Evaluation of 
Therapeutic 
Equivalence 
Guidance for Industry 
 
 
 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Susan Levine 240-402-7936.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2022 
Generics 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Evaluation of 
Therapeutic 
Equivalence 
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 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2022 
Generics 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  THERAPEUTIC EQUIVALENCE EVALUATIONS .................................................. 2 
A.  The Fundamentals of Therapeutic Equivalence ......................................................................... 2 
1. Pharmaceutical Equivalence ........................................................................................................... 2 
2. Bioequivalence ................................................................................................................................. 3 
3. Same Clinical Effect and Safety Profile ........................................................................................... 3 
B.  Products Evaluated for Therapeutic Equivalence ...................................................................... 4 
1. Drug Products Approved Under Section 505(c) of the FD&C Act ................................................. 4 
2  Drug Products Approved Under Section 505(j) of the FD&C Act .................................................. 5 
C.  The Therapeutic Equivalence Coding System ............................................................................. 6 
1. A Codes ............................................................................................................................................ 7 
2. B Codes ............................................................................................................................................ 7 
3. Three-Character Codes ................................................................................................................... 8 
D.  Revisions to Therapeutic Equivalence Evaluations .................................................................... 8 
III.  FREQUENTLY ASKED QUESTIONS .......................................................................... 9 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Evaluation of Therapeutic Equivalence 
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
7  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.   
10   
11   
12  I.  INTRODUCTION  
13   
14  This guidance explains FDAs therapeutic equivalence evaluations, including the assignment of 
15  therapeutic equivalence codes (or TE codes).  As defined in 21 CFR 314.3(b), therapeutic 
16  equivalents are 
17   
18  approved drug products that FDA has determined are pharmaceutical equivalents for 
19  which bioequivalence has been demonstrated, and that can be expected to have the same 
20  clinical effect and safety profile when administered to patients under the conditions 
21  specified in the labeling.   
22   
23  FDAs therapeutic equivalence evaluations are listed for multisource2 prescription drug products 
24  approved under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 
25  U.S.C. 355) in the active section of the Approved Drug Products With Therapeutic Equivalence 
26  Evaluations (commonly known as the Orange Book)3.  As FDA explained when it first proposed 
27  to make available a list of all approved drug products, together with therapeutic evaluations of  
28  listed products that are available from more than one manufacturer,  therapeutic equivalence 
29  evaluations have been prepared to serve as public information and advice to state health 
30  agencies, prescribers, and pharmacists to promote public education in the area of drug product 
31  selection and to foster containment of health care costs.4  For example, the Orange Book can 
32  assist in the establishment of formularies that States and other entities may use in determining 
33  when drug products may be substituted for one another.  If lower-cost, therapeutically equivalent 
34  drug products are available, American consumers are more likely to receive savings on these 
 
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.  
2 For purposes of therapeutic equivalence evaluations, multisource drug products are, in most instances, 
pharmaceutical equivalence available from more than one manufacturer.  In contrast, single-source drug products 
are those products for which there is only one approved product available for that active ingredient, dosage form, 
route of administration, and strength.  See Orange Book Preface (42nd edition 2022) at xii. 
3The electronic version of the Orange Book can be found at 
https://www.fda.gov/drugs/informationondrugs/ucm129662.htm.  
4 See, e.g., 44 FR 2932 (January 12, 1979) and 45 FR 72582 (October 31, 1980). 
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35  products.5  Therapeutic equivalence evaluations are a scientific judgment based upon evidence, 
36  while generic substitution may involve social and economic policy administered by the states, 
37  e.g., reducing the cost of drugs to consumers.  These evaluations do not constitute determinations 
38  that any product is in violation of the FD&C Act or that any product is preferable to any other.   
39   
40  The contents of this document do not have the force and effect of law and are not meant to bind 
41  the public in any way, unless specifically incorporated into a contract. This document is intended 
42  only to provide clarity to the public regarding existing requirements under the law. FDA 
43  guidance documents, including this guidance, should be viewed only as recommendations, unless 
44  specific regulatory or statutory requirements are cited. The use of the word should in FDA 
45  guidance means that something is suggested or recommended, but not required. 
46   
47  II.  THERAPEUTIC EQUIVALENCE EVALUATIONS 
48   
49  A.  The Fundamentals of Therapeutic Equivalence 
50   
51  The scientific and regulatory foundation for the evaluation of therapeutic equivalence of 
52  prescription drug products involves:  
53    Pharmaceutical equivalence, 
54    Bioequivalence, and 
55    Same clinical effect and safety profile for the conditions of use specified in the labeling.6 
56   
57  Therapeutic equivalence can be evaluated only for products that are (or will become upon 
58  approval) multisource prescription drug products.7 FDA approval includes, among other things, a 
59  determination that the drug product is adequately labeled, and that the methods used in, and the 
60  facilities and controls used for, the manufacture, processing, and packaging of a drug product are 
61  adequate to preserve its identity, strength, quality, and purity.8   
62   
63  FDA believes products classified as therapeutically equivalent can be substituted with the full 
64  expectation that the substituted product will produce the same clinical effect and safety profile as 
65  the prescribed product when administered to patients under the conditions specified in the 
66  labeling. 
67   
68  1.  Pharmaceutical Equivalence 
69   
70  To be therapeutically equivalent, drug products must be pharmaceutically equivalent.9  As 
71  defined in 21 CFR 314.3(b), pharmaceutical equivalents are drug products:  
 
