Immunogenicity Information 
in Human Prescription 
Therapeutic Protein and Select 
Drug Product Labeling  
Content and Format 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Eric Brodsky at 301-796-0855 or 
(CBER) the 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) 
 
February 2022 
Labeling
43171044dft.docx 
01/31/22   
Immunogenicity Information 
in Human Prescription 
Therapeutic Protein and Select 
Drug Product Labeling  
Content and Format 
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) 
 
February 2022 
Labeling
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................4 
III.  GENERAL PRINCIPLES ....................................................................................5 
A.  Labeling Content Requirements and Immunogenicity Information ............................ 5 
B.  Format and Organization of Immunogenicity Information in Labeling ...................... 5 
IV.  IMMUNOGENICITY (12.6) SUBSECTION UNDER THE CLINICAL 
PHARMACOLOGY SECTION ...........................................................................6 
A.  When the Methodology for Immunogenicity Evaluation Is Inadequate ...................... 6 
B.  When the Methodology for Immunogenicity Evaluation Is Adequate ......................... 7 
1. Clinically Significant Anti-Drug Antibodies ....................................................................... 8 
2. Insufficient Data to Determine the Clinical Effect(s) of Anti-Drug Antibodies .................. 9 
3. Clinically Insignificant Anti-Drug Antibodies ................................................................... 10 
V.  ADVERSE REACTIONS SECTION .................................................................11 
A.  Anti-Drug Antibodies Associated With Adverse Reactions ........................................ 11 
B.  When the Clinical Effect(s) of Anti-Drug Antibodies on Safety Is Unknown ............ 11 
C.  Anti-Drug Antibodies With No Clinically Significant Effect on Safety ...................... 12 
VI.  CLINICAL STUDIES SECTION ......................................................................12 
A.  Anti-Drug Antibodies Associated With Clinically Significant Change in 
Effectiveness ..................................................................................................................... 12 
B.  When the Clinical Effect(s) of Anti-Drug Antibodies on Effectiveness Is Unknown 13 
C.  Anti-Drug Antibodies With No Clinically Significant Effect on Effectiveness .......... 13 
VII.  WARNINGS AND PRECAUTIONS SECTION ..............................................14 
VIII.  OTHER SECTIONS OF LABELING ...............................................................14 
IX.  PROCEDURAL INFORMATION  UPDATING IMMUNOGENICITY 
INFORMATION IN THE LABELING .............................................................15 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Immunogenicity Information in Human Prescription  
2  Therapeutic Protein and Select Drug Product Labeling   
3  Content and Format 
4  Guidance for Industry1 
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  I.  INTRODUCTION 
15   
16  The purpose of this guidance is to assist applicants with incorporating immunogenicity 
17  information into the labeling of human prescription biological products, specifically therapeutic 
18  protein products,2 and of select drug products3 that have immunogenicity assessments.4 
19   
 
1 This guidance has been prepared by the Labeling Policy Team in the Office of New Drugs, the Office of Clinical 
Pharmacology, and the Office of Biotechnology Products in the Center for Drug Evaluation and Research in 
cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration. 
 
2 For the purposes of this guidance, unless otherwise specified, all references to biological products pertain to 
human therapeutic protein products licensed under section 351(a) of the Public Health Service (PHS) Act (42 U.S.C. 
262).  This guidance does not apply to biological products that are devices regulated under a biologics license 
application (BLA), vaccines, or allergenic products, or biological products that are licensed under section 351(k) of 
the PHS Act.  However, if the labeling for a reference product for a 351(k) application is revised so that the content 
and format of the immunogenicity information is consistent with the recommendations in this guidance, with respect 
to incorporating such immunogenicity information into the 351(k) product labeling, the 351(k) applicant should 
follow the general labeling recommendations in section III of the guidance for industry Labeling for Biosimilar 
Products (July 2018) (i.e., the biosimilar product labeling should incorporate relevant immunogenicity data and 
information from the reference product labeling, with appropriate modifications) and should no longer follow the 
recommendations in section IV.C.3 of that guidance.  Therefore, in such a situation, the labeling of the 351(k) 
product, like the labeling for the reference product, would include subsection 12.6 Immunogenicity, incorporating 
relevant immunogenicity data and information from the reference product labeling under that subsection and not in 
the ADVERSE REACTIONS section. 
 
