage form, strength, and labeling, and it is the product bioequivalence is demonstrated against. The RLD does not decide which product you actually dose in the study, since FDA's reference standard does that. The regulatory definition also ties the RLD to ANDAs, not to 505(b)(2) applications, which rely on a listed drug while deliberately differing from it.
The RLD decision is made before protocol design, because it sets the bioequivalence comparator, the labeling to be copied or carved around, and the patent and exclusivity certifications the ANDA must carry. Teams confirm the RLD still meets the listed drug definition, check whether FDA has selected a different product as the reference standard, and file a suitability petition first when the intended product will differ.
Not to be confused with
- Reference standard
- the product FDA selects that you must actually dose in the in vivo bioequivalence study. The RLD is the legal basis of the application; the reference standard is the comparator in the lab. They are ordinarily the same product, and the regulation says so only with "ordinarily".
- Listed drug
- the broader statutory category of approved, unwithdrawn products. Every RLD is a listed drug, but a listed drug becomes an RLD only when FDA identifies it as the product an ANDA relies on.
- Reference product
- the biologics analogue under section 351(k) of the Public Health Service Act. A biosimilar shows high similarity to a reference product; a generic shows bioequivalence to an RLD. Different statute, different evidence standard.
- The brand or innovator product
- a commercial description, not a regulatory designation. The originator product is usually the RLD, but FDA can select an approved ANDA as the reference standard, so "the brand" and "the product you test against" are not automatically the same record.
The RLD obligations sit inside the ANDA content rules rather than in a standalone regulation.
What you must do
- 1Refer the ANDA to a specific listed drug, ordinarily the drug product FDA selected as the reference standard for conducting bioequivalence testing21 CFR 314.94(a)(3)
- 2State that the active ingredient of the proposed drug product is the same as that of the reference listed drug21 CFR 314.94(a)(5)
- 3Submit information showing the drug product is bioequivalent to the reference listed drug relied on, including a complete study report for the study relied on for approval21 CFR 314.94(a)(7)
- 4Verify the RLD still meets the listed drug definition, meaning it has not been withdrawn or suspended and has not been withdrawn from sale for what FDA determined were reasons of safety or effectiveness21 CFR 314.3
- 5Obtain FDA permission through an approved suitability petition before submitting an ANDA that is not identical to the listed drug in route of administration, dosage form, and strength, or that substitutes one active ingredient in a listed combination drug21 CFR 314.93
Common mistakes
Treating the RLD and the reference standard as one decision
Teams design the bioequivalence study against the brand product and later find FDA selected a different reference standard. The study gets repeated, which costs a full BE cycle plus clinical site time and pushes the filing date out by quarters.
Filing before the suitability petition is approved
21 CFR 314.93(b) requires the sponsor to obtain permission first, so the petition has to precede the ANDA rather than accompany it. Sponsors who discover this after the fact lose the petition review time on top of the filing delay, with formulation work already sunk.
Not rechecking the RLD's status before locking labeling
A product withdrawn from sale for reasons of safety or effectiveness falls outside the definition of a listed drug, so an application built on it cannot be approved. Status and labeling both move, and an RLD confirmed at program kickoff is not evidence of anything at submission.
When This Matters
- The ANDA names the RLD as the 10 mg tablet, so the 5 mg strength needs a suitability petition first.
- The RLD is withdrawn from sale, but FDA selected a marketed ANDA as the reference standard, so the BE study doses that product.
- Confirm the RLD before we lock the protocol - the comparator and the labeling both fall out of that choice.
Frequently Asked Questions
The RLD is the approved listed drug an ANDA relies on for approval; the reference standard is the drug product FDA selects that the applicant must use in the in vivo bioequivalence study. They are usually the same product, but not always, so confirm both before designing the study.
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