By Kurt R. Karst –
There’s a lot of parlance (legal and scientific) bandied about in the food and drug world, and perhaps nowhere more so than in the world of Hatch-Waxman. Things can get confusing. Take, for example, the term “Reference Listed Drug,” or “RLD.”
FDA’s regulation at 21 C.F.R. § 314.3(b) defines the term “reference listed drug” to mean “the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its abbreviated application.” (A “listed drug” is defined in the same regulation to mean, in part, “a new drug product that has an effective approval under section 505(c) of the act for safety and effectiveness or under section 505(j) of the act. . . .”).
Fast forward through the Code of Federal Regulations to FDA’s ANDA content and format regulations, which require, among other things, that an ANDA sponsor identify a basis for submission. Specifically, 21 C.F.R. § 314.94(a)(3) says that an ANDA “must refer to a listed drug. Ordinarily, that listed drug will be the drug product selected by the agency as the reference standard for conducting bioequivalence testing” (emphasis added). That “reference standard” is identified in the paper version of the Orange Book with a “+”. (The electronic version of the Orange Book does not use “+”. Instead, it has a column titled “RLD” where each drug product listing is set to either “Yes” or “No.”)
Now on to the Preface to the Orange Book, which states the following in a section titled “Reference Listed Drug (RLD)”:
A reference listed drug (21 CFR 314.94(a)(3)) means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.
FDA has identified in the Prescription Drug Product and OTC Drug Product Lists those reference listed drugs to which the in vivo bioequivalence (reference standard) and, in some instances, the in vitro bioequivalence of the applicant's product is compared. By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were compared to different reference listed drugs.
Unfortunately, none of these references clearly delineate what we’ll call the “big RLD” and the “little rld.” Instead, they tend to mosh them together.
So . . . . When someone uses the term “reference listed drug,” is that person referring, generally, to a drug approved under an NDA (i.e., the “big RLD”), or to the particular reference standard identified in FDA’s Orange Book with a “+” (i.e., the “little rld”)? Not understanding the difference between the “big RLD” and the “little rld” can lead to faulty decisions and costly mistakes – at least insofar as decisions to submit ANDAs are concerned.
Here’s an example to illustrate this point . . . . FDA approves an NDA for a drug with multiple strengths but delays making a decision on which particular strength is the reference standard (i.e., which strength should get the “+” in the Orange Book). Generic Company No. 1 takes a “big RLD” approach. It believes that all that is needed as a basis for ANDA submission is a drug approved under an NDA. It does not wait for FDA to identify a reference standard and instead conducts bioequivalence testing on all of the approved strengths and submits its ANDA with a Paragraph IV certification to an Orange Book-listed patent. Generic Company No. 2 takes a “little RLD” approach. It thinks that FDA must first add the “+” in the Orange Book for a particular strength, becuase without it there is not a basis for ANDA submission. As such, it waits for FDA to identify a specific reference standard, then conducts bioequivalence testing and submits an ANDA with a Paragraph IV certification to an Orange Book-listed patent.
Which company, Company No. 1 or Company No. 2, was smarter? Answer: Company No. 1, which in this scenario would have submitted the first ANDA to FDA containing a Paragraph IV certification making that company eligible for a period of 180-day marketing exclusivity. Why? Because Company No. 1 correctly understood that all that is needed as a basis for ANDA submission is an approved NDA drug to reference (along with, of course, bioequivalence data and information). FDA does not need to identify a particular reference standard before accepting an application.
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