3 This guidance applies to select drug products (e.g., peptides, oligonucleotides, low molecular weight heparins) 
regulated under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355).  Given the relatively 
small number of drug products for which an immunogenicity assessment is conducted, this guidance and the 
examples provided herein focus primarily on biological products; however, the principles and recommendations 
described in this guidance should be applied to all affected products.  For purposes of this guidance the term product 
includes biological products as described in footnote 2 and applicable drug products. 
 
4 For low molecular weight heparin products, see the guidance for industry Immunogenicity-Related Considerations 
for Low Molecular Weight Heparin (February 2016).  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. 
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20  This guidance provides recommendations to help ensure that clinically relevant immunogenicity 
21  information is included in and distributed appropriately across sections and subsections of 
22  product labeling,5 in accordance with regulatory requirements for the content and format of 
23  human prescription drug and biological product labeling.6  The goal of appropriate inclusion and 
24  distribution of clinically relevant immunogenicity information in the labeling is to enable health 
25  care practitioners to easily access, understand, and use this information to inform prescribing 
26  decisions and patient management, and to help enable safe and effective use of applicable 
27  products. 
28   
29  This guidance does not apply to products intended to induce a specific immune response to 
30  prevent or treat a disease or condition (such as vaccines and allergenic products).   
31   
32  When finalized, this guidance will supersede the immunogenicity labeling-specific 
33  recommendations in the guidance for industry Labeling for Biosimilar Products (July 2018)7 and 
34  the guidance for industry Clinical Pharmacology Section of Labeling for Human Prescription 
35  Drug and Biological Products  Content and Format (December 2016).8 
36   
37  This guidance does not address scientific aspects of immunogenicity assessments, including the 
38  following: 
39   
 
5 The term labeling, as used in this guidance, refers only to the Prescribing Information (PI).  Other types of 
labeling, as defined in 21 U.S.C. 321(m), 21 CFR 201.100(d), and 21 CFR 1.3(a), are excluded for the purposes of 
this guidance. 
 
6 21 CFR 201.56(d) and 201.57; see the final rule Requirements on Content and Format of Labeling for Human 
Prescription Drug and Biological Products (also known as PLR), published January 24, 2006 (21 CFR 201.56 and 
201.57; 71 FR 3922). 
 
7 Specifically, this guidance, when finalized, will supersede the recommendations in section IV.C.3., ADVERSE 
REACTIONS, Immunogenicity, of the guidance for industry Labeling for Biosimilar Products, including the 
statement Immunogenicity information for therapeutic protein products is usually placed in a subsection in the 
ADVERSE REACTIONS section entitled Immunogenicity and statements recommended for inclusion as the first 
paragraph in the ADVERSE REACTIONS subsection that precedes the immunogenicity data.  The Agency intends 
to issue additional guidance on the recommended content and format of immunogenicity data in the labeling of 
biological products licensed under section 351(k) of the PHS Act.   
 
8 Specifically, this guidance, when finalized, will supersede the immunogenicity-related recommendations under the 
following sections of the guidance for industry Clinical Pharmacology Section of Labeling for Human Prescription 
Drug and Biological Products  Content and Format: (1) section IV.B., Subsection 12.2 Pharmacodynamics 
(Information supporting the clinical impact of anti-product antibody formation on PD [pharmacodynamics] without 
a clinically significant change in PK [pharmacokinetics].  If both PK and PD are affected by anti-product antibody 
formation, information supporting the clinical impact of anti-product antibody formation will be included in 
subsection 12.3 Pharmacokinetics); (2) section IV.C., Subsection 12.3 Pharmacokinetics (Headings or 
subheadings can be added as appropriate (e.g., Anti-Product Antibody Formation Affecting PK)); and (3) section 
III.A., Content and Organization, that additional labeling subsections under the CLINICAL PHARMACOLOGY 
section should be given sequential identifying numbers beginning with 12.6. 
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40    Development and validation of assays for anti-drug antibody detection9 
41   
42    Immunogenicity risk assessment10 
43   
44    Design and conduct of immunogenicity studies 
45   
46    Scientific and clinical analysis of immunogenicity data (e.g., criteria for determining 
47  whether observed anti-drug antibodies affect the pharmacokinetics, pharmacodynamics, 
48  effectiveness, or safety of a product) 
49   
50  The contents of this document do not have the force and effect of law and are not meant to bind 
51  the public in any way, unless specifically incorporated into a contract.  This document is 
52  intended only to provide clarity to the public regarding existing requirements under the law. 
53  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
54  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
55  FDA guidance means that something is suggested or recommended, but not required. 
56   
57   
 
9 For information on this topic, see the guidance for industry Immunogenicity Testing of Therapeutic Protein 
Products  Developing and Validating Assays for Anti-Drug Antibody Detection (January 2019) and other 
applicable FDA guidances. 
 
