This guidance is intended to provide information to potential applicants on how to identify a reference listed drug (RLD), reference standard, and the basis of submission in an abbreviated new drug application (ANDA) submission.
Section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) permits any person to submit to the Food and Drug Administration (FDA or the Agency) an ANDA to seek approval to market a generic drug. FDA’s regulations use certain terms for products that relate to an ANDA. In general, to obtain approval of an ANDA for a generic drug, an ANDA applicant first must identify the previously approved drug product it seeks to duplicate, i.e., the reference listed drug (RLD), and must show, among other things, that the generic drug is bioequivalent to the RLD. A reference standard selected by FDA is the specific drug product that the ANDA applicant must use in conducting any in vivo bioequivalence testing required to support approval of its ANDA. The reference standard, selected by FDA, is ordinarily the RLD. However, there may be circumstances (e.g., where the RLD is no longer marketed) in which the reference standard is a drug product other than the RLD. FDA regulations require an ANDA applicant to include in an ANDA its “basis for ANDA submission” (referred hereinafter as “basis of submission”). The basis of submission includes, among other things, the name of the RLD.
A variety of factors has led to confusion among stakeholders on what the terms RLD, reference standard, and basis of submission mean, and how ANDA applicants should use them. These factors include the discontinued marketing of many approved drug products and FDA’s identification of reference standards with the RLD symbol (“+”) in the printed version, and under the “RLD” column in the electronic version, of FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book).
The purpose of this guidance is to address this confusion by explaining what these terms mean and clarifying the differences among them. This guidance provides recommendations on how applicants can accurately use these terms in an ANDA, how persons can request FDA designation of an RLD, and how persons can request FDA selection of a reference standard. Because of the confusion regarding use of these terms up until now, previously issued CDER guidances may not use these terms as we are clarifying them in this guidance.