Reference listed drug, reference standard and basis of submission, explained

FDA's Orange Book flags 4,506 product entries as reference standards, the products a generic company must test against in its human bioequivalence study. In GxRadar's analysis of the Orange Book data files⁸, downloaded Nov. 3, 2026, 1,443 of those entries, about 32 percent, are themselves generics approved under abbreviated new drug applications.

Those files also flag 7,843 entries as reference listed drugs, the approved products generics copy. Of those, 3,104 sit in the Discontinued section, meaning the original product is no longer sold even though it can still anchor new copies.

The two terms sound interchangeable, and for years FDA's own Orange Book blurred them. The reference listed drug, or RLD, fixes what a generic must match. The reference standard is what the generic is dosed against in the clinic. A third term, basis of submission, is what the applicant writes on the application form. This piece explains each, how FDA picks them and what they look like for the generics most people take.

Three terms with different jobs

FDA's regulations at 21 CFR 314.3⁵ define the first two in a sentence each. A reference listed drug "is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA." A reference standard "is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval." The requirement to name the RLD as the basis of submission sits in 21 CFR 314.94(a)(3)⁶.

FDA's October 2020 guidance on referencing approved drug products¹ spells out the division. "An ANDA's proposed labeling and formulation must be compared to the RLD, and not the reference standard," it says, and the applicant "must address any unexpired patents and exclusivity for the RLD." The reference standard matters only for the bioequivalence study.

Where the confusion came from

Before 2017, the electronic Orange Book had a single column labeled RLD. According to the 2020 guidance, a "Yes" in that column sometimes marked the true RLD and sometimes marked the product FDA had picked for bioequivalence testing. Some in the industry started calling generic reference standards "second RLDs." The guidance calls that description "not accurate" and says FDA had received citizen petitions asking for a second RLD when the petitioner actually wanted a new reference standard.

FDA cleaned this up in three steps. FDA's final rule on ANDAs and 505(b)(2) applications⁴, published Oct. 6, 2016, and effective Dec. 5, 2016, wrote the separate definitions into the regulations. A draft guidance announced Jan. 17, 2017³ explained them, and that year FDA split the Orange Book into separate RLD and reference standard columns. The guidance was finalized in October 2020, according to FDA's guidance page². Our explainer on the Orange Book covers the rest of the listing.

How FDA picks a reference standard

"Ordinarily, FDA selects the RLD as the reference standard," the 2020 guidance¹ says, and it usually picks the highest approved strength. When the RLD has left the market for reasons other than safety or effectiveness, FDA generally selects a previously approved generic that is therapeutically equivalent to it. If several qualify, the agency "usually will select the generic market leader, based on commercial data."

FDA can also swap in a new reference standard when the current one is no longer marketed, when the change would help prevent a shortage, or when so little of the product is in distribution that applicants cannot buy enough to run a study. The guidance cites a June 2013 case in which a brand liposomal doxorubicin injection was in shortage and FDA named an approved generic version as the reference standard instead, because the shortage had left no product for would-be competitors to test against. Once FDA picks a new reference standard, it generally stays even if the original returns. Applicants can ask FDA to select one through controlled correspondence, as the Orange Book preface⁷ also notes.

What the Orange Book shows for common generics

GxRadar checked the reference standard and RLD flags for the 47 generic products on our price tracker, matching ingredient and dosage form in the Orange Book data files⁸. For 28 of them, at least one prescription reference standard is a generic. For 23, every prescription reference standard is a generic. Some examples follow.

FDA's habit of picking the highest strength shows up in nearly every row. For simvastatin and clopidogrel, the brand is still listed as the RLD, yet the reference standard is a generic. The guidance lists the reasons FDA may name a new reference standard, among them a product that is no longer marketed or too scarce to buy for testing, but the Orange Book does not record which reason applied to each product.

Levothyroxine is a special case. The Orange Book preface⁷ says there are multiple RLDs for levothyroxine sodium tablets and that FDA's usual two- or three-character therapeutic equivalence codes "may be potentially confusing and inadequate" for them, so it publishes a separate chart pairing each AB1 through AB4 code with its RLD and reference standard.

What each one controls after filing

Once made, the choice of RLD is close to permanent. Under the 2020 guidance¹, the law and FDA's regulations bar an applicant from amending a pending ANDA to change its RLD. A company that wants a different RLD must file a new application. Mislabeling the reference standard as the RLD on the form is treated as a correctable error rather than a change of RLD.

A discontinued RLD can still anchor a generic, with a condition. Before approving a generic that relies on it, FDA must determine that the product was not withdrawn for safety or effectiveness reasons, and the guidance says an applicant relying on a discontinued RLD without a published determination must file a citizen petition asking for one alongside its ANDA. When FDA publishes a favorable finding, the Orange Book listing carries a note reading "Federal Register determination that product was not discontinued or withdrawn for safety or effectiveness reasons." In GxRadar's table, the metformin, warfarin and amoxicillin RLD entries carry that kind of note for some or all strengths.

Generics that differ from the RLD in strength, dosage form or route, or that swap one active ingredient in a combination, need an approved suitability petition first, a step that sits between the ANDA route and the 505(b)(2) pathway. Their basis of submission is the RLD plus that petition, and a later generic copying the petitioned product generally uses it as the reference standard while still naming the original RLD.

For patients, none of this shows up on a pharmacy label. It decides which product sits at the center of a generic's paperwork, which one is in the volunteers' blood samples, and whose patents the applicant has to clear. The Orange Book data files GxRadar used are refreshed regularly, and FDA's preface⁷ says the agency "intends to update periodically the RLDs" in its product lists.