10 See the guidance for industry Immunogenicity Assessment for Therapeutic Protein Products (August 2014).  
During development of a biological product, sponsors should perform an immunogenicity risk assessment and 
discuss with FDA appropriate plans for immunogenicity study(ies), as needed, for their proposed products.  This risk 
assessment is influenced by various factors, including, but not limited to, product quality attributes, the intended 
population, therapeutic context, and duration of product use.   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
58  II.  BACKGROUND 
59   
60  Evaluation of immunogenicity risk and its potential clinical effect generally plays an important 
61  role in the assessment of a biological products safety and effectiveness11 for each proposed 
62  indication.  For the purposes of this guidance, immunogenicity is defined as the propensity of a 
63  therapeutic protein product or other applicable drug product3 to generate an immune response to 
64  itself, a related structure, or product complex; and/or to induce immunologically related adverse 
65  clinical events.  Because most of the adverse events resulting from elicitation of an immune 
66  response to a therapeutic protein product appear to be mediated by humoral mechanisms, 
67  circulating antibody to the therapeutic protein product has been the chief criterion for defining an 
68  immune response to these products.12  The focus of this guidance is on incorporating information 
69  on anti-drug antibodies into product labeling; however, the general labeling principles outlined in 
70  this guidance apply to other immune-mediated mechanisms (e.g., cell-mediated immune 
71  responses to therapeutic protein products) when such data are available and clinically relevant. 
72   
73  Anti-drug antibodies may or may not be associated with safety concerns or loss of effectiveness.  
74  Historically, immunogenicity information typically has been included in the ADVERSE 
75  REACTIONS section of labeling.  However, such location may, for products whose anti-drug 
76  antibodies do not affect safety, unintentionally imply a relationship between anti-drug antibodies 
77  and adverse reactions.  FDA believes that having a dedicated subsection (i.e., 12.6 
78  Immunogenicity) under the CLINICAL PHARMACOLOGY section allows a consistent 
79  location for summarizing data on anti-drug antibody incidence and its pharmacokinetic and 
80  pharmacodynamic effects, while reserving other sections (e.g., ADVERSE REACTIONS, 
81  CLINICAL STUDIES, WARNINGS AND PRECAUTIONS, as applicable) for description of 
82  only clinically significant effects.  Presenting immunogenicity information in a consistent 
83  manner will enable health care practitioners to more easily identify and differentiate products 
84  associated with clinically significant anti-drug antibodies from products whose anti-drug 
85  antibodies are not associated with clinically significant effects on pharmacokinetics, 
86  pharmacodynamics, safety, or effectiveness.  This guidance also provides recommendations for 
87  consistently stating when such information is unknown, if appropriate. 
88   
89  This guidance provides general recommended approaches to the inclusion and distribution of 
90  immunogenicity information in biological product labeling.13  For product- and indication-
91  specific questions, applicants are encouraged to contact the applicable FDA review division.   
92   
 
11 FDA will approve a 351(a) BLA if, among other things, the BLA demonstrates that the biological product that is 
the subject of the application is safe, pure, and potent.  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)).  In this guidance, we use the terms safety and effectiveness and safety, purity, and potency synonymously. 
 
