Labeling for Biosimilar 
and Interchangeable 
Biosimilar Products 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Sandra Benton at 301-796-1042, or 
(CBER) Office of Communication, Outreach and Development at 800-835-4709 or 240-402-
8010.  
 
 
 
 
 
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) 
 
September 2023 
Labeling 
Revision 1 
    
Labeling for Biosimilar 
and Interchangeable 
Biosimilar Products 
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/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
 
 
 
 
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) 
 
September 2023 
Labeling 
Revision 1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL PRINCIPLES FOR DRAFT LABELING OF PROPOSED 
BIOSIMILAR AND INTERCHANGEABLE BIOSIMILAR PRODUCTS ........................... 4 
IV.  SPECIFIC RECOMMENDATIONS ON CONTENT OF BIOSIMILAR AND 
INTERCHANGEABLE BIOSIMILAR PRODUCT LABELING ........................................... 6 
A.  Recommended Approaches to Product Identification ................................................................ 7 
1. Recommendations for When to Use the Biosimilar or Interchangeable Biosimilar Product Name 7 
2. Recommendations for When to Use the Reference Product Name .................................................. 8 
3. Recommendations for When to Use the Core Name Followed by the Word Products, ................. 8 
4. Recommendations for When to Use More Than One Product Identification Approach ................ 10 
5. Recommendations for When the Reference Product Labeling Describes a Clinical Study 
Conducted With a Non-U.S.-Approved Biological Product ............................................................... 10 
B.  Recommended Approaches to Content Presentation ............................................................... 11 
C.  Recommended Approaches to Specific Sections of Biosimilar and Interchangeable 
Biosimilar Product Labeling ............................................................................................................... 12 
1. HIGHLIGHTS OF PRESCRIBING INFORMATION .................................................................... 12 
2. INDICATIONS AND USAGE Section ............................................................................................ 13 
3. USE IN SPECIFIC POPULATIONS, Pediatric Use Subsection ................................................... 14 
4. CLINICAL PHARMACOLOGY, Immunogenicity Subsection ........................................................ 17 
V.  FDA-APPROVED PATIENT LABELING OF BIOSIMILAR AND 
INTERCHANGEABLE BIOSIMILAR PRODUCTS............................................................. 18 
VI.  REVISING BIOSIMILAR AND INTERCHANGEABLE BIOSIMILAR 
PRODUCT LABELING ............................................................................................................. 19 
A.  Updating Information, Including Safety Information .............................................................. 19 
B.  Adding Conditions of Use ............................................................................................................ 19 
VII.  HOW TO SUBMIT INITIAL AND REVISED BIOSIMILAR AND 
INTERCHANGEABLE BIOSIMILAR PRODUCT LABELING ......................................... 20 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Labeling for Biosimilar and  
2  Interchangeable Biosimilar Products 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance is intended to help applicants develop draft labeling for proposed biosimilar and 
18  interchangeable biosimilar products2 for submission in an application under section 351(k) of the 
19  Public Health Service Act (PHS Act) (42 U.S.C. 262(k)) (351(k) application).  The 
20  recommendations for biosimilar and interchangeable biosimilar product labeling3 in this 
21  guidance pertain only to the Prescribing Information, except for certain recommendations in 
22  section V, FDA-Approved Patient Labeling of Biosimilar and Interchangeable Biosimilar 
23  Products, pertaining to FDA-approved patient labeling (e.g., Patient Information, Medication 
24  Guide, Instructions for Use).4   
25   
26  When finalized, this guidance will revise and replace the guidance for industry Labeling for 
27  Biosimilar Products (July 2018).  Significant changes from the July 2018 guidance include 
28  recommendations on the following topics:  
29   
30    Labeling for interchangeable biosimilar products  
31   
32    Product identification when the reference product labeling describes a clinical study 
33  conducted with a non-U.S.-approved biological product  
34   
 
1 This guidance has been prepared by the Office of New Drugs, Office of Therapeutic Biologics and Biosimilars, in 
the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and 
Research (CBER) at the Food and Drug Administration.  
 
2 In this guidance, interchangeable biosimilar product refers to a biosimilar product that FDA has also determined to 
be interchangeable with the reference product (see section 351(i)(3) and (k)(4) of the Public Health Service Act).   
 
3 For clarity, the recommendations in this guidance generally apply to all biosimilar and interchangeable biosimilar 
products that are subject to the requirements in 21 CFR 201.56(d) and 201.57. 
 
4 Unless otherwise specified, the term labeling as used in this guidance addresses only the Prescribing Information 
as described in 21 CFR 201.56 and 201.57. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
35    Pediatric use statements  
36   
37    Incorporating relevant immunogenicity data and information from the reference product 
38  labeling in the biosimilar or interchangeable biosimilar product labeling 
39   
40  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
41  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
42  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
43  the word should in Agency guidances means that something is suggested or recommended, but 
44  not required.   
45   
46   
47  II.  BACKGROUND 
48   
49  Section 351(k) of the PHS Act provides an abbreviated licensure pathway for biological products 
50  shown to be biosimilar to, or interchangeable with, an FDA-licensed reference product.5  Section 
51  351(k) of the PHS Act sets forth the requirements for an application for a proposed biosimilar 
52  product and an application or a supplement for a proposed interchangeable biosimilar product. 
53   
54  Section 351(i) of the PHS Act defines biosimilarity to mean that the biological product is highly 
55  similar to the reference product notwithstanding minor differences in clinically inactive 
56  components and that there are no clinically meaningful differences between the biological 
57  product and the reference product in terms of the safety, purity, and potency of the product.   
58   
59  To meet the standard for interchangeability, an applicant must provide sufficient information to 
60  demonstrate biosimilarity and also to demonstrate that the biological product can be expected to 
61  produce the same clinical result as the reference product in any given patient and, if the biological 
62  product is administered more than once to an individual, the risk in terms of safety or diminished 
63  efficacy of alternating or switching between the use of the biological product and the reference 
64  product is not greater than the risk of using the reference product without such alternation or 
65  switch.6  Interchangeable biosimilar products may be substituted for the reference product 
66  without the intervention of the prescribing health care provider.7 
67   
68  An application submitted under section 351(k) of the PHS Act must contain, among other things, 
69  information demonstrating that the biological product is biosimilar to a reference product based 
70  upon data derived from the following: 
71   
72    Analytical studies that demonstrate that the biological product is highly similar to the 
73  reference product notwithstanding minor differences in clinically inactive components; 
 
5 Reference product means the single biological product licensed under section 351(a) of the PHS Act against which 
a biological product is evaluated in a 351(k) application (section 351(i)(4) of the PHS Act). 
 