5 Id. 
 
6 See 21 CFR 314.3(b). 
7 See id; see also Orange Book Preface (42nd edition 2022) at vii and xii.  Prescription drug products are considered 
multisource when pharmaceutical equivalents are available (i.e., are not on the Discontinued Drug Product list in the 
Orange Book) from more than one manufacturer. 
8 See 21 CFR 314.127(a).  
9 21 CFR 314.3(b). 
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72   
73    in identical dosage form and route(s) of administration; 
74   
75    Contain identical amounts of the identical active drug ingredient, i.e., the same salt or 
76  ester of the same therapeutic moiety, or, in the case of modified-release dosage forms 
77  that require a reservoir or overage or such forms as prefilled syringes where residual 
78  volume may vary, that deliver identical amounts of the active drug ingredient over 
79  the identical dosing period;  
80   
81    Do not necessarily contain the same inactive ingredients; and  
82   
83    Meet the identical compendial or other applicable standard of identity, strength, 
84  quality, and purity, including potency and, where applicable, content uniformity, 
85  disintegration times, and/or dissolution rates.10  
86   
87  2.  Bioequivalence 
88   
89  To be therapeutically equivalent, drug products must also be bioequivalent.11  Bioequivalence is, 
90  in pertinent part:  
91   
92  the absence of a significant difference in the rate and extent to which the active ingredient 
93  or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes 
94  available at the site of drug action when administered at the same molar dose under 
95  similar conditions in an appropriately designed study.12   
96   
97  For drug products that are not intended to be absorbed into the bloodstream, applicants may 
98  assess bioequivalence by conducting scientifically valid measurements that are intended to 
99  reflect the rate and extent to which the active ingredient or active moiety becomes available at 
100  the site of action.13  FDA has promulgated regulations regarding demonstrating bioequivalence,14 
101  and the Agency routinely publishes guidances for industry and product-specific guidances to 
102  assist applicants and sponsors in demonstrating bioequivalence.15   
103     
104  3.     Same Clinical Effect and Safety Profile 
105   
 
10 21 CFR 314.3(b) (bullets added).   
11 Id. 
12 Id.    
13 Id. 
14 See, e.g., 21 CFR 314.94(a)(7) and 21 CFR part 320. 
15 For example, as an initial step for selecting a methodology for generic drug development, applicants may refer to 
the draft guidance for industry Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under 
an ANDA (August 2021).  When final, this guidance will represent the FDAs current thinking on this topic.  For the 
most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. Product-specific guidances are available at 
https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development. 
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106  Therapeutic equivalents are expected to have the same clinical effect and safety profile when 
107  administered to patients under the conditions of use specified in the labeling.16  Labeling plays a 
108  critical role in the therapeutic equivalence evaluation. FDA evaluates the labeling to determine 
109  whether the drug products have the same clinical effect and safety profile under the conditions of 
110  use that the labeling specifies.  As a result, pharmaceutically equivalent products with 
111  differences in labeling may not be considered therapeutically equivalent to one another.   
112   
113  The evaluation of whether drug products have the same clinical effect and safety profile is 
114  product-specific.  For example, whether a proposed generic drug-device combination product 
115  with a user interface that contains differences from that for the RLD17 can be substituted with the 
116  full expectation that the generic combination product will produce the same clinical effect and 
117  safety profile as the RLD under the conditions specified in the labeling is a product specific 
118  determination, and additional information and/or data relating to the user interface may be 
119  appropriate to support approval and to perform this evaluation.  
120   
121  B.  Products Evaluated for Therapeutic Equivalence 
122   
123  FDA only evaluates certain drug products approved under section 505 of the FD&C Act for 
124  therapeutic equivalence.  Section 505 establishes the following approval pathways for drug 
125  products: stand-alone new drug applications (NDAs); 505(b)(2) applications; and abbreviated 
126  new drug applications (ANDAs), which include petitioned ANDAs.18 
127   
128  1.  Drug Products Approved Under Section 505(c) of the FD&C Act 
129   
130  A stand-alone NDA is an application submitted under section 505(b)(1) and approved under 
131  section 505(c) of the FD&C Act that contains full reports of investigations of safety and 
132  effectiveness that were conducted by or for the applicant or for which the applicant has a right of 
133  reference or use.  
134     
135  A 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under 
136  section 505(c) of the FD&C Act that contains full reports of investigations of safety and 
137  effectiveness, where at least some of the information required for approval comes from studies 
138  not conducted by or for the applicant and for which the applicant has not obtained a right of 
139  reference or use (e.g., the Agencys finding of safety and/or effectiveness for a listed drug, 
 