12 See the guidance for industry Immunogenicity Assessment for Therapeutic Protein Products.   
 
13 Additional published labeling guidances are available to assist applicants with developing labeling that complies 
with content and format requirements for human prescription drug and biological products.  See the Prescription 
Drug Labeling Resources web page at https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-
resources. 
4  Contains Nonbinding Recommendations 
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93   
94  III.  GENERAL PRINCIPLES 
95   
96  A.  Labeling Content Requirements and Immunogenicity Information 
97   
98  For all prescription drug and biological products, labeling must contain a summary of the 
99  essential scientific information needed for the safe and effective use of the product,14 and the 
100  labeling must be informative and accurate and neither promotional in tone nor false or 
101  misleading in any particular.15   
102   
103  Because a biological products immunogenic potential may be relevant to the assessment of its 
104  safety16 and/or effectiveness, a summary of this information is considered clinically relevant 
105  information to health care practitioners and, therefore, should be included in the products 
106  labeling.  Immunogenicity-related content should be communicated in the labeling in a manner 
107  that is understandable17 to health care practitioners without specialized immunology or clinical 
108  pharmacology expertise.  The inclusion of specific immunogenicity-related content, and its 
109  location within the labeling, are discussed in sections IV through IX of this guidance.    
110   
111  B.  Format and Organization of Immunogenicity Information in Labeling 
112   
113  The Prescribing Information must be organized by standard headings (e.g., sections, subsections) 
114  as defined in regulations.18  Although the location of immunogenicity information in labeling is 
115  not specifically identified in the regulations, additional subsections may be created within the 
116  standard sections to enhance labeling organization, presentation, or ease of use.19   
117   
118  FDA recommends the use of a dedicated subsection, 12.6 Immunogenicity, under the 
119  CLINICAL PHARMACOLOGY section when summarizing results from immunogenicity 
120  studies (see section IV of this guidance).  Similar to other subsections recommended by guidance 
121  (e.g., Microbiology (12.4), Pharmacogenomics (12.5)),20 the subsection number 12.6 should be 
 
14 21 CFR 201.56(a)(1). 
 
15 21 CFR 201.56(a)(2). 
 
16 The word safety means the relative freedom from harmful effect to persons affected, directly or indirectly, by a 
product when prudently administered, taking into consideration the character of the product in relation to the 
condition of the recipient at the time (21 CFR 600.3(p)). 
 
17 A biological products immunogenicity-related content can be presented as text, tables, and/or figures where 
appropriate to ensure clarity and understanding for the health care practitioner.  For example, a table with 
appropriate footnotes of essential information such as the assay methodology may be more useful than text to 
communicate immunogenicity-related content for a biological product with multiple approved indications. 
 
18 21 CFR 201.56(d)(1). 
 
19 21 CFR 201.56(d)(2). 
 
20 See the guidance for industry Clinical Pharmacology Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format. 
5  Contains Nonbinding Recommendations 
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122  reserved for the Immunogenicity subsection.  Additional subsections, when needed, should be 
123  given sequential identifying numbers beginning with 12.7.21 
124   
125  In addition to summarizing the results from immunogenicity studies in 12.6 Immunogenicity, 
126  immunogenicity-related information may be appropriate for other sections of labeling (see 
127  sections V, VI, VII, and VIII of this guidance).  When immunogenicity information is relevant 
128  to, and included in, more than one section of the labeling, cross-references should be used to 
129  refer the reader to the additional details or discussion contained in other relevant sections.22 
130   
131  Information recommended for inclusion in 12.6 Immunogenicity and under other sections (e.g., 
132  WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, CLINICAL STUDIES) is 
133  described below and depends upon (1) adequacy of the methodology for detection of anti-drug 
134  antibodies, (2) sufficiency of data to draw clinical conclusions, and (3) whether the anti-drug 
135  antibodies may have clinically significant effect(s). 
136   
137   
138  IV.  IMMUNOGENICITY (12.6) SUBSECTION UNDER THE CLINICAL 
139  PHARMACOLOGY SECTION 
140   
141  For a biological product with immunogenicity data, the labeling should include an 
142  Immunogenicity (12.6) subsection under the CLINICAL PHARMACOLOGY section.23 
143   
144  A.  When the Methodology for Immunogenicity Evaluation Is Inadequate 
145   
146  If the methodology for the submitted immunogenicity evaluation is inadequate, such that it 
147  precludes an assessment of the incidence of anti-drug antibodies, FDA recommends that the 
148  following or similar statement appear in the Immunogenicity subsection: 
149   
 
21 See footnote 8.  When this guidance is finalized, the recommendation that additional labeling subsections under 
the CLINICAL PHARMACOLOGY section be numbered sequentially beginning from 12.7 will supersede previous 
guidance recommendation that additional subsections be numbered from 12.6.   
 
22 For additional discussion of general format requirements and recommendations for organizing the PI, including 
use of cross-references, see the guidance for industry Labeling for Human Prescription Drug and Biological 
Products  Implementing the PLR Content and Format Requirements (February 2013). 
 