6 See section 351(k)(4) of the PHS Act. 
 
7 See section 351(i)(3) of the PHS Act.  Information about whether a biosimilar product is licensed as an 
interchangeable biosimilar product can be found at https://purplebooksearch.fda.gov. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
74   
75    An assessment of toxicity (which may rely on, or consist of, a study or studies described 
76  in section 351(k)(2)(A)(i)(I)(aa) or (cc)); and 
77   
78    A clinical study or studies (including the assessment of immunogenicity and 
79  pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, 
80  and potency in one or more appropriate conditions of use for which the reference product 
81  is licensed and intended to be used and for which licensure is sought for the biological 
82  product. 
83   
84  Under the PHS Act, FDA has the discretion to determine that an element described above is 
85  unnecessary in a 351(k) application.   
86   
87  Under FDA regulations, prescription drug and biological product labeling must provide adequate 
88  information to enable health care providers to use the drug safely and for the purposes for which 
89  it is intended;8 to this end, approved Prescribing Information summarizes the essential scientific 
90  information needed by health care providers for the safe and effective use of a drug or biological 
91  product.9  Prescription drug and biological product labeling reflects FDAs finding of safety and 
92  effectiveness10,11 for the drug or biological product under the labeled conditions of use and 
93  facilitates prescribing decisions, thereby enabling the safe and effective use of drugs and 
94  biological products and reducing the likelihood of medication errors.12   
95   
96   
 
8 See 21 CFR 201.100. 
 
9 See 21 CFR 201.56(a)(1). 
 
10 The standard for licensure of a biological product as potent under section 351(a) of the PHS Act has long been 
interpreted to include effectiveness.  See 21 CFR 600.3(s) and the guidance for industry Providing Clinical Evidence 
of Effectiveness for Human Drug and Biological Products (May 1998).  See also the draft guidance for industry 
Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (December 2019), 
which, when final, will represent the FDAs current thinking 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/regulatory-information/search-fda-guidance-documents. 
 
11 In this guidance, the terms safety and effectiveness and safety, purity, and potency are used synonymously in the 
discussions pertaining to biosimilar and interchangeable biosimilar products.   
 
12 Section 351(k)(2)(A)(iii) of the PHS Act requires that a biosimilar or interchangeable biosimilar product 
application include publicly-available information regarding the Secretarys previous determination that the 
reference product is safe, pure, and potent.  FDA has stated that publicly-available information in this context 
generally includes the current FDA-approved labeling for the reference product and the types of information found 
in the action package for a biologics license application (BLA) (see section 505(l)(2)(C) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act)).  See Q.I.13 in the guidance for industry Questions and Answers on Biosimilar 
Development and the BPCI Act (September 2021) (Final QA Biosimilar guidance). 
 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
97  III.  GENERAL PRINCIPLES FOR DRAFT LABELING OF PROPOSED 
98  BIOSIMILAR AND INTERCHANGEABLE BIOSIMILAR PRODUCTS  
99   
100  The goal of a biosimilar product development program is to demonstrate biosimilarity (or, for a 
101  proposed interchangeable biosimilar product, to demonstrate interchangeability) between the 
102  proposed product and the reference product  not to independently establish safety and 
103  effectiveness of the proposed product.  A demonstration of biosimilarity or interchangeability 
104  means, among other things, that FDA has determined that there are no clinically meaningful 
105  differences between the proposed product and the reference product in terms of safety, purity, 
106  and potency.13  Thus, FDAs finding of safety and effectiveness for the reference product, as 
107  reflected in its FDA-approved Prescribing Information, may be relied upon to provide health care 
108  providers with the essential scientific information needed to facilitate prescribing decisions for 
109  the proposed biosimilar or interchangeable biosimilar products labeled conditions of use (e.g., 
110  indication(s), dosing regimen(s)).  Accordingly, FDA recommends that biosimilar and 
111  interchangeable biosimilar product labeling incorporate relevant data and information from the 
112  reference product labeling, with appropriate modifications, such as those described in sections 
113  IV, Specific Recommendations on Content of Biosimilar and Interchangeable Biosimilar Product 
114  Labeling, V, FDA-Approved Patient Labeling of Biosimilar and Interchangeable Biosimilar 
115  Products, and VI, Revising Biosimilar and Interchangeable Biosimilar Product Labeling.14  
116   
117  Relevant data and information from the reference product labeling that should be incorporated in 
118  biosimilar and interchangeable biosimilar product labeling, with appropriate modifications, 
119  includes clinical data and other information that supported FDAs finding of safety and 
120  effectiveness for the reference product.  As a general matter, biosimilar and interchangeable 
121  biosimilar product labeling should not include a description of, or data from, clinical studies 
122  conducted to support a demonstration of biosimilarity or interchangeability.15  The proposed 
123  biosimilar or interchangeable biosimilar product labeling should describe information and data 
124  from a clinical study of the proposed product in the proposed products labeling only when 
125  necessary to inform safe and effective use by a health care provider.   
126   
127  As part of the demonstration of biosimilarity, a 351(k) application generally will contain data 
128  derived from a clinical study or studies sufficient to demonstrate safety, purity, and potency in 
129  one or more appropriate conditions of use for which the reference product is licensed and for 
130  which the biosimilar or interchangeable biosimilar product applicant is seeking licensure.16  
 
13 See sections 351(i)(2) and 351(k)(4) of the PHS Act. 
 
14 Sections V and VI of this guidance describe examples of areas in which the reference product labeling and 
biosimilar or interchangeable biosimilar product labeling might differ. 
 
15 FDA posts on its website certain documents generated by FDA related to its review of a 351(k) application, as 
appropriate.  For products regulated by CDER, see the web page Drugs@FDA: FDA-Approved Drugs available at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.  For products regulated by CBER, see the CBER 
Freedom of Information Office Biologics Electronic Reading Room (eFOI) web page at https://www.fda.gov/about-
fda/center-biologics-evaluation-and-research-cber/biologics-electronic-reading-room-efoi.  You can refer to those 
documents if interested in FDAs review of data and information submitted in a 351(k) application. 
 
16 See section 351(k)(2)(A)(i)(I)(cc) of the PHS Act. 
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
131  Generally, however, clinical studies conducted to support a demonstration of biosimilarity or 
132  interchangeability are not designed to support an independent demonstration of safety or 
133  effectiveness of the proposed biosimilar or interchangeable biosimilar product.  Thus, in general, 
134  inclusion of data from such studies in labeling would not be expected to facilitate an 
135  understanding of the proposed biosimilar or interchangeable biosimilar products safety and 
136  effectiveness.  For example, the endpoints used in a clinical study conducted to support a 
137  demonstration of no clinically meaningful differences may not be the same endpoints evaluated 
138  to support licensure of the reference product and thus may not inform prescribing decisions.     
139   
140  Similarly, the patient population in a study or studies conducted to support a demonstration of 
141  biosimilarity or interchangeability may differ from the patient population studied in the clinical 
142  trials that supported the determination of safety and effectiveness of the reference product.  For 
143  example, in a study conducted to support a demonstration of no clinically meaningful differences 
144  between the biosimilar or interchangeable biosimilar product and the reference product, subjects 
145  could have been healthy volunteers, or the study could have been conducted in a condition of use 
146  for which the reference product has not been previously licensed,17 but for which sufficient data 
147  indicate that the population or condition of use is adequately sensitive to detect clinically 
148  meaningful differences between the products, should they exist.18   
149   
150  As required under 21 CFR 201.56(c)(1), biosimilar and interchangeable biosimilar product 
151  labeling must meet the content and format requirements of the physician labeling rule (PLR) as 
152  described in 21 CFR 201.56(d) and 201.57 regardless of the format of the reference product 
153  labeling.19  In addition, biosimilar and interchangeable biosimilar product labeling must meet the 
154  content and format requirements of the pregnancy and lactation labeling final rule (PLLR) as 
155  described in 21 CFR 201.57(c)(9)(i) through (iii), regardless of whether the reference product 
156  must meet these requirements.20 
157   
158   
 