16 21 CFR 314.3(b). 
17 The RLD is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking 
approval of its ANDA. 21 CFR 314.3(b).   
18 Prescription drug products that have been approved by FDA are generally listed in the Orange Book.  See section 
505(j)(7)(A) and (B) of the FD&C Act; 21 CFR 314.3(b). The Orange Book includes drug products whose 
applications became effective before the 1962 Amendments to the FD&C Act (and were deemed approved upon 
enactment of the 1962 amendments) on the basis of a demonstration of safety, where the effectiveness for their 
intended use was determined through the Drug Efficacy Study Implementation (DESI) process.  Drugs marketed 
prior to the enactment of the Federal Food, Drug & Cosmetic Act of 1938 were not subject to premarket approval 
procedures and are excluded from the Orange Book. 
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140  published literature).19  FDA generally will refuse to file a 505(b)(2) application for a drug that is 
141  a duplicate20 of a listed drug and eligible for approval under section 505(j) of the FD&C Act.21  
142   
143  FDA generally does not conduct therapeutic equivalence evaluations upon approval of drug 
144  products in stand-alone NDAs.  In most cases, a stand-alone NDA drug product would not be 
145  pharmaceutically equivalentand thus not therapeutically equivalentto another approved 
146  stand-alone NDA drug product.  Drug products approved in stand-alone NDAs are generally 
147  designated as reference listed drugs upon which prospective generic drug applicants can rely in 
148  developing their ANDA drug products. 
149   
150  FDA does not routinely conduct therapeutic equivalence evaluations for every product approved 
151  in a 505(b)(2) application.  A person seeking to have a therapeutic equivalence rating for a drug 
152  product approved in a 505(b)(2) application may petition the Agency through the citizen petition 
153  procedure (see 21 CFR 10.25(a) and 21 CFR 10.30).22  When therapeutic equivalence is 
154  evaluated, the differences between a product approved in a 505(b)(2) application and another 
155  listed drug may preclude a finding that the products are therapeutically equivalent.  These 
156  differences may include, for example, a different active ingredient or a new indication, dosage 
157  form, strength, or route of administration, or certain formulation differences.23 See question and 
158  answer 3, 4, and 5 for more information specifically on 505(b)(2) applications and TE codes, 
159  including information on requesting a therapeutic equivalence evaluation for a drug product that 
160  is the subject of an approved or pending 505(b)(2) application.  Like those in stand-alone NDAs, 
161  drug products approved in 505(b)(2) applications are generally designated as reference listed 
162  drugs upon which prospective generic drug applicants can rely in developing their ANDA drug 
163  products. 
164   
165  2   Drug Products Approved Under Section 505(j) of the FD&C Act 
166   
167  An ANDA24 generally is an application submitted and approved under section 505(j) of the 
168  FD&C Act for a drug product that is a duplicate of a previously approved drug product, the 
 
19 For more information on 505(b)(2) applications, see the guidance for industry Determining Whether to Submit an 
ANDA or 505(b)(2) Application (May 2019) and the draft guidance for industry Applications Covered by Section 
505(b)(2) (October 1999).  When final, this guidance will represent the FDAs current thinking on this topic.   
20 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.   
21 21 CFR 314.101(d)(9) (noting that FDA may refuse to file an NDA if the NDA is submitted as a 505(b)(2) 
application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the 
[FD&C] Act).  
22 See Orange Book Preface (42nd edition 2022) at xxiv. 
23 For examples of applications that may be submitted under section 505(b)(2) of the FD&C Act see the draft 
guidance for industry Applications Covered by Section 505(b)(2) (December 1999). When final, this guidance will 
represent the FDAs current thinking on this topic.   
24 For purposes of this guidance, the terms generic, abbreviated new drug application, and ANDA refer to 
products submitted and approved under section 505(j) of the FD&C Act. The Orange Book also refers to certain 
products approved under pre-Hatch-Waxman abbreviated applications (PANDAs) as ANDAs. In general, the 
 
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169  RLD.  An ANDA generally must contain information to show that the proposed generic product 
170  (1) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of 
171  administration, dosage form, strength, and labeling (with certain permissible differences) and (2) 
172  is bioequivalent to the RLD. If the statutory requirements are met, an ANDA may rely on FDAs 
173  finding that the previously approved drug product, the RLD, is safe and effective.    
174   
175  A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its 
176  dosage form, route of administration, strength, or active ingredient (in a product with more than 
177  one active ingredient) and for which FDA has determined, in response to a petition submitted 
178  under section 505(j)(2)(C) of the FD&C Act (suitability petition), that studies are not necessary 
179  to establish the safety and effectiveness of the proposed drug product.  For approval, the drug 
180  product approved in a petitioned ANDA may rely on the finding of safety and effectiveness for 
181  the RLD that was the basis of the suitability petition, but would not be therapeutically equivalent 
182  to its RLD because the differences permissible in a petitioned ANDA would render the product 
183  not pharmaceutically equivalent to the RLD. 
184   
185  In general, with the exception of a drug product approved in a petitioned ANDA, when FDA 
186  approves a drug product under an ANDA it is therapeutically equivalent to its RLD because the 
187  requirements for ANDA approval include the data and information that establish therapeutic 
188  equivalence.  Accordingly, an ANDA applicant does not need to request a therapeutic 
189  equivalence evaluation from the Agency.  In contrast to FDAs general practice to designate 
190  stand-alone NDAs and 505(b)(2) applications as reference listed drugs upon approval, FDAs 
191  general practice has not been to designate ANDAs as reference listed drugs upon approval 
192  because ANDAs do not contain independent findings of safety and effectiveness upon which 
193  other ANDAs can rely. 25      
194   
195  C.  The Therapeutic Equivalence Coding System26 
196   
197  FDA lists its therapeutic equivalence evaluations in the Orange Book using a system of multi-
198  letter codes assigned to multi-source drug products. The coding system is designed to allow users 
199  to determine quickly whether the Agency has evaluated a particular approved drug product as 
200  therapeutically equivalent to another approved pharmaceutically equivalent drug product.  
201  Generally, the first letter of the code indicates whether the Agency has determined that a 
202  particular approved drug product is therapeutically equivalent to another drug product.   
203  The coding system also uses additional specific letters to provide further information based on 
204  FDAs evaluations.   
 