23 Less commonly, FDA may determine that immunogenicity studies are unnecessary for a particular type of 
biological product, and therefore a PI for such a product would not include the Immunogenicity subsection.   
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150  12.6   Immunogenicity 
151  There is insufficient information to characterize the anti-drug antibody response to [proper 
152  name]24 and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, 
153  safety, or effectiveness of [core name]25, 26 products. 
154   
155  B.  When the Methodology for Immunogenicity Evaluation Is Adequate 
156   
157  If the methodology for the submitted immunogenicity evaluation is adequate, such that it allows 
158  for an assessment of anti-drug antibody incidence, the Immunogenicity subsection should have 
159  the following: 
160   
161    Include the following paragraph at the beginning of the subsection, preceding the 
162  presentation of immunogenicity data. 
163   
164  12.6   Immunogenicity 
165  The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and 
166  specificity of the assay.  Differences in assay methods preclude meaningful comparisons 
167  of the incidence of anti-drug antibodies in the studies described below with the 
168  incidence of anti-drug antibodies in other studies, including those of [proper name] or of 
169  other [core name] products.27 
170   
171    Report the incidence of anti-drug antibodies, including neutralizing antibodies, following 
172  the paragraph above.  Applicants should consider the following: 
173   
174    Data should be summarized whether findings are positive (presence of observed anti-
175  drug antibodies, regardless of titer) or negative (absence of observed anti-drug 
176  antibodies). 
177   
 
24 For applicable drug products, depending on drug product-specific considerations, either the phrase [active moiety 
name] or [active ingredient name] should be used in place of [proper name] when conveying immunogenicity 
information. 
 
25 Core name means the component shared among an originator biological product and any related biological 
product, biosimilar product, or interchangeable product as part of the proper names of those products.  Two 
examples of a core name are pegfilgrastim and infliximab.  See the guidance for industry Nonproprietary Naming of 
Biological Products (January 2017). 
 
26 For applicable drug products, depending on drug product-specific considerations, either the phrase [active 
moiety] products or [active ingredient name] should be used in place of [core name] products. 
 