17 A BLA submitted under section 351(k) of the PHS Act cannot be licensed for a condition of use for which the 
reference product has not been previously approved, even if the biosimilar or interchangeable biosimilar product 
applicant conducts a clinical study in such a condition of use.  See section 351(k)(2)(A)(i)(III) of the PHS Act.  
18 See the guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 
(April 2015). 
19 See the final rule, Requirements on Content and Format of Labeling for Human Prescription Drug and Biological 
Products, published January 24, 2006 (71 FR 3922).  This rule is commonly referred to as the physician labeling 
rule because it addresses prescription drug and biological product labeling that is used by prescribing physicians and 
other health care providers.  Also, see additional labeling guidances on the FDA Prescription Drug Labeling 
Resources web page at https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources.  
 
20 See the final rule Content and Format of Labeling for Human Prescription Drug and Biological Products; 
Requirements for Pregnancy and Lactation Labeling published December 4, 2014 (79 FR 72064).  The final rule 
describes the implementation schedule for applications submitted on or after the effective date of the rule, 
applications pending at the time the rule became effective, and applications approved before the rule became 
effective (79 FR 72064 at 7209596). 
 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
159  IV.  SPECIFIC RECOMMENDATIONS ON CONTENT OF BIOSIMILAR AND 
160  INTERCHANGEABLE BIOSIMILAR PRODUCT LABELING 
161   
162  FDA recommends that biosimilar and interchangeable biosimilar product labeling incorporate 
163  relevant data and information from the reference product labeling, with appropriate 
164  modifications, as explained in this section and in sections V, FDA-Approved Patient Labeling of 
165  Biosimilar and Interchangeable Biosimilar Products, and VI, Revising Biosimilar and 
166  Interchangeable Biosimilar Product Labeling.  The relevant data and information from the 
167  reference product labeling that should be incorporated into the biosimilar and interchangeable 
168  biosimilar product labeling will depend on whether the applicant is seeking licensure for all 
169  conditions of use (e.g., indication(s), dosing regimen(s)) or fewer than all conditions of use for 
170  which the reference product has been previously licensed.21   
171   
172  In sections of the biosimilar and interchangeable biosimilar product labeling that are based on the 
173  reference product labeling, it is anticipated that the text will be similar to the corresponding text 
174  in the reference product labeling.  Text based on the reference product labeling need not be 
175  identical to the reference product labeling and should reflect currently available information 
176  necessary for the safe and effective use of the biosimilar or interchangeable biosimilar product.  
177  Certain differences may be appropriate.  For example, biosimilar or interchangeable biosimilar 
178  product labeling conforming to PLR and/or PLLR may differ from reference product labeling 
179  because the reference product labeling may not be required to conform to those requirements at 
180  the time of licensure of the biosimilar or interchangeable biosimilar product.  In addition, 
181  biosimilar or interchangeable biosimilar product labeling may include information specific to the 
182  biosimilar or interchangeable biosimilar product that is necessary to inform safe and effective 
183  use, including preparation, administration, storage conditions, or safety information.  This 
184  information may differ from that of the reference product labeling to reflect differences between 
185  the biosimilar or interchangeable biosimilar product and the reference product that do not 
186  preclude licensure.   
187   
 
21A 351(k) application must include information demonstrating that the condition or conditions of use prescribed, 
recommended, or suggested in the proposed labeling submitted for the proposed biosimilar or interchangeable 
biosimilar product have been previously licensed for the reference product (see section 351(k)(2)(A)(i)(III) of the 
PHS Act).  However, a biosimilar or interchangeable biosimilar product applicant generally may seek licensure for 
fewer than all conditions of use for which the reference product has been previously licensed.  See Q.I.7 in the Final 
QA Biosimilar guidance; see also the draft guidance for industry Biosimilars and Interchangeable Biosimilars:  
Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed (February 
2020) (COU draft guidance), which, when final, will represent the FDAs current thinking on this topic.  Even if the 
applicant does not intend to seek licensure for all of the reference products licensed conditions of use, FDA expects 
that applicants seeking to demonstrate interchangeability will submit data and information to support a showing that 
the proposed interchangeable biosimilar product can be expected to produce the same clinical result as the reference 
product in all of the reference products licensed conditions of use.  See the guidance for industry Considerations in 
Demonstrating Interchangeability With a Reference Product (May 2019). 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
188  A.  Recommended Approaches to Product Identification22 
189   
190  In biosimilar and interchangeable biosimilar product labeling, the recommended approach to 
191  product identification depends on the context of the information being presented.  FDA 
192  acknowledges that there will be variations on the general concepts outlined in this section 
193  because the recommended approach to product identification depends on the specific statements 
194  in the labeling.  The illustrative examples in this section use a fictional reference product 
195  JUNEXANT (replicamab-hjxf) and a fictional biosimilar product NEXSYMEO (replicamab-
196  cznm).  
197   
198  1.  Recommendations for When to Use the Biosimilar or Interchangeable Biosimilar 
199  Product Name 
200   
201  The biosimilar or interchangeable biosimilar product name should be used in labeling text that is 
202  specific to the biosimilar or interchangeable biosimilar product or that refers solely to it, as well 
203  as for emphasis in labeling text such as directive statements and recommendations for 
204  preventing, monitoring, managing, or mitigating risks.  If a biosimilar or interchangeable 
205  biosimilar product has a proprietary name, the proprietary name (e.g., NEXSYMEO) should be 
206  used in the appropriate sections (except when referring to the drug substance, as noted below).  
207  However, if the biosimilar or interchangeable biosimilar product does not have a proprietary 
208  name, its proper name (e.g., replicamab-cznm) should be used.23   
209   
210  The biosimilar or interchangeable biosimilar products proprietary name (or, if it does not have a 
211  proprietary name, its proper name) should be used in circumstances such as the following: 
212   
213    In sections where the information described is specific to the biosimilar or 
214  interchangeable biosimilar product  this may include, but is not limited to, the 
215  following labeling sections:  INDICATIONS AND USAGE, DOSAGE AND 
216  ADMINISTRATION, DOSAGE FORMS AND STRENGTHS, DESCRIPTION, and 
217  HOW SUPPLIED/STORAGE AND HANDLING.   
218   
219    For directive statements and recommendations for preventing, monitoring, managing, or 
220  mitigating risks (e.g., Discontinue NEXSYMEO in patients with [adverse reaction])  
221    such statements are typically included in, but are not limited to, the following labeling 
222  sections:  BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND 
223  PRECAUTIONS, and DRUG INTERACTIONS.  
224   
 
22 Additional recommendations relating to product identification in the Pediatric Use subsection of biosimilar and 
interchangeable biosimilar product labeling are provided in section IV.C.3., USE IN SPECIFIC POPULATIONS, 
Pediatric Use Subsection.  The recommendations for product identification described in this section (IV.A) apply to 
the Pediatric Use subsection of biosimilar and interchangeable biosimilar labeling only to the extent such 
recommendations do not conflict with the recommendations in section IV.C.3.  See section IV.C.3 for additional 
information. 
 
