Referencing Approved 
Drug Products in 
ANDA Submissions 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2020 
Generics 
 
   
Referencing Approved 
Drug Products in 
ANDA Submissions 
  
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2020 
Generics 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 2 
II.  BACKGROUND ............................................................................................................... 3 
III.  DISCUSSION .................................................................................................................... 4 
A.  Listed Drug ..................................................................................................................................... 4 
B.  Reference Listed Drug ................................................................................................................... 5 
1. FDAs Identification of Listed Drugs That Have Been Designated as RLDs .................................. 5 
2. Choosing an RLD ............................................................................................................................. 6 
3. The Role of an RLD in an ANDA ..................................................................................................... 7 
4. Identification of the RLD in the Orange Book ................................................................................. 8 
5. Changing the RLD ........................................................................................................................... 8 
C.  Reference Standard ....................................................................................................................... 9 
1. Selection of a Reference Standard ................................................................................................... 9 
2. Selection of a New Reference Standard ......................................................................................... 10 
3. Requesting Selection of a Reference Standard .............................................................................. 11 
D.  Basis of Submission ...................................................................................................................... 11 
1. Basis of Submission for an ANDA for a Generic Drug That Is a Duplicate of Its RLD ................ 12 
2. Basis of Submission for a First Petitioned ANDA ......................................................................... 12 
3. Basis of Submission for a Generic Drug That Is a Duplicate of a Drug Product Approved in a 
Petitioned ANDA ................................................................................................................................ 13 
APPENDIX 1: QUICK REFERENCE ..................................................................................... 14 
TABLE: REFERENCING APPROVED DRUG PRODUCTS IN AN ANDA ..................... 15 
   
i  Contains Nonbinding Recommendations 
Referencing Approved Drug Products in ANDA Submissions 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to provide information to potential applicants on how to identify a 
reference listed drug (RLD), a reference standard, and the basis of submission in an abbreviated 
new drug application (ANDA) submission.2   
 
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.3  FDAs 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, 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.4  The reference standard selected by FDA is ordinarily the RLD.  
However, there may be circumstances (e.g., when the RLD is no longer marketed) in which the 
reference standard is a drug product other than the RLD.  In addition, FDA regulations require an 
ANDA applicant to include in an ANDA its basis for ANDA submission (referred to 
hereinafter as basis of submission).5  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 FDAs past 
practice of identifying reference standards with the RLD symbol (+) in the printed version, and 
                                                 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at 
the Food and Drug Administration in cooperation with the Center for Biologics Evaluation and Research.  
2 An ANDA includes all amendments and supplements to the application.  21 CFR 314.3(b). 
3 Throughout this guidance we use the term generic drug to refer to a new drug product described in an ANDA 
submitted under section 505(j) of the FD&C Act.  
4 21 CFR 314.3(b). 
5 21 CFR 314.94(a)(3). 
 
  2  Contains Nonbinding Recommendations 
with a Yes under the RLD column in the electronic version, of FDAs Approved Drug 
Products with Therapeutic Equivalence Evaluations (the Orange Book).6 
 
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.  
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.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
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.  An NDA for an innovator drug must contain, among other things, a demonstration of 
the safety and effectiveness of the drug for the conditions of use for which approval is sought.7  
A 505(b)(1) application, also known as a stand-alone NDA, is an application that contains full 
reports of investigations of safety and effectiveness that were conducted by or for the applicant 
or for which the applicant has a right of reference or use (referred to hereinafter as a 505(b)(1) 
NDA).  A 505(b)(2) application is an NDA that contains full reports of investigations of safety 
and effectiveness where at least some of the information required for approval comes from 
studies not conducted by or for the applicant and for which the applicant has not obtained a right 
of reference or use (e.g., published literature).  An application submitted under section 505(b) is 
approved under section 505(c) of the FD&C Act. 
 
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 FDAs 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.8  An ANDA applicant also must demonstrate that 
its proposed generic drug is bioequivalent to the RLD9 and, if in vivo bioequivalence studies are 
                                                 
6 The Orange Book is available at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. 
7 Section 505(b)(1) of the FD&C Act. 
8 Section 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD&C Act; see also 21 CFR 314.94(a). 
9 Section 505(j)(2)(A)(iv) of the FD&C Act. 
 