27 For a fixed-combination product, portions of the recommended language should be modified accordingly, as 
appropriate.  For example, for a fictitious fixed-combination product DRUG-X that is a combination of ingredient-A 
and ingredient-B, this introductory paragraph may be modified to state The observed incidence of anti-drug 
antibodies is highly dependent on the sensitivity and specificity of the assay.  Differences in assay methods preclude 
clinically meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the 
incidence of anti-drug antibodies in other studies, including those of [core name of ingredient-A and core name of 
ingredient-B] products, or of [core name of ingredient-A] products or [core name of ingredient-B] products. 
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178    Anti-drug antibody incidence(s) should be reported, regardless of whether a 
179  correlation has been identified between the anti-drug antibodies and any changes in 
180  pharmacokinetics, pharmacodynamics, safety, or effectiveness of the product. 
181   
182    The duration of exposure to the drug and time period over which sampling for anti-
183  drug antibodies was conducted should be described with the anti-drug antibody 
184  incidence data. 
185   
186    Summarize the known effect(s) of anti-drug antibodies on the pharmacokinetics and 
187  pharmacodynamics of the product (including the time period of observation) under the 
188  headings Anti-Drug Antibody Effects on Pharmacokinetics and Anti-Drug Antibody 
189  Effects on Pharmacodynamics, respectively.   
190   
191  1.  Clinically Significant Anti-Drug Antibodies 
192   
193  If a product is associated with anti-drug antibodies that affect pharmacokinetics and the product 
194  has a pharmacokinetic (PK)-efficacy and/or PK-safety relationship, the Immunogenicity 
195  subsection should include the following (after the brief summary of anti-drug antibody-PK effect 
196  as described under section IV.B of this guidance): 
197   
198    Briefly identify the potential clinical effect(s) based on the known PK-efficacy and/or 
199  PK-safety relationship; and 
200   
201    Cross-reference the WARNINGS AND PRECAUTIONS section and/or other section(s), 
202  as applicable, for more detailed discussion of the clinical effect(s) and pertinent clinical 
203  recommendations (see Example 1 below). 
204   
205  Similarly, if a product is associated with anti-drug antibodies that affect pharmacodynamics 
206  independent of changes in pharmacokinetics and the product has a pharmacodynamic (PD)-
207  efficacy and/or PD-safety relationship, the Immunogenicity subsection should include the 
208  following (after the brief summary of anti-drug antibody-PD effect as described under section 
209  IV.B of this guidance): 
210   
211    Briefly identify the potential clinical effect(s) based on the known PD-efficacy and/or 
212  PD-safety relationship; and 
213   
214    Cross-reference the WARNINGS AND PRECAUTIONS section and/or other section(s), 
215  as applicable, for more detailed discussion of the clinical effect(s) and pertinent clinical 
216  recommendations. 
217   
218  The following two examples illustrate a fictitious biological product, DRUG-X (drugimab-
219  wxyz), having clinically significant anti-drug antibodies.  In Example 1, anti-drug antibodies 
220  were associated with PK changes leading to clinically significant effects.  In Example 2, anti-
221  drug antibodies had clinically significant effects but were not known to be correlated with PK 
222  changes. 
223   
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224  Example 1: 
225   
226  12.6   Immunogenicity 
227  ... 
228  During the 6-month treatment period in Studies A, B, and C, 312/1200 (26%) of DRUG-
229  X-treated patients developed anti-drugimab-wxyz antibodies. 
230   
231  Anti-Drug Antibody Effects on Pharmacokinetics 
232  The presence of anti-drugimab-wxyz antibodies increased drugimab-wxyz clearance. 
233  After 6 months of dosing every 3 weeks, drugimab-wxyz serum trough concentrations in 
234  patients who developed anti-drugimab-wxyz antibodies ranged from < 0.1 (undetectable) 
235  to 2 mcg/mL compared to a range of 3 to 6 mcg/mL in patients who had not developed 
236  anti-drugimab-wxyz antibodies. Anti-drugimab-wxyz antibody formation was associated 
237  with reduced efficacy [see Warnings and Precautions (5.x) and Clinical Studies (14)]. 
238   
239  Example 2: 
240   
241  12.6   Immunogenicity 
242  ... 
243  During the 6-month treatment period in Studies A, B, and C, 312/1200 (26%) of DRUG-
244  X-treated patients developed anti-drugimab-wxyz antibodies. Anti-drugimab-wxyz 
245  antibody formation was associated with a higher incidence of hypersensitivity adverse 
246  reactions than observed in DRUG-X-treated patients without anti-drugimab-wxyz 
247  antibodies [see Adverse Reactions (6.1)]. The effect of anti-drug antibodies on 
248  pharmacokinetics and effectiveness have not been fully characterized.  
249   
250  2.  Insufficient Data to Determine the Clinical Effect(s) of Anti-Drug Antibodies 
251   
252  When available data are too limited to assess the clinical effect(s) of anti-drug antibodies,28 the 
253  uncertainty of effect on pharmacokinetics, pharmacodynamics, safety, and/or effectiveness 
254  should be described in the Immunogenicity subsection, for example: 
255   
256  12.6   Immunogenicity 
257  ... 
258  In the 6-month treatment period in Studies A, B, and C, the incidence of anti-drugimab-wxyz 
259  antibody formation was 1% (12 of 1,200 total DRUG-X-treated patients). Because of the low 
260  occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, 
261  pharmacodynamics, safety, and/or effectiveness of drugimab products is unknown. 
262  
263  When anti-drug antibodies are identified to have effects on pharmacokinetics and/or 
264  pharmacodynamics, but it is unknown whether the PK/PD changes are clinically significant (e.g., 
265  no identified PK-/PD-efficacy or PK-/PD-safety relationship), the anti-drug antibody effects on 
 