23 The proper name is the nonproprietary name designated by FDA in the license for a biological product licensed 
under the PHS Act (see section 351(a)(1)(B)(i) of the PHS Act and 21 CFR 600.3(k)). 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
225  When referring to the drug substance, the biosimilar or interchangeable biosimilar products 
226  proper name, as opposed to its proprietary name, should be used.  An example would be to use 
227  the biosimilar or interchangeable biosimilar products proper name (e.g., replicamab-cznm) in 
228  the DESCRIPTION section when referring to the drug substance. 
229   
230  2.  Recommendations for When to Use the Reference Product Name 
231   
232  When clinical studies or specific data derived from studies with the reference product are 
233  described in biosimilar or interchangeable biosimilar product labeling, the reference products 
234  proper name (e.g., replicamab-hjxf) should be used.  This information would typically be 
235  included in labeling sections such as ADVERSE REACTIONS (Clinical Trials Experience 
236  subsection) and CLINICAL STUDIES (see Table 1 for an example of using the reference 
237  products proper name in the Clinical Trials Experience subsection). 
238   
239  Table 1:  Example of Using the Reference Products Proper Name 
240   
Reference Product Labeling  Biosimilar or Interchangeable Biosimilar 
Product Labeling 
Hypoglycemia occurred more frequently  Hypoglycemia occurred more frequently 
in patients treated with JUNEXANT  in patients treated with replicamab-hjxf 
compared to patients treated with  compared to patients treated with placebo 
placebo (10% versus 2%, respectively)  (10% versus 2%, respectively) (Study 1).  
(Study 1).  
241     
242  3.  Recommendations for When to Use the Core Name Followed by the Word 
243  Products24,25 
244   
245  The overall benefit-risk profile of the reference product is relevant to the biosimilar or 
246  interchangeable biosimilar product, even if a particular adverse reaction or other risk included in 
 
24 Core name means the component shared among an originator biological product and any related biological 
product, biosimilar product, or interchangeable biosimilar product as part of the proper names of those products.  
Two examples of a core name are trastuzumab and adalimumab.  The proper name for biological products generally 
includes a distinguishing suffix composed of four lowercase letters attached to the core name with a hyphen.  Two 
examples of a proper name are trastuzumab-dkst and adalimumab-atto.  See the guidance for industry 
Nonproprietary Naming of Biological Products (January 2017) (Naming guidance) for more information, including 
information regarding the meaning of the term related biological product.  See also the draft guidance for industry 
Nonproprietary Naming of Biological Products:  Update (March 2019).  This draft guidance, when finalized by 
revising the Naming guidance, will represent the FDAs current thinking on this topic. 
 
25 The term core name + products (or core name + product) refers to the reference product and licensed biosimilar 
products, including interchangeable biosimilar products, if any, that share the same core name.  To illustrate, 
replicamab products refers to the reference product replicamab-hjxf and the licensed biosimilar product, 
replicamab-cznm; it would not, however, include a product with two biological product components, e.g., a 
biological product with the proper name replicamab and drugimab-xxxx, or a drug-biologic combination product.  
For additional information about the naming policy, see the Naming guidance and the draft guidance for industry 
Nonproprietary Naming of Biological Products:  Update (March 2019).  This draft guidance, when finalized by 
revising the Naming guidance, will represent the FDAs current thinking on this topic.   
 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
247  the reference product labeling may not have been reported with the biosimilar or interchangeable 
248  biosimilar product at the time of licensure.  For statements incorporated into the reference 
249  product labeling that convey information, such as risk information or what is known about the 
250  reference products mechanism of action,26 that is applicable to both the biosimilar or 
251  interchangeable biosimilar product and the reference product, the core name of the reference 
252  product followed by the word products (e.g., replicamab products) should be used in the 
253  biosimilar or interchangeable biosimilar product labeling.27   
254   
255  Therefore, in the labeling sections where the risk or other information necessary for the safe use 
256  of the product applies to both the biosimilar or interchangeable biosimilar product and the 
257  reference product (e.g., BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND 
258  PRECAUTIONS, ADVERSE REACTIONS (Postmarketing Experience subsection)), it would 
259  be appropriate to use the core name + products terminology (e.g., replicamab products) to 
260  convey, for instance,  that the relevant information applies to both the biosimilar or 
261  interchangeable biosimilar product and the reference product (see section IV.B., Recommended 
262  Approaches to Content Presentation).  FDA recommends using this terminology regardless of 
263  whether the adverse reaction or risk is described in the reference product labeling as one that 
264  has occurred, occurs, or may occur with the reference product.  
265   
266  Table 2, below, provides examples of the recommended core name + products terminology in the 
267  WARNINGS AND PRECAUTIONS section. 
268   
269  Table 2:  Examples of the Core Name + Products Terminology 
270   
Reference Product Labeling  Biosimilar or Interchangeable Biosimilar 
Product Labeling 
Treatment with JUNEXANT increases  Treatment with replicamab products 
the risk of serious infections involving  increases the risk of serious infections 
various organ systems and sites that may  involving various organ systems and sites 
lead to hospitalization or death.  that may lead to hospitalization or death.  
 
Hematologic adverse reactions,  Hematologic adverse reactions, including 
including neutropenia,  neutropenia, thrombocytopenia, and 
thrombocytopenia, and anemia, have  anemia, have been reported with use of 
been reported with use of JUNEXANT.  replicamab products. 
 
26 See 21 CFR 201.57(c)(13)(i)(A). 
 
27 In some cases, a drug approved under section 505 of the FD&C Act (21 U.S.C. 355) or a biological product 
licensed under section 351 of the PHS Act (in the following examples, referred to as DRUG-X) may be indicated 
for use only in conjunction with a biological product (as reflected in the INDICATIONS AND USAGE section) or 
may be recommended for concomitant use with a biological product (as reflected in the DOSAGE AND 
ADMINISTRATION section).  In these situations, when describing use of DRUG-X with such biological product, 
the labeling for DRUG-X might identify the biological product by the reference product proper name (replicamab-
hjxf) or by core name + products (replicamab products).  If a biosimilar product or an interchangeable biosimilar 
product has been licensed for the relevant condition of use that has been previously approved for the reference 
product, FDA generally considers such labeling statements for DRUG-X identifying the biological product by the 
reference product proper name to include use of the biosimilar product or the interchangeable biosimilar product. 
 