  3  Contains Nonbinding Recommendations 
required for approval of the ANDA, the applicant must use the reference standard selected by 
FDA.10  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.11   
 
FDAs approval of an ANDA for a generic drug that is a duplicate12 of an RLD reflects the 
Agencys 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.13   
 
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.14  Such petitions are referred to as 
suitability petitions.  FDA will not approve a suitability petition if, for instance, investigations 
must be conducted to show the safety and effectiveness of the proposed generic drug.15  Because 
therapeutic equivalents must be pharmaceutical equivalents16, a generic drug for which FDA 
permits a difference under an approved suitability petition (petitioned ANDA) is not 
therapeutically equivalent to its RLD.   
 
III.  DISCUSSION     
 
A.  Listed 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.17   
                                                 
10 See 21 CFR 314.3(b).   
11 Section 505(j)(2)(A)(vi) of the FD&C Act. 
12 The term duplicate generally refers to a drug product that has the same active ingredient(s), dosage form, 
strength, route of administration, and conditions of use as a listed drug.  See 54 FR 28872 at 28877 (July 10, 1989).  
However, the term duplicate, as used in this context, does not mean identical in all aspects to the listed drug.  
13 See 21 CFR 314.3(b).  Pharmaceutical equivalents are drug products in identical dosage forms and route(s) of 
administration that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the 
same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such 
forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug 
ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the 
identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, 
where applicable, content uniformity, disintegration times, and/or dissolution rates.  See 21 CFR 314.3(b). 
14 Section 505(j)(2)(C) of the FD&C Act; 21 CFR 314.93(b). 
15 21 CFR 314.93(e)(1)(i). 
16 See 21 CFR 314.3(b).  
17 21 CFR 314.3(b); see also section 505(j)(7) of the FD&C Act.   
 
  4  Contains Nonbinding Recommendations 
 
Drug products approved under an NDA, either a 505(b)(1) or a 505(b)(2) application, may be 
listed drugs.  Likewise, a drug product approved under an ANDA may be a listed drug.  A drug 
product is deemed to be a listed drug on the date of approval of the NDA or ANDA for the drug 
product.18  Each strength of a drug is a distinct drug product and, therefore, a distinct listed drug.  
Listed drugs appear in FDAs Orange Book.     
 
When a drug product is approved, generally it appears in the Orange Book section entitled the 
Prescription Drug Product List or the Over-the-Counter Drug Product List; these sections are 
commonly referred to as the Active Section.  When an approved drug product is not marketed, it 
appears in the Orange Books Discontinued Drug Product List, which is commonly referred to 
as the Discontinued Section.  In general, a listed drug is moved to the Discontinued Section when 
the applicant notifies FDA that it is withdrawing the listed drug from sale or the listed drug is not 
available for sale or FDA otherwise determines that the listed drug has been withdrawn from sale 
or is not available for sale.19  A listed drug also may be moved to the Discontinued Section if the 
applicant requests that approval of the NDA or ANDA be withdrawn because the drug product is 
no longer being marketed.20    
 
B.  Reference Listed Drug 
 
1.  FDAs Identification of Listed Drugs That Have Been Designated as RLDs 
 
The FD&C Act and FDAs 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.21  This listed 
drug is the RLD.22 
 
Because an ANDA applicant is relying on FDAs finding that the RLD is safe and effective, 
FDAs general practice is to designate as RLDs drug products that have been approved for safety 
and effectiveness under section 505(c) of the FD&C Act.  Although drug products that were 
submitted and approved under section 505(j) of the FD&C Act, which was established by the 
Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417), 
commonly referred to as the Hatch-Waxman Amendments, are listed drugs and may be selected 
as reference standards, FDA generally does not intend to designate these products as RLDs.  
 
                                                 
18 21 CFR 314.3(b). 
19 Section 506I of the FD&C Act requires the holder of an application approved under section 505(c) or (j) of the 
FD&C Act to submit certain notifications to FDA regarding the marketing status of the drug product, and requires 
FDA to update the Orange Book based on the information provided.  For more information see FDAs draft 
guidance for industry Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic 
Act (January 2019). When final, this guidance will represent FDAs current thnking on this topic.   
20 An applicant may request that approval of an NDA or ANDA be withdrawn because the drug product that is the 
subject of the NDA or ANDA is no longer being marketed.  21 CFR 314.150(c).  FDA will withdraw approval of 
the NDA or ANDA based on the applicants request provided none of the conditions in 314.150(a) or (b) applies. 
21 Section 505(j)(2) of the FD&C Act; 21 CFR 314.94(a)(3). 
22 21 CFR 314.3(b).  There may be multiple approved drugs each of which may be eligible to be an RLD for a 
particular drug product (e.g., either Trandate 100 milligram (mg) tablets (NDA 018716) or Normodyne 100 mg 
tablets (NDA 018687) are eligible to be the RLD for an ANDA for Labetalol Hydrochloride 100 mg tablets). 
 