discussion of ANDAs and generics in this document do not include such products. For more information on 
PANDAs, see Notice: Drug Products Approved in Abbreviated New Drug Applications Before the Enactment of the 
Hatch-Waxman Amendments; Establishment of a Public Docket; Request for Comments (referred to as PANDA 
Notice), Docket No. FDA-2020-N-1245, available at: https://www.govinfo.gov/content/pkg/FR-2021-08-
13/pdf/2021-17378.pdf, and Pre-Hatch-Waxman Abbreviated New Drug Applications in the Orange Book, available 
at: https://www.govinfo.gov/content/pkg/FR-2021-08-13/pdf/2021-17378.pdf.  
25 We note that PANDAs have been designated as RLDs even though they are described in the Orange Book as 
ANDAs (see PANDA Notice). 
26 The Preface to the Orange Book explains therapeutic equivalence codes in greater detail.  See the Orange Book 
Preface (42nd edition 2022) discussion beginning at p. xii.       
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205   
206  1.  A Codes 
207   
208  Drug products are assigned an A as the first letter of their therapeutic equivalence code if FDA 
209  considers them to be therapeutically equivalent to other pharmaceutically equivalent products.  
210  Drug products considered to be therapeutically equivalent are grouped together in the Orange 
211  Book. 
212   
213  For products that are therapeutically equivalent (i.e., those codes in which an A is the first letter), 
214  the second letter in the code identifies that either: 
215   
216  (1) actual or potential bioequivalence problems have been resolved with adequate 
217  evidence, or  
218  (2) there are no known or suspected bioequivalence problems.   
219   
220  In the former case, for pharmaceutically equivalent products that have raised questions of 
221  bioequivalence and for which in vivo and/or in vitro methods were used to establish 
222  bioequivalence, FDA assigns them an AB code.  In the latter case (when there are no known or 
223  suspected bioequivalence problems), the second letter in the therapeutic equivalence code (i.e., 
224  the A, N, O, P, or T in AA, AN, AO, AP, or AT) identifies the dosage form.27  For active 
225  ingredients or dosage forms for which no in vivo bioequivalence issue is known or suspected, the 
226  information necessary to show bioequivalence (between pharmaceutically equivalent products) is 
227  either presumed and considered self-evident (based on other information in the application for 
228  some dosage forms (e.g., solutions)),28 or satisfied by a showing that an acceptable in 
229  vitro approach is met.   
230   
231  2.   B Codes 
232   
233  Drug products are assigned a B as the first letter of their therapeutic equivalence code if, at this 
234  time, actual or potential bioequivalence problems have not been resolved with adequate evidence 
235  of bioequivalence. Until actual or potential bioequivalence questions are resolved, FDA 
236  considers such products not to be therapeutically equivalent to other pharmaceutically equivalent 
237  products. 
238   
239  For such products, the second letter in the therapeutic equivalence code (i.e., the C, D, E, N, P, R, 
240  S, T, X, and B* in BC, BD, BE, BN, BP, BR, BS, BT, BX, or BB*) either identifies the dosage 
241  form or provides further general information regarding why the product is not considered to be 
 