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271   
272  FDA recognizes that application of these recommendations depends on the context and that it 
273  may not be clear whether a statement in the reference product labeling is describing specific 
274  results from a clinical study conducted with the reference product (and so generally would be 
275  appropriate to use the reference products proper name in the biosimilar or interchangeable 
276  biosimilar product labeling) or, for example, a risk that applies to both the biosimilar or 
277  interchangeable biosimilar product and the reference product (for which it generally would be 
278  appropriate to use core name + products in the biosimilar or interchangeable biosimilar product 
279  labeling).  The recommended approach to product identification depends on the specific 
280  statement and its context.   
281   
282  4.  Recommendations for When to Use More Than One Product Identification 
283  Approach 
284   
285  There may be biosimilar or interchangeable biosimilar product labeling text appropriately based 
286  on the reference product labeling in which more than one product identification approach should 
287  be used to convey information accurately.  All text in biosimilar and interchangeable biosimilar 
288  product labeling, even in sections based on reference product labeling, should be carefully 
289  evaluated for the most appropriate product identification approach.  In some cases, it is 
290  appropriate to use different product identification approaches, each based on its particular 
291  context of use, in the same section, as illustrated in the following example: 
292   
293  Replicamab products can cause hepatotoxicity and acute hepatic failure.  In clinical trials 
294  of replicamab-hjxf, 10% of patients developed elevated ALT or AST greater than three 
295  times the upper limit of normal and 5% progressed to acute hepatic failure.  Evaluate 
296  serum transaminases (ALT and AST) and bilirubin at baseline and monthly during 
297  treatment with NEXSYMEO  ...  
298   
299  5.  Recommendations for When the Reference Product Labeling Describes a Clinical 
300  Study Conducted With a Non-U.S.-Approved Biological Product 
301   
302  In rare circumstances, none of the above approaches for product identification may be 
303  appropriate.  For example, if the reference product labeling describes a clinical study conducted 
304  with a non-U.S.-approved product (e.g., a clinical study conducted to support the safety, purity, 
305  and potency of the reference product was conducted with a non-U.S.-approved product, with an 
306  appropriate scientific bridge), the biosimilar or interchangeable biosimilar product labeling 
307  should incorporate the same terminology as the reference product labeling (see Table 3 for an 
308  example).   
309   
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310  Table 3:  Example of Product Identification When a Clinical Study Was Conducted With a 
311  Non-U.S.-Approved Biological Product 
312   
Reference Product Labeling  Biosimilar or Interchangeable Biosimilar 
Product Labeling 
In an open-label, controlled clinical  In an open-label, controlled clinical study 
study (Study 1), 12% of patients treated  (Study 1), 12% of patients treated with a 
with a non-U.S.-approved replicamab  non-U.S.-approved replicamab product 
product developed infusion-related  developed infusion-related reactions. 
reactions. 
313   
314  B.  Recommended Approaches to Content Presentation  
315   
316  Biosimilar and interchangeable biosimilar product labeling should be specific to the conditions 
317  of use (e.g., indication(s), dosing regimen(s)) sought for the biosimilar or interchangeable 
318  biosimilar product and should be consistent with language previously approved for the reference 
319  product for those conditions of use.   
320   
321  When a biosimilar or interchangeable biosimilar product applicant obtains licensure for fewer 
322  than all conditions of use for which the reference product is licensed, certain text in the reference 
323  product labeling related to condition(s) of use for the reference product that are not licensed for 
324  the biosimilar or interchangeable biosimilar product would generally not be included in the 
325  biosimilar or interchangeable biosimilar product labeling.28   
326   
327  However, in certain circumstances it may be necessary to include information in the biosimilar 
328  or interchangeable biosimilar product labeling relating to an indication(s) or other condition(s) of 
329  use for which the product is not licensed, to help ensure safe use (e.g., when safety information 
330  in the reference product labeling is related to use of the biosimilar or interchangeable biosimilar 
331  product and is not specific to a particular licensed indication(s) or other condition(s) of use, or 
332  when information specific to only the biosimilar or interchangeable biosimilar products 
333  indication(s) or other condition(s) of use cannot be easily extracted).29  Such text should be 
334  written in a manner that does not imply that the biosimilar or interchangeable biosimilar product 
335  is licensed for a reference product indication(s) or use(s) that has not been licensed for the 
336  biosimilar or interchangeable biosimilar product.  In these circumstances, specific sections of 
337  labeling that could be affected include BOXED WARNING, CONTRAINDICATIONS, 
338  WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, DRUG INTERACTIONS, and 
339  USE IN SPECIFIC POPULATIONS. 
340   
341  For example, for sections such as WARNINGS AND PRECAUTIONS and ADVERSE 
342  REACTIONS, the reference product labeling may pool data on adverse reactions from all the 
343  reference product clinical trials for all the indications for which the reference product is licensed.  
344  A biosimilar or interchangeable biosimilar product applicant may decide not to seek licensure for 
 
28 See Q.I.7 in the Final QA Biosimilar guidance; see also the COU draft guidance, which, when final, will represent 
the FDAs current thinking on this topic.     
 