  5  Contains Nonbinding Recommendations 
FDA identifies in the Orange Book listed drugs that have been designated as RLDs.  A listed 
drug approved for safety and effectiveness under section 505(c) of the FD&C Act that appears in 
the Active Section of the Orange Book may be eligible to be an RLD.  A listed drug approved for 
safety and effectiveness under section 505(c) of the FD&C Act that appears in the Discontinued 
Section also may be eligible to be an RLD, unless FDA makes a determination that the listed 
drug was withdrawn from sale for reasons of safety or effectiveness.  If FDA makes such a 
determination, the listed drug will be removed from the Orange Book and is no longer eligible to 
be an RLD.23   
 
Under FDA regulations, the Agency may determine at any time whether a listed drug was 
withdrawn from sale for reasons of safety or effectiveness.  However, FDA must determine 
whether a listed drug was withdrawn from sale for reasons of safety or effectiveness: (1) before 
FDA can approve an ANDA that refers to the listed drug as its RLD; (2) whenever the listed 
drug is voluntarily withdrawn from sale if any approved ANDA already refers to that listed drug; 
and (3) when any person petitions for such a determination.24  These determinations are 
completed by the Agency and subsequently are published in a Notice in the Federal Register.25  
Historically FDA generally did not approve ANDAs for which the Agency had made a 
determination that the RLD was not withdrawn from sale for reasons of safety or effectiveness 
until after that determination was published in a Notice in the Federal Register.  In order to 
expedite the availability of generic drugs, FDA decided that it may approve a generic drug for 
which it has made a final determination that the RLD was not withdrawn from sale for safety or 
effectiveness reasons even if that determination has not yet published in a Notice in the Federal 
Register and will proceed with Federal Register publication as expeditiously as is practicable.    
 
If FDA determines that a listed drug in the Discontinued Section was not withdrawn from sale 
for safety or effectiveness reasons and publishes that determination in a Notice in the Federal 
Register, the Agency generally adds the following notation to that product listing information in 
the Orange Book: **Federal Register determination that product was not discontinued or 
withdrawn for safety or efficacy reasons**.26  If FDA determines that the listed drug was 
withdrawn from sale for reasons of safety or effectiveness, the Agency will remove the listed 
drug from the Orange Book and the Agency will not accept for review or approve ANDAs that 
refer to the drug product.27 
 
2.  Choosing an RLD 
 
                                                 
23 21 CFR 314.162. 
24 21 CFR 314.161(a). 
25 See, e.g., Determination that KENALOG (Triamcinolone Acetonide) Lotion and Other Drug Products Were Not 
Withdrawn From Sale for Reasons of Safety or Effectiveness (81 FR 13797; March 15, 2016); and Determination 
that Ondansetron (Ondansetron Hydrochloride) Injection, USP, in PL 2408 Plastic Container, 32 Milligrams in 50 
Milliliters, Was Withdrawn From Sale for Reasons of Safety or Effectiveness (80 FR 32962; June 10, 2015).   
26 The Orange Book may not include notations for all such determinations published in Notices in the Federal 
Register and does not reflect determinations published in Notices in the Federal Register before 1995.  A potential 
applicant should refer to the Federal Register to see if FDA has published a Notice that announces a determination 
about whether a listed drug has been voluntarily withdrawn from sale for safety or effectiveness reasons. 
27 21 CFR 314.162(a).   
 
  6  Contains Nonbinding Recommendations 
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.28   
 
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.    
 
For an ANDA based on an approved suitability petition (a petitioned ANDA), an applicant must 
choose as its RLD the listed drug that is referenced in the approved suitability petition.29   
 
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.30  Such petition 
must contain all evidence available to the petitioner concerning the reason that the drug product 
was withdrawn from sale.31  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.32 
 
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. 
 