27 At a high level, the A codes, other than AA, indicate the following things. A solution or powder for aerosolization 
that is therapeutically equivalent to another such approved product and for which there are no known or suspected 
bioequivalence problems would be coded AN.  AA identifies products in conventional dosage forms, e.g., tablets or 
capsules, not presenting bioequivalence problems. All oral dosage forms nonetheless must meet an appropriate 
bioequivalence standard for approval. AO identifies injectable oil solutions. AP identifies injectable aqueous 
solutions and, in certain instances, intravenous non-aqueous solutions. AT identifies topical products.  See the 
Orange Book Preface (42nd edition 2022) discussion beginning at p. xiii. 
28 See 21 CFR 320.22 for a discussion on when bioequivalence may be self-evident. 
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242  therapeutically equivalent.29  In its description of the B codes, the Orange Book describes 
243  circumstances under which FDA may find that a drug product is not therapeutically equivalent to 
244  another approved pharmaceutically equivalent drug product.30   
245   
246  3.  Three-Character Codes 
247   
248  In some instances, a number is added to certain codes to make a three-character code.  Three- 
249  character codes generally are assigned only in situations in which more than one RLD of the 
250  same strength has been designated under the same product heading (i.e., same active 
251  ingredient(s), dosage form, route(s) of administration, and strength) in the Orange Book.  For 
252  example, for the listing for Diltiazem Hydrochloride Capsule, Extended Release, multiple RLDs 
253  are designated, including Tiazac (NDA 020401 for 120, 180, 240, 300, 360, and 420 milligrams 
254  (mg)), Cardizem CD (NDA 020062 for 120, 180, 240, 300, and 360 mg), and Dilacor XR (NDA 
255  020092 for 120, 180, and 240 mg).  ANDAs that reference Tiazac have the AB4 rating, ANDAs 
256  that reference Cardizem CD have the AB3 rating, and ANDAs that referenced Dilacor XR have 
257  the AB2 rating. 
258   
259  D.  Revisions to Therapeutic Equivalence Evaluations 
260   
261  FDA may revise its therapeutic equivalence evaluation for a particular drug product if, based on 
262  data or information FDA receives or becomes aware of, FDA determines that such a revision is 
263  warranted.  FDA may revise either the first or second letter of the therapeutic equivalence code.  
264  The following is a non-exhaustive list of examples: 
265   
266    FDA will revise a therapeutic equivalence code if it decides that another therapeutic 
267  equivalence code would be more accurate than the current one.   
268    FDA will remove any associated therapeutic equivalence code for a drug product that is 
269  moved from the Active section to the Discontinued Drug Product List section of the 
270  Orange Book.   
271    FDA will remove the therapeutic equivalence code for a drug product listed in the Active 
272  section of the Orange Book if that drug product becomes a single-source product.   
273   
274  FDA also may change a drug products therapeutic equivalence code from an A-rating to a B-
275  rating if FDA becomes aware of information that raises questions about the data and information 
276  that the Agency relied on in approving that product.  For example, if FDA discovers significant 
277  issues at a facility where a drug product was used in testing to support its approval and those 
 
29 At a high level, the B codes indicate the following things. BC identifies extended-release dosage forms (e.g., 
capsules, injectables, and tablets). BE identifies delayed-release oral dosage forms. BN identifies products in 
aerosol-nebulizer drug delivery systems. BR identifies suppositories or enemas that deliver drugs for systemic 
absorption. BT identifies topical products with bioequivalence issues.  BD indicates active ingredients and dosage 
forms with documented bioequivalence problems. BS indicates that products have drug standard deficiencies. BP 
indicates active ingredients and dosage forms with potential bioequivalence problems. B* indicates that a drug 
product requires further FDA investigation and review to determine therapeutic equivalence, and BX indicates that 
the data available to FDA are insufficient to determine therapeutic equivalence.  See the Orange Book Preface (42nd 
edition 2022) discussion at pp. xviii-xx. 
30 See the Orange Book Preface (42nd edition 2022) discussion beginning at p. xviii. 
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278  issues are relevant to the underlying therapeutic equivalence evaluation, FDA may change an AB 
279  therapeutic equivalence code to a BX code until the related facility issues and questions about 
280  their impact on the application are resolved. 
281   
282  III.  FREQUENTLY ASKED QUESTIONS 
283   
284  1.      When are therapeutic equivalence codes for ANDAs listed in the Orange Book? 
285   
286  Because the approval standards for a drug product in an ANDA (other than a drug product in a 
287  petitioned ANDA) require in general, among other things, a demonstration that the proposed 
288  drug product has the same dosage form, route of administration, strength, and active ingredient 
289  as its RLD, is bioequivalent to its RLD, and generally has the same labeling as its RLD, with 
290  limited exceptions,31 a generic drug is considered therapeutically equivalent to its RLD upon 
291  approval.  In general, the therapeutic equivalence code for an approved ANDA will be listed 
292  with the approved ANDA at the time that ANDA is added to the Orange Book,32 and the ANDA 
293  holder does not need to request a therapeutic equivalence evaluation to its RLD. 
294   
295  2.  Are there any instances in which an approved ANDA drug product would not have 
296  a therapeutic equivalence code? 
297   
298  Yes.  Generally, FDA assigns a therapeutic equivalence code for an ANDA drug product at the 
299  time of the drugs approval, and this code is included in the listing for that drug product in the 
300  Orange Book.  However, there are limited instances in which a drug product approved under 
301  section 505(j) would not have a therapeutic equivalence code.  For example: 
302   
303    If an RLD is discontinued or withdrawn from sale for reasons other than safety or 
304  effectiveness33 and a drug product approved under the ANDA that references that 
305  RLD becomes a single-source product, then any assigned therapeutic equivalence 
306  codes for the RLD and the ANDA are removed from the Orange Book; the ANDA 
307  will not have a TE code until it becomes a multisource product, for example through 
308  the approval of a therapeutically equivalent ANDA or 505(b)(2) application.34   
309   
310    If FDA approves an ANDA based on an approved suitability petition for a change 
311  permissible under section 505(j)(2)(C) of the FD&C Act (including a change in 
312  dosage form, route of administration, and strength), the approved ANDA would not 
313  be pharmaceutically equivalent to its RLD and, therefore, would not be 
314  therapeutically equivalent to the RLD or have a therapeutic equivalence code to the 
 
