Recently FDA published the guidance for industry on ‘Referencing Approved Drug Products in ANDA Submissions’. From this guidance you can know how to identify a reference listed drug (RLD), a reference standard, and the basis of submission in an abbreviated new drug application (ANDA) submission.
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, which is 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.
Related: Difference Between RLD and RS
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.The purpose of this guidance is to address this confusion by explaining what these terms mean and by 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.
The process for obtaining approval to market an innovator drug approved under a new drug application (NDA) differs from that for obtaining approval to market a generic drug under an ANDA.To obtain approval for a generic drug, an ANDA applicant is not required to provide independent evidence of the safety and effectiveness of the proposed generic drug. Instead, the applicant relies on FDA’s finding that a previously approved drug product, i.e., the RLD, is safe and effective, and must demonstrate, among other things, that the proposed generic drug is the same as the RLD in certain ways. Specifically, with limited exceptions described in this section, a drug product for which an ANDA is submitted must have, among other things, the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the RLD.An ANDA applicant also must demonstrate that its proposed generic drug is bioequivalent to the RLD and, if in vivo bioequivalence studies arerequired for approval of the ANDA, the applicant must use the reference standard selected by FDA. A generic drug must meet the same high standards of quality and manufacturing as drug products approved under section 505(c) of the FD&C Act.
FDA’s approval of an ANDA for a generic drug that is a duplicate of an RLD reflects the Agency’s determination that the proposed generic drug is therapeutically equivalent to its RLD. Therapeutic equivalents are approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.
To submit an ANDA for a generic drug that is not the same as its RLD because it has one different active ingredient (in a fixed combination drug product), or has a different route of administration, dosage form, or strength than that of the RLD, an applicant first must obtain permission from FDA through the citizen petition process.Such petitions are referred to as suitability petitions. FDA will not approve a suitability petition if, for instance, investigationsmust be conducted to show the safety and effectiveness of the proposed generic drug.
FDA regulations define a listed drug as a new drug product that has been approved under section 505(c) of the [FD&C Act] for safety and effectiveness or under section 505(j) of the [FD&C Act], which has not been withdrawn or suspended under section 505(e)(1) through (5) or section (j)(6) of the [FD&C Act], and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness.
The FD&C Act and FDA’s regulations require an ANDA applicant to “refer” in its ANDA to the specific listed drug on which the applicant relies in seeking approval of its ANDA. This listed drug is the RLD.
- An ANDA applicant must first choose an RLD. If FDA has not designated an RLD for a drug product the applicant intends to duplicate, the potential applicant may submit controlled correspondence to FDA identifying the drug it intends to duplicate (e.g., by NDA number and by active ingredient, dosage form, route of administration and strength) and asking FDA to designate an RLD.
- If FDA has designated a listed drug as an RLD, but the potential applicant intends to refer to a different listed drug that was approved for safety and effectiveness under section 505(c) of the FD&C Act and is a pharmaceutical equivalent to the drug designated as an RLD, the potential applicant may submit controlled correspondence to FDA to request that FDA designate that different listed drug as an RLD.
- If an RLD appears in the Discontinued Section and FDA has not published in the Federal Register a determination whether the drug was withdrawn from sale for reasons of safety or effectiveness, the applicant must submit a citizen petition seeking a safety and effectiveness determination for the listed drug at the same time as the ANDA submission. Such petition must contain all evidence available to the petitioner concerning the reason that the drug product was withdrawn from sale. A determination whether an RLD has been withdrawn for safety or effectiveness reasons must be made before FDA may approve an ANDA that refers to an RLD in the Discontinued Section.
- If an applicant has a question about which listed drug it should identify as the RLD, the applicant may submit controlled correspondence to seek input from the Agency.
The Role of an RLD in an ANDA
The RLD is the listed drug to which the ANDA applicant must show its proposed generic drug is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use, among other characteristics.