29 See also 21 CFR 201.57(c)(6)(i). 
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345  all the indications or other conditions of use for which the reference product is licensed.  In this 
346  case, the pooled data described in the reference product labeling should be included in the 
347  biosimilar or interchangeable biosimilar product labeling in a manner that does not imply that the 
348  biosimilar or interchangeable biosimilar product is licensed for an indication or other condition 
349  of use that has not been licensed for that product.  Additionally, any text in biosimilar or 
350  interchangeable biosimilar product labeling that refers to an indication or other condition of use 
351  for which the applicant is not seeking licensure but that is included to ensure safe use of the 
352  biosimilar or interchangeable biosimilar product should be written to avoid an implication that 
353  the product has been licensed for that indication(s) or other condition(s) of use.    
354   
355  As an example, if information from a particular study or studies conducted with the reference 
356  product is included in the proposed biosimilar or interchangeable biosimilar product labeling, 
357  FDA recommends that the data reflect the total number of patients who received the reference 
358  product in such study or studies, and not just those who received the reference product for the 
359  indication(s) included in the proposed labeling for the biosimilar or interchangeable biosimilar 
360  product.  In other words, data should reflect the analyses of such study or studies and should not 
361  be recalculated to reflect only the indication(s) for which the biosimilar or interchangeable 
362  biosimilar product is licensed, and the labeling should appropriately anonymize the indication(s) 
363  for which licensure was not sought.   
364   
365  To help further illustrate, the labeling of JUNEXANT states that in nine clinical trials in adult 
366  patients with rheumatoid arthritis, ulcerative colitis, or Crohns disease, the rate of serious 
367  infection was 6.7 per 100 patient-years in 583 patients treated with JUNEXANT.  If a biosimilar 
368  or interchangeable biosimilar product applicant sought licensure only for the rheumatoid arthritis 
369  and ulcerative colitis indications, the labeling should also convey that in the nine clinical trials, 
370  the rate of serious infection was 6.7 per 100 patient-years in 583 patients treated with 
371  replicamab-hjxf (i.e., the data should not be recalculated to remove the data based on adult 
372  patients with Crohns disease, and the term Crohns disease as used in the reference product 
373  labeling should be appropriately anonymized in the biosimilar or interchangeable biosimilar 
374  product labeling). 
375   
376  C.  Recommended Approaches to Specific Sections of Biosimilar and 
377  Interchangeable Biosimilar Product Labeling 
378   
379  1.  HIGHLIGHTS OF PRESCRIBING INFORMATION 
380   
381  a.  Initial U.S. approval 
382   
383  The initial U.S. approval in the Highlights of Prescribing Information (Highlights) is the year 
384  that the biosimilar or interchangeable biosimilar product is initially licensed.  If a biological 
385  product is initially licensed as a biosimilar product, and is later licensed as an interchangeable 
386  biosimilar product, the initial approval in the Highlights is the year that the product was initially 
387  licensed in the U.S. as a biosimilar product. 
388   
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389  b.  Biosimilarity statement  
390   
391  For a biosimilar or an interchangeable biosimilar product, FDA recommends including a 
392  statement that the product is biosimilar to the reference product.  The statement should be placed 
393  on the line immediately beneath the initial U.S. approval in the Highlights.  The statement should 
394  read as follows: 
395   
396  [BIOSIMILAR OR INTERCHANGEABLE BIOSIMILAR PRODUCTS PROPRIETARY 
397  NAME (biosimilar or interchangeable biosimilar products proper name)] is biosimilar* to 
398  [REFERENCE PRODUCTS PROPRIETARY NAME (reference products proper name)]. 
399   
400  If a biosimilar or an interchangeable biosimilar product does not have a proprietary name, the 
401  statement should refer only to its proper name.  The asterisk should appear as a footnote symbol 
402  inserted after the word biosimilar.  For example, for the fictitious biosimilar product 
403  NEXSYMEO (replicamab-cznm) and the fictitious reference product JUNEXANT (replicamab-
404  hjxf), the statement should read as follows: 
405   
406  NEXSYMEO (replicamab-cznm) is biosimilar* to JUNEXANT (replicamab-hjxf).    
407   
408  The footnote should appear at the end of the Highlights (but above the revision date)30 and state 
409  the following: 
410   
411  *Biosimilar means that the biological product is approved based on data demonstrating 
412  that it is highly similar to an FDA-approved biological product, known as a reference 
413  product, and that there are no clinically meaningful differences between the biosimilar 
414  product and the reference product.  Biosimilarity of [BIOSIMILAR OR 
415  INTERCHANGEABLE BIOSIMILAR PRODUCTS PROPRIETARY NAME] has been 
416  demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), 
417  strength(s), dosage form(s), and route(s) of administration described in its Full 
418  Prescribing Information. 
419   
420  To have a consistent approach with all biosimilar and interchangeable biosimilar product 
421  labeling, the biosimilarity statement as well as the associated footnote in the Highlights 
422  should appear in regular font (not bold font).  The font of the biosimilarity statement in the 
423  Highlights should be at least eight points, but the associated biosimilarity footnote in the 
424  Highlights should be six points. 
425   
426  2.  INDICATIONS AND USAGE Section 
427   
428  Information in the INDICATIONS AND USAGE section should be specific to the licensed 
429  indication(s) for the biosimilar or interchangeable biosimilar product and should be consistent 
430  with information previously approved for the reference product.  The biosimilar or 
431  interchangeable biosimilar product labeling should include text from the reference product 
 
30 The revision date must be placed at the end of the Highlights (see 21 CFR 201.57(a)(15)).  The footnote should be 
placed after the Patient Counseling Information statement (if applicable). 
 
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432  labeling regarding any Limitations of Use relevant to the biosimilar or interchangeable biosimilar 
433  products indication(s).  See section IV.B., Recommended Approaches to Content Presentation, 
434  for recommendations regarding text that refers to an indication for which licensure has not been 
435  sought by the biosimilar or interchangeable biosimilar product applicant. 
436   
437  3.  USE IN SPECIFIC POPULATIONS, Pediatric Use Subsection31 
438   
439  In general, pediatric use information should be discussed in the Pediatric Use subsection and 
440  included in other sections of labeling as appropriate.32  In general, the pediatric use statements 
441  are framed in terms of whether or not safety and effectiveness of a drug or biological product in 
442  pediatric patients have been established based on supporting studies with that drug or biological 
443  product.33 
444   
445  A licensed biosimilar or interchangeable biosimilar product is expected to be as safe and 
446  effective as its reference product for the conditions of use for which it is licensed.  Biosimilar 
447  and interchangeable biosimilar product applicants are not required to independently reestablish 
448  safety and effectiveness.  Although, in general, a 351(k) application is required to include data 
449  from a clinical study or studies,34 the studies (if any) that are relevant to the Pediatric Use 
450  subsection generally would have been conducted with the reference product, not the biosimilar or 
451  interchangeable biosimilar product.35  This is because a biosimilar or interchangeable biosimilar 
452  product applicant can, as appropriate, provide a scientific justification to support licensure under 
453  section 351(k) of the PHS Act for nonstudied indications (including pediatric indications) or 
454  other conditions of use.  The scientific justification to support such licensure is typically based 
455  on all available data and information in the biosimilar or interchangeable biosimilar product 
456  application (including, in general, the demonstration of biosimilarity and, if applicable, 
457  interchangeability, and consideration of the mechanism of action, pharmacokinetics, 
 
31 The recommendations in this section of the guidance provide additional guidance specific to biosimilar and 
interchangeable biosimilar products on the content of pediatric use information in the Pediatric Use subsection of 
labeling.  See footnote 5 of the guidance for industry Pediatric Information Incorporated into Human Prescription 
Drug and Biological Product Labeling (March 2019) (Pediatric Labeling guidance).  
 
32 See 21 CFR 201.57(c)(9)(iv).  See also the Pediatric Labeling guidance. 
 
33 Although in general pediatric use statements are framed in this manner, the types of information to support a 
labeling change need not have been conducted by or on behalf of the applicant.  See the final rule, Specific 
Requirements on Content and Format of Labeling for Human Prescription Drugs; Revision of Pediatric Use 
Subsection in the Labeling, (1994 rule) published December 13, 1994 (59 FR 64240, 64246). 
 
34 See section 351(k)(2)(A)(i)(I)(cc) and (k)(2)(A)(ii) of the PHS Act. 
 
35 Although a biosimilar product that has not been determined to be interchangeable is considered to have a new 
active ingredient for purposes of the Pediatric Research Equity Act (PREA) (see section 505B(l) of the FD&C Act), 
in general, biosimilar product applicants can satisfy PREA requirements without conducting a clinical study with 
pediatric subjects, as described in the Final QA Biosimilar guidance.  See Q.I.16 in the Final QA Biosimilar 
guidance.   
 