31 As noted in section II.B.2.c of this guidance, approval of ANDAs under a suitability petition would not constitute 
a finding of therapeutic equivalence because the ANDA products are not pharmaceutical equivalents to their RLDs. 
32 The Orange Book Staff provides daily updates to the electronic Orange Book for new generic drug approvals.  
33 See 21 CFR 314.161. 
34 If an RLD is discontinued or withdrawn and there are multiple ANDAs that reference that RLD, the remaining 
ANDAs retain their existing therapeutic equivalence codes.  Subsequently approved ANDAs that are pharmaceutical 
equivalents to the RLD would be assigned the same therapeutic equivalence code. 
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315  RLD.  If a second ANDA is approved for the petitioned change, that second ANDA 
316  and the first ANDA would be designated as therapeutically equivalent to each other. 
317   
318  3.  Are there any instances in which an approved NDA drug product would not have a 
319  therapeutic equivalence code? 
320   
321  Yes, there are instances in which an approved NDA drug product listed in the Orange Book 
322  would not have a therapeutic equivalence code.  For example, if an NDA drug product does not 
323  have a therapeutic equivalence code, it could indicate that: 
324   
325    The drug product is one for which there are no therapeutically equivalent products listed 
326  in the Active Section of the Orange Book. 
327   
328    The drug product was approved in a 505(b)(2) application and is not therapeutically 
329  equivalent to the listed drug it references because it is not a pharmaceutical equivalent 
330  (for example, it is for a strength that was not approved for the listed drug).     
331   
332    The drug product was approved in a 505(b)(2) application and is pharmaceutically 
333  equivalent to a stand-alone NDA, but the 505(b)(2) application holder has not made a 
334  request for, and FDA has not conducted, a therapeutic equivalence evaluation for the 
335  505(b)(2) application.   
336   
337  4.  What is an example of a 505(b)(2) application for which a request for an A rating 
338  may be granted? 
339   
340  As noted in Section II.B.1, a drug product approved in a 505(b)(2) application may have  
341  differences from other listed drugs which may preclude a finding of therapeutic  
342  equivalence.  However, a drug product approved in a 505(b)(2) application that meets the criteria  
343  for therapeutic equivalence as described in 21 CFR 314.3(b) may receive an appropriate  
344  therapeutic equivalence code.  
345   
346  For example, FDA may determine that an injectable solution drug product submitted under a 
347  505(b)(2) application is therapeutically equivalent to the listed drug it references if that drug 
348  product is pharmaceutically equivalent and bioequivalent to the listed drug but because of a 
349  difference in excipients from the listed drug35 it references it could not have been approved in an 
350  ANDA.  
351   
352  5.  How do I request therapeutic equivalence evaluation of a drug product submitted in 
353  a 505(b)(2) application? 
354   
355  The holder of an approved 505(b)(2) application drug product may request a therapeutic 
356  equivalence evaluation in a citizen petition submitted under 21 CFR 10.25(a) and 10.30.  FDA 
357  will evaluate whether a therapeutic equivalence code for a 505(b)(2) application is appropriate, 
 
35 See 21 CFR 314.94(a)(9)(ii)  (v) for a discussion on permissible differences in exception excipients. 
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358  after the drug product is approved and FDA has received a therapeutic equivalence code request 
359  from the 505(b)(2) application holder. 
360   
361  In many cases, FDA will assess therapeutic equivalence for a 505(b)(2) application utilizing 
362  information supporting the safety, effectiveness, and quality of the drug product that is already 
363  contained in the NDA file.  If the applicant for a product submitted in a 505(b)(2) application 
364  intends to request a therapeutic equivalence evaluation upon approval, we recommend that the 
365  applicant contact the regulatory project manager for the division to discuss how the applicants 
366  presentation of data and information will facilitate a therapeutic equivalence evaluation and/or to 
367  discuss which additional information (if any) may be needed.36   
368   
369  6.  Does FDA assign a therapeutic equivalence code to tentatively approved37 drug 
370  products? 
371   
372  A drug product that is tentatively approved is not an approved drug product and cannot be 
373  marketed.38  Accordingly, FDA does not list that drug product in the Orange Book and does not 
374  give it a therapeutic equivalence code. 
375   
376  7.  If a drug product is repackaged and distributed by either the applicant or a party 
377  other than the applicant, will it be given its own therapeutic equivalence code? 
378   
379  No. In the Orange Book, FDA would not include a separate listing with separate TE code for a 
380  product that has been repackaged and distributed. 
381   
382  8.   How do instructions in the labeling regarding reconstitution, dilution, or other 
383  manipulation(s) before dispensing or administration affect FDAs determination of 
384  dosage form? 
385   
386  The labeling for a drug product may include instructions for reconstitution, dilution, or other 
387  manipulation(s) of the drug product before use. FDA evaluates the dosage form of such a drug 
388  product before such reconstitution, dilution, or other manipulation(s).  Thus, for example, a 
 