28 For example, assay methodology may be adequate to assess the incidence of anti-drug antibodies; however, a low 
incidence of anti-drug antibodies could preclude an assessment of whether the anti-drug antibodies affect safety 
and/or effectiveness of the product.  Other reasons for insufficient data may include assay and sample size 
limitations. 
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266  pharmacokinetics/pharmacodynamics, as applicable, should be summarized under their 
267  respective headings (see section IV.B of this guidance) in the Immunogenicity subsection, 
268  followed by a statement that it is unknown whether the observed anti-drug antibody-associated 
269  PK/PD changes affect the safety or effectiveness of the product.  For example: 
270  
271  12.6   Immunogenicity 
272  ... 
273  During the 1-year treatment period in Study A, 15/300 (5%) of DRUG-X-treated patients 
274  developed anti-drugimab-wxyz antibodies.   
275   
276  Anti-Drug Antibody Effects on Pharmacokinetics 
277  Among DRUG-X-treated patients who developed anti-drug antibodies, 5 of 7 patients with 
278  drugimab-wxyz exposure data available had reduced drugimab-wxyz concentrations 
279  (approximately 20% lower compared to patients who did not develop anti-drugimab-wxyz 
280  antibodies). There is insufficient data to assess whether the observed anti-drug antibody-
281  associated pharmacokinetic changes reduce effectiveness. 
282   
283  3.  Clinically Insignificant Anti-Drug Antibodies 
284   
285  If data are sufficient to support a determination that observed anti-drug antibodies are not 
286  clinically significant (anti-drug antibodies having no clinical effect or having clinically 
287  insignificant effect on pharmacokinetics, pharmacodynamics, safety, and effectiveness of the 
288  product), the Immunogenicity subsection should include a statement about the lack of clinically 
289  significant effect.  For example: 
290   
291  12.6   Immunogenicity 
292  ... 
293  During the 6-month treatment period in Studies A, B, and C, 312/1200 (26%) of DRUG-X-
294  treated patients developed anti-drugimab-wxyz antibodies. There was no identified clinically 
295  significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or 
296  effectiveness of DRUG-X over the treatment duration of 6 months. 
297  
298  When anti-drug antibodies are identified to have effects on pharmacokinetics and/or 
299  pharmacodynamics, and the available data are sufficient to conclude that the anti-drug antibody-
300  associated PK/PD changes do not affect safety or effectiveness, the anti-drug antibody effects on 
301  pharmacokinetics/pharmacodynamics, as applicable, should be summarized under their 
302  respective headings (see section IV.B of this guidance) in the Immunogenicity subsection, 
303  followed by a statement that these PK/PD changes were not clinically significant.   
304  For example: 
305   
306  12.6   Immunogenicity 
307  ... 
308  During the 1-year treatment period in Study A, 15/300 (5%) of DRUG-X-treated patients 
309  developed anti-drugimab-wxyz antibodies. 
310   
311  Anti-Drug Antibody Effects on Pharmacokinetics 
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312  Among DRUG-X-treated patients who developed anti-drug antibodies, 5 of 7 patients with 
313  drugimab-wxyz exposure data available had reduced drugimab-wxyz concentrations 
314  (approximately 10% lower compared to patients who did not develop anti-drugimab-wxyz 
315  antibodies). These anti-drug antibody-associated pharmacokinetic changes were not 
316  identified to be clinically significant. 
317   
318   
319  V.  ADVERSE REACTIONS SECTION 
320   
321  A.  Anti-Drug Antibodies Associated With Adverse Reactions 
322   
323  The ADVERSE REACTIONS section of labeling should summarize the adverse reactions 
324  associated with anti-drug antibodies (e.g., hypersensitivity, urticaria, rash, anaphylaxis), along 
325  with the treatment period during which anti-drug antibodies and adverse reactions occurred. 
326   
327  Depending on whether the adverse reactions were observed in clinical trials or in spontaneous 
328  reports or observational studies, the anti-drug antibody-associated adverse reaction data should 
329  be presented under either the Clinical Trials Experience (6.1) subsection or the Postmarketing 
330  Experience (6.2) subsection, respectively.  The data should be presented under the heading 
331  Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions and should include a cross-
332  reference to the Immunogenicity subsection for the detailed information on anti-drug antibody 
333  incidence and on anti-drug antibody-associated changes in pharmacokinetics and/or 
334  pharamcodynamics, if any (see section IV.B of this guidance).  For example: 
335   
336  6.1   Clinical Trials Experience 
337  ... 
338  Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions 
339  In Studies A, B, and C in patients with psoriasis, hypersensitivity reactions (urticaria, 
340  pruritus, and flushing) occurred in 9% of DRUG-X-treated patients with anti-drugimab-wxyz 
341  antibodies and in 2% of DRUG-X-treated patients who did not develop anti-drugimab-wxyz 
342  antibodies during the 6-month treatment period [see Clinical Pharmacology (12.6)]. In these 
343  studies, one DRUG-X-treated patient with anti-drugimab-wxyz antibodies developed 
344  anaphylaxis [see Warnings and Precautions (5.x)].  
345   
346  Since anti-drug antibody-associated hypersensitivity reactions, including anaphylaxis, may occur 
347  independent of or without demonstrated anti-drug antibody formation, a separate heading, if 
348  appropriate, can be used to summarize total overall hypersensitivity reactions, of which patients 
349  with anti-drug antibodies is a subset (e.g., separate headings such as Hypersensitivity Reactions 
350  Including Anaphylaxis and Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions 
351  under the Clinical Trials Experience subsection).      
352   
353  B.  When the Clinical Effect(s) of Anti-Drug Antibodies on Safety Is Unknown 
354   
355  Generally, if the clinical effect(s) of anti-drug antibodies on safety (e.g., adverse reactions) is 
356  unknown (e.g., data are too limited to assess whether anti-drug antibodies are associated with 
357  adverse reactions), this uncertainty should be conveyed in the Immunogenicity subsection under 
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358  the CLINICAL PHARMACOLOGY section (see section IV.B.2 of this guidance) and not in the 
359  ADVERSE REACTIONS section of the labeling.   
360   
361  However, when the uncertain effect of anti-drug antibodies on adverse reactions is critical for 
362  health care practitioners to recognize (e.g., products for which minimal concentration changes 
363  may lead to serious toxicities or a loss of effectiveness, but for which anti-drug antibody-related 
364  PK effects are unknown), then a statement about this uncertainty should be included in the 
365  ADVERSE REACTIONS section under the Clinical Trials Experience subsection under the 
366  heading Immunogenicity: Unknown Clinical Effects of Anti-Drug Antibodies.  A cross-reference 
367  to the anti-drug antibody incidence information in the Immunogenicity subsection should be 
368  included, as in the following example: 
369   
370  6.1   Clinical Trials Experience 
371  ... 
372  Immunogenicity: Unknown Clinical Effects of Anti-Drug Antibodies 
373  There are insufficient data to evaluate the effect of anti-drug antibodies on adverse reactions 
374  [see Clinical Pharmacology (12.6)].  
375   
376  C.  Anti-Drug Antibodies With No Clinically Significant Effect on Safety 
377   
378  If data are sufficient to support a determination that there is no clinically significant effect of 
379  anti-drug antibodies on safety, then the heading Immunogenicity: Anti-Drug Antibody-
380  Associated Adverse Reactions is not applicable and, therefore, should not be included in the 
381  labeling.29  For such a product, the immunogenicity information would be included only under 
382  the Immunogenicity subsection (see section IV.B.3 of this guidance), accompanied by the 
383  statement that there is no clinically significant effect of anti-drug antibodies on safety (and 
384  pharmacokinetics, pharmacodynamics, and effectiveness, as applicable). 
385   
386   
387  VI.  CLINICAL STUDIES SECTION 
388   
389  A.  Anti-Drug Antibodies Associated With Clinically Significant Change in 
390  Effectiveness 
391   
392  When the development of anti-drug antibodies is associated with clinically significant changes in 
393  the effectiveness of a product, this information should be summarized in the CLINICAL 
394  STUDIES section, along with the time period of observation of the effect.  The overall efficacy 
395  results from the clinical trial data should be presented along with the results for the drug 
396  treatment by anti-drug antibody status.   
397   
398  A cross-reference to the Immunogenicity subsection should be included using the format 
399  described previously (see section VI.A of this guidance).   
400   
 