3.  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.   
 
                                                 
28 See FDAs draft guidance for industry on Controlled Correspondence Related to Generic Drug Development 
(November 2017).  When final, this guidance will represent FDAs current thnking on this topic.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA guidance web 
page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
29 21 CFR 314.94(a)(3)(i). 
30 21 CFR 314.122(a).  If a citizen petition seeking a safety and effectiveness determination for the listed drug 
already has been submitted to FDA, the ANDA applicant should reference the pending petition in its ANDA and 
FDA will consider the ANDA to be accompanied by the petition.  Id.  If the listed drug is moved to the 
Discontinued Section while the ANDA is pending, a safety and effectiveness determination must be made by FDA 
before the ANDA can be approved.  21 CFR 314.161(a)(1). 
31 21 CFR 314.122(a).  FDA will consider the evidence in the petition, as well as any other information before the 
Agency, to determine whether the listed drug was withdrawn from sale for safety or effectiveness reasons. 21 CFR 
314.122(b). 
32 21 CFR 314.161(a). 
 
  7  Contains Nonbinding Recommendations 
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.33  
Accordingly, an ANDA applicant must compare its proposed products labeling to that of the 
RLD, even if FDA has selected a new reference standard for use in in vivo bioequivalence 
studies, as described in detail in section III.C. below.34  Similarly, in evaluating drug product 
formulation and inactive ingredients, an ANDA applicant must compare its proposed generic 
drug to the RLDs formulation, not the formulation of the reference standard.    
 
4.  Identification of the RLD in the Orange Book 
 
Prior to 2017, the column in the electronic Orange Book labeled RLD, and the symbol in the 
printed version described as identifying the RLD, at times indicated the drug product FDA 
selected as the reference standard and at other times indicated the RLD, contributing to 
confusion about which drug is the RLD and which drug is the reference standard.  In 2017, FDA 
began to identify in the Orange Book which listed drugs, including some in the Discontinued 
Section, FDA has designated as RLDs, and which listed drugs in the Active Section FDA has 
selected as reference standards.  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. 
 
5.  Changing the RLD 
 
Once an ANDA applicant chooses the RLD on which it intends to rely, the FD&C Act and FDA 
regulations prohibit the applicant from amending or supplementing its ANDA to change the 
RLD after the ANDA has been submitted.35  An ANDA applicant that seeks to change its RLD 
                                                 
33 The FD&C Act and FDAs regulations permit labeling differences because of differences approved under a 
suitability petition or because the generic drug and the RLD are produced or distributed by different manufacturers.  
Section 505(j)(4)(G) of the FD&C Act and 21 CFR 314.94(a)(8)(iv).  In certain instances, the labeling for the 
generic drug may differ from the labeling for the RLD if FDA permits the ANDA applicant to omit (carve out) an 
indication or other aspect of the RLDs labeling protected by patent, or by exclusivity, and obtain approval for the 
remaining, non-protected conditions of use, provided the differences do not render the proposed product less safe or 
effective than the RLD for all remaining non-protected conditions of use.  See, e.g., section 505(j)(2)(A)(viii) of the 
FD&C Act; 21 CFR 314.127(a)(7). 
34 An applicant is responsible for checking appropriate sources in order to obtain the RLD labeling.  FDA posts 
approved labels and labeling for most drug products on Drugs@FDA 
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Other sources such as FDAs Online Label 
Repository athttps://dailymed.nlm.nih.gov/dailymed/index.cfm, and PRPLLRTM (Pragmatic Regulated Product 
Labeling Listing and Registration) may not necessarily display the most recently approved labeling.  In instances 
where the RLD labeling cannot be located, an applicant for convenience initially may compare its proposed generic 
drugs labeling with the labeling of another ANDA that referenced the same RLD and currently is marketed.  Where 
FDA has withdrawn approval of the application for the RLD for reasons other than safety or effectiveness, the 
ANDA applicant, before approval of the generic drug, may need to revise labeling to reflect certain updated 
information that would have been necessary for the RLD had the application for the RLD not been withdrawn.  See 
FDAs draft guidance for industry Updating ANDA Labeling After the Marketing Application for the Reference 
Listed Drug Has Been Withdrawn (July 2016).  When final, this guidance will represent FDAs current thnking on 
this topic.  
35 Section 505(j)(2)(D) of the FD&C Act; 21 CFR 314.96(c) and 314.97(b).  We note that where an applicant has 
previously mistakenly identified the reference standard (described in detail in section III.C.) as the RLD on Form 
 
  8  Contains Nonbinding Recommendations 
must submit a new ANDA to obtain approval under section 505(j) of the FD&C Act.36  We 
recommend that an ANDA applicant request withdrawal of the pending ANDA before seeking to 
change its RLD.  
 