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458  immunogenicity, and toxicity for each indication (including pediatric indications)), and FDAs 
459  finding of safety and effectiveness for other licensed indications for the reference product.36 
460   
461  Accordingly, the following statements, which adequately characterize the available data on 
462  pediatric use (including when none is available) for the proposed biosimilar or interchangeable 
463  biosimilar product, are examples of pediatric use statements that the Agency recommends 
464  including in the Pediatric Use subsection of biosimilar or interchangeable biosimilar product 
465  labeling.  The recommendations for product identification described in section IV.A., 
466  Recommended Approaches to Product Identification, apply to the Pediatric Use subsection of 
467  biosimilar and interchangeable biosimilar product labeling only to the extent such 
468  recommendations do not conflict with the recommendations in this section of the guidance.  The 
469  recommendations in this section are intended to balance the objectives of ensuring that product 
470  labeling adequately describes data on pediatric use (including when no such data exists) and the 
471  unique considerations for biosimilar or interchangeable biosimilar products described above.  
472   
473  The following scenarios in Table 4, which provide context for the examples of recommended 
474  pediatric use statements, parallel those described in the guidance for industry Pediatric 
475  Information Incorporated into Human Prescription Drug and Biological Product Labeling.  For 
476  illustrative purposes, these examples use the fictitious biosimilar product NEXSYMEO 
477  (replicamab-cznm) and the fictitious reference product JUNEXANT (replicamab-hjxf).37 
478   
 
36 See the guidances for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 
(April 2015) and Considerations in Demonstrating Interchangeability with a Reference Product (May 2019). 
 
37 There may be situations when the biosimilar or interchangeable biosimilar product is not licensed for a pediatric 
indication even though its reference product is licensed for such a pediatric indication because a biosimilar or 
interchangeable biosimilar product applicant generally may obtain licensure for fewer than all of the conditions of 
use for which the reference product is licensed.  See the COU draft guidance, which, when final, will represent the 
FDAs current thinking on this topic.  In these situations, it may be appropriate to use an alternative pediatric use 
statement.  See 21 CFR 201.57(c)(9)(iv)(G). 
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479  Table 4:  Examples of Pediatric Use Statements  
480   
Scenario for the  Biosimilar or Interchangeable 
Reference Product Labeling 
Reference Product  Biosimilar Product Labeling 
Evidence supports  The safety and effectiveness of  The safety and effectiveness of 
the safety and  JUNEXANT (for Indication Y)  NEXSYMEO (for Indication Y) have 
effectiveness for an  have been established in pediatric  been established in pediatric patients 
indication in pediatric  patients aged 6 months and older.   aged 6 months and older.  Use of 
patients   Use of JUNEXANT for this  NEXSYMEO for this indication is 
indication is supported by evidence  supported by NEXSYMEOs approval 
from adequate and well-controlled  as a biosimilar to replicamab-hjxf and 
studies in adults with additional  evidence from adequate and well-
pharmacokinetic and safety data in  controlled studies of replicamab-hjxf in 
pediatric patients aged 6 months  adults with additional pharmacokinetic 
and older.  and safety data of replicamab-hjxf in 
pediatric patients aged 6 months and 
older. 
 
The evidence does  The safety and effectiveness of  The safety and effectiveness of 
not support the safety  JUNEXANT have not been  NEXSYMEO have not been established 
and effectiveness for  established in pediatric patients (for  in pediatric patients (for Indication Y).  
an indication in  Indication Y).  Effectiveness was  Effectiveness was not demonstrated in 
pediatric patients.   not demonstrated in two adequate  two adequate and well-controlled 
Results of studies  and well-controlled studies  studies conducted in 120 pediatric 
conducted in that  conducted in 120 JUNEXANT- patients treated with replicamab-hjxf, 
population with the  treated pediatric patients, aged 6  aged 6 months to younger than 17 years 
reference product  months to younger than 17 years for  for Indication Y. 
were either negative*  Indication Y. 
or inconclusive. 
There is no evidence  The safety and effectiveness of  The safety and effectiveness of 
available to support  JUNEXANT have not been  NEXSYMEO have not been established 
safety and  established in pediatric patients.  in pediatric patients.     
effectiveness for any 
indication in pediatric 
patients 
Contraindicated for  JUNEXANT is contraindicated in  NEXSYMEO is contraindicated in 
use in pediatric  pediatric patients because of deaths  pediatric patients because of deaths 
patients based on  observed in a juvenile animal study  observed in a juvenile animal study 
available evidence   with administration of replicamab- with administration of replicamab-hjxf 
hjxf to juvenile rats at clinically  to juvenile rats at clinically relevant 
relevant doses.  doses. 
 
481  * In this context, study results are considered negative when they strongly suggest that the product would be 
482  ineffective or unsafe.  See the guidance for industry Pediatric Information Incorporated into Human Prescription 
483  Drug and Biological Product Labeling. 
484   
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485  4.  CLINICAL PHARMACOLOGY, Immunogenicity Subsection38 
486   
487  In accordance with FDAs recommendation that biosimilar and interchangeable biosimilar 
488  product labeling incorporate relevant data and information from the reference product labeling, 
489  with appropriate modifications, the Agency has the following recommendations with respect to 
490  incorporating relevant immunogenicity data and information from the reference product 
491  labeling:39 
492   
493    For a reference product with labeling consistent with FDAs recommendations as 
494  described in the Immunogenicity Labeling draft guidance, when finalized,40 the 
495  biosimilar or interchangeable biosimilar product labeling generally should follow the 
496  same content and format recommendations described in that guidance.  The biosimilar or 
497  interchangeable biosimilar product labeling should also incorporate the appropriate 
498  modifications recommended in this guidance (e.g., the approaches to product 
499  identification in section IV.A., Recommended Approaches to Product Identification).   
500   
501    If the reference product labeling is not consistent with FDAs recommendations as 
502  described in the Immunogenicity Labeling draft guidance, when finalized, FDA 
503  recommends that the biosimilar or interchangeable biosimilar product applicant 
504  incorporate relevant immunogenicity data and information from the reference product 
505  labeling, with appropriate modifications (e.g., the approaches to product identification in 
506  section IV.A., Recommended Approaches to Product Identification). 
507   
508  Under either scenario, if immunogenicity information is included in the reference product 
509  labeling, the Agency generally recommends including the following paragraph in the biosimilar 
510  or interchangeable biosimilar product labeling, preceding the presentation of the immunogenicity 
511  data: 
512   
513  The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and 
514  specificity of the assay.  Differences in assay methods preclude meaningful comparisons of 
515  the incidence of anti-drug antibodies in the studies described below with the incidence of 
 
38 See the draft guidance for industry Immunogenicity Information in Human Prescription Therapeutic Protein and 
Select Drug Product Labeling  Content and Format (February 2022) (Immunogenicity Labeling draft guidance); 
this draft guidance, when final, will represent the FDAs current thinking on this topic.  The Immunogenicity 
Labeling draft guidance, when finalized, will provide recommendations on incorporating immunogenicity 
information into the labeling of certain biological products licensed under section 351(a) of the PHS Act and of 
select drug products that have immunogenicity assessments.  The Immunogenicity Labeling draft guidance also 
references the guidance for industry Labeling for Biosimilar Products and acknowledges the Agencys intent to 
issue additional guidance on the content and format of immunogenicity data in the labeling of biological products 
licensed under section 351(k) of the PHS Act.  The recommendations in this section are intended to provide such 
additional guidance. 
 