36 For more information on contacting the appropriate Office of New Drugs review division, see 
https://www.fda.gov/drugs/regulatory-science-research-and-education/reorganization-office-new-drugs-
corresponding-changes-office-translational-sciences-and-office.  
37 Tentative approval is notification that an NDA or ANDA otherwise meets the requirements for approval under the 
FD&C Act, but cannot be approved because there is a 7-year period of orphan exclusivity for a listed drug under 
section 527 of the FD&C Act and 21 CFR 316.31, or that a 505(b)(2) application or ANDA otherwise meets the 
requirements for approval under the FD&C Act, but cannot be approved until the conditions in 21 CFR 
314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period of exclusivity for the listed drug under 21 CFR 
314.108; because there is a period of pediatric exclusivity for the listed drug under section 505A of the FD&C Act; 
because there is a period of exclusivity for the listed drug under section 505E of the FD&C Act; or because a court 
order pursuant to 35 U.S.C. 271(e)(4)(A) orders that the NDA or ANDA may be approved no earlier than the date 
specified.  A drug product that is granted tentative approval is not an approved drug and will not be approved until 
FDA issues an approval letter after any necessary additional review of the NDA or ANDA.  21 CFR 314.3(b). 
38 Id.  See section 505(j)(5)(B)(iv)(II)(dd)(BB) of the FD&C Act (stating that a drug that is granted tentative 
approval by the Secretary is not an approved drug and shall not have an effective approval until the Secretary issues 
an approval after any necessary additional review of the application); see also 21 CFR 314.105(d).   
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389  powder for oral solution drug product39 would have a different dosage form from a ready-to-use 
390  oral solution drug product.40 As a result, a powder for oral solution drug product and a ready-to-
391  use oral solution drug product would not be pharmaceutically equivalent and therefore not 
392  therapeutically equivalent to each other.  
393   
394  9.  Can a drug product be therapeutically equivalent if it has different packaging from 
395  the listed drug it references? 
396   
397  Drug products that vary in packaging may or may not be therapeutically equivalent to each other.  
398  For example, if the packaging difference results in a different clinical effect or safety profile of 
399  one drug product to the other or precludes the two products from being pharmaceutical 
400  equivalents, they will not be considered therapeutically equivalent.  
401   
402  10.  Can an ANDA drug product receive an A code if its labeling omits an indication(s) 
403  or other condition(s) of use, or other aspect(s) of labeling that is approved for the 
404  RLD but protected by patent or by exclusivity? 
405   
406  Yes.  An ANDA drug product can be determined to be therapeutically equivalent to its RLD 
407  even if the drug product, due to listed patents or exclusivity for the RLD, is approved for fewer 
408  than all of the indications or other conditions of use for the RLD, or omits, due to listed patents 
409  or exclusivity for the RLD, other aspects of labeling currently approved for the RLD. ANDA 
410  drug products are permitted by statute and FDAs regulations to omit or carve out, for patent 
411  or exclusivity reasons, an indication(s) or other condition(s) of use, or other aspect(s) of labeling 
412  approved for the RLD.41  In making a therapeutic equivalence determination, FDA evaluates 
413  whether the two drug products are pharmaceutical equivalents for which bioequivalence has been 
414  demonstrated, and if they can be expected to have the same clinical effect and safety profile 
415  when administered to patients under the conditions specified in the labeling.42     
416   
417  Because the approval standards for a drug product in an ANDA (other than a drug product with a 
418  permissible change in a petitioned ANDA) mean that, among other things, demonstrations of 
419  pharmaceutical equivalence to its RLD, bioequivalence to its RLD, and generally the same 
420  labeling as its RLD (with limited exceptions, including to allow for the omission, for patent or 
 
39 For purposes of this guidance, FDA uses the term powder for oral solution drug product to describe a product in 
a powder dosage form for oral administration with instructions in the labeling for reconstitution as a solution before 
administration.  
40 For purposes of this guidance, FDA uses the term ready-to-use oral solution drug product to describe a drug 
product in an oral solution dosage form for oral administration that does not include instructions for further 
manipulation, reconstitution, dilution, etc., before administration.   
41 See section 505(j)(2)(A)(v) and (viii) of the FD&C Act and 21 CFR 314.94(a)(8)(iv); see also 21 CFR 
314.127(a)(7). 
42 Prior to approval of an ANDA, FDA will determine the specific language in the labeling of the RLD that 
describes the protected use and will assess whether an ANDA that omits the protected information from its labeling 
will be rendered less safe or effective than the RLD for the remaining non-protected conditions of use. 21 CFR 
314.127(a)(7). FDA will not approve an ANDA that omits protected information from its labeling if that omission 
renders the ANDA less safe or effective for the remaining non-protected conditions of use. 
 