C.  Reference Standard 
 
1.  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.37  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.38     
 
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.39  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.40  FDA usually selects as the reference standard the 
highest strength available for drug products with multiple approved strengths.41   
 
If drug products are approved for multiple strengths but FDA has selected only one of the 
strengths as the reference standard, an applicant may use other approved strengths for certain 
testing, other than in vivo bioequivalence testing (e.g., dissolution testing to support approval of 
those strengths not selected as the reference standard), if the use of such drug product in the 
particular testing is scientifically supported.   
                                                 
FDA 356h or elsewhere in its ANDA, the applicant may submit an amendment to a pending ANDA or a supplement 
to an approved ANDA to correct the information.  FDA considers this error to be a deficiency related to 
identification of the appropriate listed drug as the RLD, rather than a change in the RLD itself.  The cover letter for 
such a submission should clearly identify that the purpose of the submission is Correction of RLD information. 
36 Section 505(j)(2)(D)(i) of the FD&C Act; 21 CFR 314.96(c) and 314.97(b). But see section 505(j)(2)(D)(ii) of the 
FD&C Act. 
37 Section 505(j)(2)(A)(iv) of the FD&C Act. 
38 21 CFR 320.24. 
39 21 CFR 314.3(b).  We note that in vivo bioequivalence evidence is not required in all circumstances, see, e.g., 21 
CFR 320.22 and 320.24(b)(6).  When in vivo bioequivalence testing is required or an applicant otherwise seeks to 
support a demonstration of bioequivalence with in vivo data, such testing should be conducted with the drug product 
FDA selects as the reference standard.  Although the regulations do not require that an applicant use a particular 
product for in vitro testing, we recommend that the reference standard also be used for in vitro testing. 
40 An ANDA applicant may use the authorized generic version of the reference standard for purposes of conducting 
an in vivo bioequivalence study required for approval.  See section 505(t) of the FD&C Act for additional 
information on authorized generics.  The ANDA applicant may contact the Office of Generic Drugs via controlled 
correspondence before conducting studies to inquire further and to discuss the necessary documentation. 
41 See Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69580 at 69619 (October 
6, 2016). There may be instances in which the highest strength would not be the appropriate reference standard for 
testing in vivo bioequivalence or the highest strength is not available for testing.  For example, FDA may select a 
different strength if testing at a different strength provides greater assurance of safety for the subject or is more 
feasible in terms of recruiting subjects who meet the study criteria. FDA also may, in limited circumstances, select 
multiple strengths in a single application as reference standards, e.g., if there is disproportionality among the product 
strengths.   
  9  Contains Nonbinding Recommendations 
 
Where FDA cannot select the RLD as the reference standard (e.g., where the RLD has been 
withdrawn from sale for reasons other than safety and effectiveness), FDA generally will select a 
previously approved ANDA that referred to, and is therapeutically equivalent to, the RLD as the 
reference standard.  If there are multiple approved generic drugs that referred to the RLD and 
have the same active ingredient, dosage form, route of administration, and strength, FDA usually 
will select the generic market leader, based on commercial data, as the reference standard.  
Where a generic drug is intended to duplicate a drug product approved in a petitioned ANDA, 
FDA generally selects a generic drug product approved under the petitioned ANDA as the 
reference standard.   
 
As discussed above, even if FDA selects a reference standard that is a drug product other than 
the RLD for use in conducting in vivo bioequivalence studies, an ANDA applicant must 
demonstrate that its proposed generic drug meets the sameness requirements in section 505(j) of 
the FD&C Act and Agency regulations in relation to the RLD.   
 
Before 2017, a reference standard selected by FDA was indicated in the electronic version of the 
Orange Book with the word Yes in the RLD column, and in the paper version of the Orange 
Book with the + symbol, for drug products listed in the Active Section.  In 2017, FDA 
modified the Orange Book to clarify which listed drugs are reference standards.  In the Active 
Section of the electronic Orange Book, there is a column for RLDs and a column for reference 
standards.  In the Active Section of the printed version of the Orange Book, the RLDs and 
reference standards are identified by distinct symbols. 
  