Regarding the same labeling requirement, the generic drug must have the same labeling as the RLD, except for differences permitted under the FD&C Act and Agency regulations. Accordingly, an ANDA applicant must compare its proposed product’s labeling to that of the RLD, even if FDA has selected a new reference standard for use in in vivo bioequivalence studies. Similarly, in evaluating drug product formulation and inactive ingredients, an ANDA applicant must compare its proposed generic drug to the RLD’s formulation, not the formulation of the reference standard.
Identification of the RLD in the Orange Book
In the electronic Orange Book, there is a column for RLDs and a column for reference standards. In the printed version of the Orange Book, the RLDs and reference standards are identified by distinct symbols.
Changing the RLD
When an ANDA applicant that seeks to change its RLDmust submit a new ANDA to obtain approval under section 505(j) of the FD&C Act. We recommend that an ANDA applicant request withdrawal of the pending ANDA before seeking to change its RLD.
Selection of a Reference Standard
As discussed above, the FD&C Act requires an ANDA to provide “information to show that the new drug is bioequivalent” to its RLD.If bioequivalence is not self-evident, there are a variety of methods by which bioequivalence may be demonstrated, including in vivo studies (in human subjects), in vitro studies (conducted in a laboratory), or both.
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 of the ANDA.FDA generally selects a single reference standard to ensure the greatest level of consistency between a generic drug and its RLD and among generic drugs. Ordinarily, FDA selects the RLD as the reference standard. FDA usually selects as the reference standard the highest strength available for drug products with multiple approved strengths.
Selection of a New Reference Standard
FDA may select a new reference standard when doing so will help to ensure that applications for generic drugs may be submitted and evaluated. In making a decision whether to select a new reference standard, FDA may consider, among other factors:
- Whether the listed drug that is the reference standard is no longer marketed;
- Whether selecting a new reference standard would help to prevent a shortage of a particular drug product or category of drug products;
- Whether or not the current reference standard is also the RLD, and the Agencydetermines that the quantity of the current reference standard in distribution is so limitedthat a potential ANDA applicant is not able to obtain a sufficient quantity for in vivobioequivalence testing (even if the current reference standard has not been withdrawnfrom sale).
There are circumstances in which a potential ANDA applicant may ask FDA to select a reference standard. These circumstances include, for example, if FDA has not selected a reference standard, if a reference standard is moved to the Discontinued Section and FDA has not selected a new reference standard for the same drug product, if a potential ANDA applicant believes areference standard other than the one selected by FDA is appropriate, or if the quantity of thereference standard in distributionis so limited that a potential ANDA applicant is not able to obtain a sufficient quantity for in vivo bioequivalence testing.
Basis of Submission for an ANDA for a Generic Drug That Is a Duplicate of Its RLD
When an applicant submits an ANDA for a generic drug that is a duplicate of its RLD, i.e., not a petitioned ANDA, the basis of submission is the RLD. Accordingly, the name of the RLD, including dosage form and strength, and its application numbershould be provided as the basis of submission on Form FDA 356h (i.e., the form that accompanies regulatory submissions by an applicant) and in the appropriate sections of the ANDA. If the reference standard selected by
FDA for the drug product is not the RLD, an applicant should not identify the reference standard as the basis of submission on Form FDA 356h. However, the reference standard should be identified in the relevant sections of the ANDA that include information pertaining to bioequivalence, such as 1.12.11 Basis for submission statement (which statement provides information about the proposed generic drug broadly, including bioequivalence and other information), 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods, 5.2 Tabular listing of all clinical studies, and 5.3.1 Reports ofbiopharmaceutic studies. FDA guidance and technical documents related to ANDA formatting are maintained and updated on FDA’s website.
Related
- Generic Drug Development Process
- Sameness Evaluation of a Generic Drug Product Formula
- Pharmaceutical RLD and RS Characterization
- A Brief Discussion on QbD Tools
- FDA Inactive Ingredient Database