39 Less commonly, FDA may determine that immunogenicity studies were unnecessary for a reference product and, 
therefore, the reference product labeling does not include an Immunogenicity subsection.  In that instance, the 
labeling for the biosimilar or interchangeable biosimilar product should also not include an Immunogenicity 
subsection. 
 
40 When final, this guidance will represent the FDAs current thinking on this topic.   
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516  anti-drug antibodies in other studies, including those of [proper name of reference product] 
517  or of other [core name] products.  
518   
519  If the methodology for the immunogenicity evaluation of the reference product precluded an 
520  assessment of the incidence of anti-drug antibodies, FDA recommends that the biosimilar or 
521  interchangeable biosimilar product applicant contact the relevant review division (additionally, 
522  the Agency anticipates that it would generally be appropriate for the biosimilar or 
523  interchangeable biosimilar product labeling to omit the above paragraph in such circumstances). 
524   
525  Additionally, the biosimilar or interchangeable biosimilar product labeling should incorporate 
526  relevant immunogenicity information contained within other sections of the reference product 
527  labeling (e.g., WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, CLINICAL 
528  STUDIES) with appropriate modifications and with use of cross-references between related 
529  information.   
530   
531   
532  V.  FDA-APPROVED PATIENT LABELING OF BIOSIMILAR AND 
533  INTERCHANGEABLE BIOSIMILAR PRODUCTS 
534   
535  If a Medication Guide is required, applicants for biosimilar and interchangeable biosimilar 
536  products must follow existing Medication Guide regulations.41  If the FDA-approved patient 
537  labeling for the reference product includes Patient Information (also known as a Patient Package 
538  Insert), the applicant should develop Patient Information for the biosimilar or interchangeable 
539  biosimilar product, incorporating relevant information from the Patient Information for the 
540  reference product, with appropriate modifications.  
541   
542  If the FDA-approved patient labeling for the reference product includes Instructions for Use 
543  (IFU),42 the IFU for the proposed biosimilar or interchangeable biosimilar product should 
544  incorporate relevant information from the IFU for the reference product and present the 
545  information in a similar manner.  The proposed IFU may differ from the IFU for the reference 
546  product where, for example, modified language or images are needed to describe the biosimilar 
547  or interchangeable biosimilar product accurately.  If other changes are proposed beyond those 
548  necessary to describe the biosimilar or interchangeable biosimilar product accurately, applicants 
549  should discuss proposed changes with the Agency, including whether additional data or a written 
550  justification would be needed to provide adequate support for such changes.  Additionally, if 
551  there are plans to conduct a human factors study and the applicant intends to submit a protocol 
552  for FDAs review, the applicant should seek FDA input on the proposed IFU for the biosimilar 
553  or interchangeable biosimilar product when the human factors study protocol is submitted for 
554  FDA review.  A full and final review of proposed biosimilar or interchangeable biosimilar 
555  product labeling, including the IFU, will occur in the context of the planned 351(k) application 
556  and may be informed by any human factors study findings submitted or other relevant data 
557  included in the application. 
 
41 See 21 CFR part 208. 
42 See the guidance for industry Instructions for Use  Patient Labeling for Human Prescription Drug and 
Biological Products  Content and Format (July 2022).   
 
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558   
559   
560  VI.  REVISING BIOSIMILAR AND INTERCHANGEABLE BIOSIMILAR 
561  PRODUCT LABELING 
562   
563  A.  Updating Information, Including Safety Information 
564   
565  During the life cycle of a biological product, changes in the labeling may be necessary to provide 
566  updated information needed for the safe and effective use of the product.  As the reference 
567  product and biosimilar or interchangeable biosimilar product are used more widely or under 
568  diverse conditions, new information may become available.  This may include new risks or new 
569  information about known risks.   
570   
571  A biosimilar or interchangeable biosimilar product license holder must comply with applicable 
572  requirements regarding adverse experience review, reporting, and record keeping.43   
573   
574  When new information becomes available that causes information in labeling to be inaccurate, 
575  false, or misleading, the biosimilar or interchangeable biosimilar product license holder must 
576  take steps to change the content of its product labeling, in accordance with 21 CFR 601.12.44  All 
577  holders of marketing applications for biological products have an ongoing obligation to ensure 
578  their labeling is accurate and up to date.45  A biological product is misbranded, in violation of the 
579  Federal Food, Drug, and Cosmetic Act, when its labeling is false or misleading; does not provide 
580  adequate directions for use and adequate warnings; or prescribes, recommends, or suggests a 
581  dosage, manner, frequency, or duration of use of the drug that is dangerous to health.46   
582   
583  B.  Adding Conditions of Use 
584   
585  FDA recognizes that a biosimilar or interchangeable biosimilar product license holder may be 
586  interested in seeking licensure for an additional condition(s) of use after product licensure, 
587  including in the following scenarios: 
588   
589    The biosimilar or interchangeable biosimilar product license holder originally obtained 
590  licensure for fewer than all of the conditions of use for which the reference product has 
591  been previously licensed and is seeking licensure for one or more of the remaining 
592  licensed conditions of use of the reference product.   
593   
 
43 See 21 CFR 600.80. 
 
44 See, for example, 21 CFR 201.56(a)(2).  In accordance with . . . [21 CFR 601.12], the labeling must be updated 
when new information becomes available that causes the labeling to become inaccurate, false, or misleading (21 
CFR 201.56(a)(2)). 
 
45 Ibid. 
 
46 See 21 U.S.C. 331(a) through (b) and 352(a), (f), and (j). 
 
19  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
594    The reference product license holder obtained licensure for a new condition of use for the 
595  reference product after the original licensure of the biosimilar or interchangeable 
596  biosimilar product, and the biosimilar or interchangeable biosimilar license holder is 
597  seeking to add that condition of use. 
598   
599  The biosimilar or interchangeable biosimilar product license holder may seek licensure for an 
600  additional condition(s) of use of the reference product in these scenarios by submitting a prior 
601  approval supplement(s) to the 351(k) application that contains the necessary data and 
602  information, including draft labeling revised to include the additional condition(s) of use 
603  sought.47 
604   
605   
606  VII.  HOW TO SUBMIT INITIAL AND REVISED BIOSIMILAR AND 
607  INTERCHANGEABLE BIOSIMILAR PRODUCT LABELING 
608   
609  New 351(k) applications and supplement submissions for biosimilar and interchangeable 
610  biosimilar product labeling should include the following: 
611   
612    A clean version of reference product labeling that was used to develop the biosimilar or 
613  interchangeable biosimilar product labeling 
614   
615    A tracked-changes and annotated version of proposed biosimilar or interchangeable 
616  biosimilar product labeling explaining the differences from the reference product labeling   
617   
618    A clean version of the proposed biosimilar or interchangeable biosimilar product labeling 
 
47 See 21 CFR 601.12.  For additional recommendations on how to support licensure for an additional condition(s) of 
use for which the reference product has been previously approved, refer to the guidance documents on biosimilar and 
interchangeable biosimilar product development on the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.  See also the COU draft guidance, which, when final, will represent the 
FDAs current thinking on this topic.   
20