2.  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;42  
 
  Whether or not the current reference standard is also the RLD, and the Agency 
determines that the quantity of the current reference standard in distribution is so limited 
that a potential ANDA applicant is not able to obtain a sufficient quantity for in vivo 
                                                 
42 Executive Order 13588 on reducing prescription drug shortages was issued on October 21, 2011, and directs FDA 
to take steps to help prevent and reduce current and future disruptions in the supply of lifesaving drug products.  For 
example, in June 2013, FDA removed Doxil (NDA 050718) as the reference standard for doxorubicin hydrochloride 
(HCl) liposome injection and selected Lipodox (ANDA 203263) as the reference standard.  The shortage and 
continued unavailability of Doxil, a lifesaving drug product for cancer treatment, meant that there existed no 
available reference standard against which to test a generic doxorubicin HCl liposome injection product, effectively 
blocking generic competition to Doxil. 
  10  Contains Nonbinding Recommendations 
bioequivalence testing (even if the current reference standard has not been withdrawn 
from sale).   
 
When selecting a new reference standard, FDA generally selects a drug product that is 
therapeutically equivalent to the RLD and is the market leader based on commercial data.  In 
certain circumstances, FDA will consider additional factors in selecting a new reference 
standard.  For example, as a practical matter, FDA may consider whether potential reference 
standards are approved under applications that cover all the RLD strengths, which may make the 
development process more efficient, or whether a potential reference standard is approved for the 
particular strength that is recommended by FDA for use in in vivo bioequivalence studies in a 
product-specific guidance.43     
 
3.  Requesting Selection of a Reference Standard 
 
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 a 
reference standard other than the one selected by FDA is appropriate, or if the quantity of the 
reference standard in distribution is so limited that a potential ANDA applicant is not able to 
obtain a sufficient quantity for in vivo bioequivalence testing.  A potential applicant may submit 
controlled correspondence to FDA to ask FDA to select a reference standard for a drug product.  
If the Agency selects a new reference standard, that product generally will remain the reference 
standard even if the original reference standard resumes marketing. 
 
Some stakeholders refer to some generic drugs that are reference standards as second RLDs.44  
That description is not accurate and has generated confusion regarding generic drug development 
and the role of the reference standard relative to that of the RLD for both industry and the 
Agency.  For example, FDA has received citizen petitions requesting designation of a second 
RLD, when in fact the petition is requesting that FDA select a new reference standard.  In 
addition, ANDA applicants mistakenly have compared their proposed generic drugs to a 
reference standard to meet requirements for approval other than in vivo bioequivalence.  While 
the reference standard is selected by FDA for the purpose of conducting any in vivo 
bioequivalence studies required for approval, an ANDA applicant must demonstrate that its 
proposed generic drug meets the sameness requirements in section 505(j) of the FD&C Act and 
Agency regulations in relation to the RLD.  Accordingly, an ANDAs proposed labeling and 
formulation must be compared to the RLD, and not the reference standard, and the applicant 
must address any unexpired patents and exclusivity for the RLD as required.45 
 
D.  Basis of Submission 
 
An ANDA applicant must identify in its application the basis of submission.46   
                                                 
43 See generally, guidance for industry Bioequivalence Recommendations for Specific Products (June 2010).   
44 See the discussion in section III.B.1 of this guidance. 
45 See, e.g., section 505(j)(2)(B) of the FD&C Act; 21 CFR 314.94(a)(12). 
46 21 CFR 314.94(a)(3). 
  11  Contains Nonbinding Recommendations 
 
1.  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 number47 should 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 of biopharmaceutic studies.48  FDA 
guidance and technical documents related to ANDA formatting are maintained and updated on 
FDAs website.49 
 
2.  Basis of Submission for a First Petitioned ANDA 
 
When an applicant submits a petitioned ANDA,50 the basis of submission is the RLD and the 
approved suitability petition.  The ANDA must contain: (1) the name of the RLD, which must be 
the same as the listed drug identified in the approved suitability petition; (2) a reference to the 
suitability petitions FDA-assigned docket number; and (3) a copy of FDAs correspondence 
approving the suitability petition.51  An applicant should identify on Form FDA 356h both the 
RLD and the RLDs application number, just as it would on Form FDA 356h for a non-
petitioned ANDA.  In the basis of submission statement section (1.12.11) of the petitioned 
ANDA, in addition to identifying the RLD and its application number (as it would for a non-
petitioned ANDA), the applicant should reference the FDA-assigned docket number for the 
approved suitability petition and include a copy of FDAs correspondence approving the 
suitability petition.  Also, the RLD should generally be identified as the reference standard in 
that section.     
 