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421  exclusivity reasons, of an indication(s) or other condition(s) of use, or other aspect(s) of 
422  labeling), an approved ANDA drug product is considered therapeutically equivalent to its RLD 
423  and will receive an A code at approval, even if its labeling omits certain indications or other 
424  conditions of use, or other aspects of labeling approved for the RLD but protected by patent or 
425  exclusivity.  
426   
427  As a hypothetical example, suppose that a drug, Drugex, is approved for three 
428  indications:  treatment of type 2 diabetes mellitus, treatment of hypertension, and prevention of 
429  heart disease.  A method-of-use patent is listed in the Orange Book, and the use code describes 
430  the approved method of use claimed by the patent as treatment of hypertension.  The Orange 
431  Book also lists a period of three-year exclusivity for Drugex with the exclusivity code of 
432  prevention of heart disease.  In this case, an ANDA applicant could seek approval of a generic 
433  drug that relies on Drugex as its RLD with labeling that retains the type 2 diabetes mellitus 
434  indication but carves out the indications for treatment of hypertension and prevention of heart 
435  disease, which are protected by patent and exclusivity, respectively.  If FDA found that the 
436  omissions did not render the ANDA drug product less safe or effective than Drugex for the 
437  remaining, non-protected conditions of use, and the ANDA met all other requirements for 
438  approval, it would be approved. The Orange Book would list an A code for the ANDA drug 
439  product, reflecting that it is therapeutically equivalent to Drugex and thus can be expected to 
440  have the same clinical effect and safety profile as Drugex when administered to patients under 
441  the conditions specified in the ANDA drug products labeling.   
442   
443  11.  How do inactive ingredients affect a therapeutic equivalence evaluation? 
444   
445  Differences in inactive ingredients between an ANDA and its RLD of the type permissible in 
446  ANDA products, e.g., preservatives, generally do not affect FDAs evaluation of therapeutic 
447  equivalence for the ANDA product.  FDA evaluates the inactive ingredients in a generic product 
448  as part of the ANDA approval process,43 and, as noted earlier, in general upon approval, an 
449  ANDA product is considered to be therapeutically equivalent to its RLD.  
450   
451  Therapeutic equivalence evaluations for a product approved through the 505(b)(2) pathway 
452  consider differences in inactive ingredients between that product and the listed drug to which a 
453  TE code is sought.   Inactive ingredients that may be in drug products approved through the 
454  505(b)(2) pathway and that may differ from the inactive ingredients in the listed drug to which a 
455  therapeutic equivalence evaluation is sought, may influence the bioequivalence, route of 
456  administration, safety profile, dosage form, or labeled indications of the drug products.  Because 
457  505(b)(2) applications are not required to demonstrate pharmaceutical equivalence or 
458  bioequivalence, differences in inactive ingredients may be part of FDAs therapeutic equivalence 
459  evaluation for 505(b)(2) products.   
460   
461  12.  How is therapeutic equivalence evaluated for drug/device combination products 
462  submitted in an ANDA? 
463   
 
43 See Section 505(j)(2)(A)(vi) of the FD&C Act (cross-referencing section 505(b)(1)(C)); 21 CFR 314.94(a)(9). 
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464  Therapeutic equivalence evaluations are made between an ANDA and its RLD at the time of 
465  approval, including for ANDAs for drug/device combination products. A generic combination 
466  product classified as therapeutically equivalent to the RLD can be expected to produce the same 
467  clinical effect and safety profile as the RLD under the conditions specified in labeling. This does 
468  not mean, however, that the proposed generic combination product and its RLD need to be 
469  identical in all respects. FDA recognizes that an identical design may not always be feasible and, 
470  in certain instances, differences in the design of the user interface for a generic combination 
471  product as compared to the RLD may exist without precluding approval of the generic 
472  combination product under an ANDA.  Any differences in device and labeling identified 
473  between a proposed generic combination product and its RLD should be adequately analyzed, 
474  scientifically justified, and otherwise not preclude approval under an ANDA.44  The extent to 
475  which differences between the proposed generic combination product and the RLD affect the 
476  approvability of the ANDA product will be evaluated on a case-by-case basis.45  In some 
477  instances in which differences exist, certain additional information and/or data relating to the 
478  user interface of the generic combination product may be appropriate to support approval of the 
479  proposed generic combination product in an ANDA. Such additional information and/or data are 
480  intended to confirm that the differences in device and labeling for the proposed generic 
481  combination product are acceptable and that the proposed generic combination product can be 
482  substituted with the full expectation that the generic combination product will produce the same 
483  clinical effect and safety profile as the RLD under the conditions specified in the labeling.   
484   
485  13.  What are special situations in the Orange Book?   
486   
487  Section 1.8 of the Orange Book Preface, Description of Certain Special Situations, identifies, 
488  among other things, special situations where a more comprehensive explanation of equivalence 
489  scenarios beyond the two- or three-character therapeutic equivalence codes in the Orange Book 
490  may aid healthcare professionals and other interested parties.   
491   
492  14.      How does an interested party comment on or contest a therapeutic equivalence 
493  evaluation? 
494   
495  An interested party who wishes to comment on or contest a therapeutic equivalence evaluation 
496  may submit a citizen petition under 21 CFR 10.25(a) and 10.30 or, in general, if a relevant 
497  citizen petition has already been submitted, an interested party may submit a comment to the 
498  docket for that citizen petition.  
 
44 See draft guidance for industry Comparative Analyses and Related Comparative Use Human Factors Studies for a 
Drug-Device Combination Product Submitted in an ANDA (January 2017).  When final, this guidance will represent 
the FDAs current thinking on this topic.  
45 See the Office of Combination Products guidance for industry and FDA staff Principles of Premarket Pathways 
for Combination Products (January 2022).  
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