                                                 
47 FDA previously has indicated in certain limited circumstances that for drug products for which one NDA holder 
holds multiple approved NDAs for different strengths of the same drug product, it may be appropriate to accept an 
ANDA that references more than one NDA number.  This promotes a more efficient use of the Agencys review 
resources.  See guidance for industry Variations in Drug Products that May Be Included in a Single ANDA 
(December 1998).  As previously  noted, 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.   
48 See Comprehensive Table of Contents Headings and Hierarchy, 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSub
missions/UCM315023.pdf, for electronic submissions. 
49 See, e.g., Attachment 1 of MAPP 5200.14 Filing Review of Abbreviated New Drug Applications, which provides 
technical information on how to organize an ANDA submission.   
50 See discussion of suitability petitions in the Background section of this guidance.   
51 21 CFR 314.94(a)(3)(i) and (iii). 
 
  12  Contains Nonbinding Recommendations 
However, if after approval of a suitability petition and before approval of an ANDA submitted 
pursuant to the approved petition, a drug product is approved in an NDA for the change 
described in the petition, the suitability petition and the listed drug identified in the petition can 
no longer be the basis of submission, irrespective of whether FDA has withdrawn approval of the 
petition.  Under these circumstances, an applicant seeking approval for a drug product with the 
change approved in the suitability petition must submit a new ANDA that identifies the drug 
product with the same active ingredient, dosage form, route of administration, and strength that 
has been approved for safety and effectiveness under section 505(c) of the FD&C Act as the 
RLD and as its basis of submission and comply with applicable regulatory requirements.52     
 
3.  Basis of Submission for a Generic Drug That Is a Duplicate of a Drug Product 
Approved in a Petitioned ANDA 
 
When an ANDA applicant seeks approval of a generic drug that is a duplicate of a drug product 
in an approved petitioned ANDA (and for which the same drug has not been approved for safety 
and effectiveness under section 505(c) of the FD&C Act), the basis of submission is the RLD 
and the approved suitability petition.  The ANDA must contain: (1) the name of the RLD, which 
must be the same as the listed drug identified in the approved suitability petition, and RLD 
application number; (2) a reference to the suitability petitions FDA-assigned docket number; 
and (3) a copy of FDAs correspondence approving the suitability petition.  The drug product 
approved under the first petitioned ANDA generally will be selected by FDA as the reference 
standard and should be used for and identified in the appropriate sections of a subsequent ANDA 
as the reference standard.   
   
                                                 
52 21 CFR 314.93(f)(2).  See also Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 
FR 69580 at 69621-69622 (October 6, 2016). 
  13  Contains Nonbinding Recommendations 
APPENDIX 1: QUICK REFERENCE 
 
This appendix summarizes the concepts discussed in this guidance.  We recommend that an 
ANDA applicant refer to the appropriate section of the guidance for more detailed information, 
as needed. 
 
  The reference listed drug (RLD) for an ANDA is the drug product that the 
proposed generic drug is intended to duplicate and to which the ANDA applicant 
must refer in its ANDA.  FDA designates as RLDs listed drugs approved for 
safety and effectiveness under section 505(c) of the FD&C Act.  The Orange 
Book identifies which listed drugs have been designated by FDA as RLDs, 
including some listed drugs in the Discontinued Section of the Orange Book.  In 
the electronic Orange Book, there is a column for RLDs.  In the printed version of 
the Orange Book, RLDs are identified by a distinct symbol. 
 
  The reference standard selected by FDA must be used in conducting any in vivo 
bioequivalence study required for approval of the ANDA.  The reference standard 
may or may not be the same listed drug as the RLD.  Other comparisons of the 
proposed generic drug to determine whether it meets the statutory requirements 
for approval under section 505(j) of the FD&C Act (e.g., sameness requirements) 
generally must be to the RLD.   
 
The drug product selected by FDA as the reference standard generally is 
identified in the Orange Book.  In the electronic Orange Book, there is a column 
for reference standards.  In the printed version of the Orange Book, reference 
standards are identified by a distinct symbol. 
 
  If you mistakenly identify the reference standard as the RLD in your ANDA, you 
may submit an amendment to a pending ANDA or a supplement to an approved 
ANDA to correct the information.  FDA considers this error to be a deficiency 
related to identification of the appropriate listed drug as the RLD, rather than a 
change in the RLD itself.  The cover letter for such a submission should clearly 
identify that the purpose of the submission is Correction of RLD information. 
 
  The basis of submission statement in an ANDA (e.g., in section 1.12.11 of the 
ANDA) and in Form FDA 356h (field 20) should include the name of the RLD 
and the RLD application number.  For a petitioned ANDA, the basis of 
submission statement in the ANDA (e.g., in section 1.12.11 of the ANDA) also 
should include a reference to the FDA-assigned docket number for the approved 
suitability petition and a copy of FDAs correspondence approving the suitability 
petition.  The reference standard, if it is different from the RLD, should be 
identified in the appropriate sections of the ANDA (e.g., sections 1.12.11, 2.7.1, 
5.2, and 5.3.1).   
   
  14  Contains Nonbinding Recommendations 
 
TABLE: REFERENCING APPROVED DRUG PRODUCTS IN AN ANDA 
What drug product  Identification of Basis of Submission in  Identification 
is the generic drug  ANDA  of reference 
intended to be the  Form FDA  standard in 
same as?  RLD  Reference Standard  356h  ANDA  ANDA 
ANDA for a generic  The RLD is a  Generally, the RLD  Fill in the name  Identify the RLD and  Identify the 
drug that is a  listed drug  also is the reference  of RLD and its  its application number  reference 
duplicate of its RLD  approved for  standard if it is being  application  in section 1.12.11.  standard in 
safety and  marketed.  number for field    sections 
effectiveness    20 on the form.    1.12.11, 2.7.1, 
under section  The applicant should  5.2, and 5.3.1 of 
505(c) of the  check the Orange Book  the ANDA. 
FD&C Act and  to confirm the listed 
identified as an  drug that FDA has 
RLD in the Orange  selected as the 
Book.   reference standard for 
that drug product. 
ANDA for a generic  The listed drug,  Generally the listed  Fill in the name  In section 1.12.11:  Identify the 
drug for which a  approved for  drug identified in the  of RLD and its   Identify the RLD  reference 
suitability petition  safety and  approved suitability  application  and its application  standard in 
has been approved  effectiveness,  petition is the reference  number for field  number,   sections 
identified in the  standard.  20 on the form.   Identify the FDA-  1.12.11, 2.7.1, 
approved    assigned docket  5.2, and 5.3.1 of 
suitability petition     number for the  the ANDA. 
is the RLD.  approved suitability 
petition, and 
 Include a copy of 
FDAs 
correspondence 
approving the 
suitability petition 
  15  Contains Nonbinding Recommendations 
 
TABLE: REFERENCING APPROVED DRUG PRODUCTS IN AN ANDA (contd) 
What drug  Identification of Basis of Submission in 
product is the  ANDA  Identification 
generic drug  of reference 
intended to  standard in 
reference?  RLD  Reference Standard  Form FDA 356h  ANDA  ANDA 
ANDA for a  The listed drug,  The drug product  Fill in the name of  In section 1.12.11:  Identify the 
generic drug that is  approved for  approved in the first  RLD and its   Identify the RLD and  reference 
the same as a drug  safety and  petitioned ANDA  application  its application  standard in 
product approved in  effectiveness,   generally is the  number for field  number,   sections 1.12.11, 
a petitioned ANDA  identified in the  reference standard.  20 on the form.   Identify the FDA-  2.7.1, 5.2, and 
approved    assigned docket  5.3.1 of the 
suitability  The applicant should  number for the  ANDA.  
petition is the  check the Orange  approved suitability 
RLD.   Book to confirm the  petition, and 
listed drug that FDA    Include a copy of 
has selected as the  FDAs 
reference standard for  correspondence 
that drug product.  approving the 
suitability petition. 
 
  16