29 See 21 CFR 201.56(d)(4). 
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401  Depending on the clinical significance of the alteration in effectiveness, this information should 
402  additionally be considered for description under the WARNINGS AND PRECAUTIONS 
403  section, if appropriate.  For example: 
404   
405  14   CLINICAL STUDIES 
406  ... 
407  In Studies A, B, and C in patients with psoriasis, the primary endpoint was the proportion of 
408  patients who achieved a reduction in the Psoriasis Area and Severity Index (PASI) score of at 
409  least 75% from baseline to month 6 (PASI 75). At month 6, 89% (890/1000) of DRUG-X-
410  treated and 10% (100/1000) of control-treated patients in the pooled studies achieved PASI 
411  75, respectively. Among DRUG-X-treated patients who developed anti-drugimab-wxyz 
412  antibodies (anti-drug antibody positive subgroup) during the 6-month treatment period, 50% 
413  (15/30) achieved PASI 75, compared to 90% (875/970) of DRUG-X-treated patients who did 
414  not develop anti-drugimab-wxyz antibodies (anti-drug antibody negative subgroup) ... [see 
415  Warnings and Precautions (5.x) and Clinical Pharmacology (12.6)].  
416   
417  B.  When the Clinical Effect(s) of Anti-Drug Antibodies on Effectiveness Is 
418  Unknown 
419   
420  Generally, if the clinical effect(s) of anti-drug antibodies on a products effectiveness is unknown 
421  (e.g., methodology is adequate, but the data are too limited to assess any association of the anti-
422  drug antibodies with changes in effectiveness), this uncertainty should be conveyed in the 
423  Immunogenicity subsection (see section IV.B.2 of this guidance) instead of the CLINICAL 
424  STUDIES section.   
425   
426  However, when the uncertain effect of anti-drug antibodies on effectiveness is critical for health 
427  care practitioners to recognize (e.g., products for which minimal concentration changes may lead 
428  to a loss of effectiveness), then a statement about this uncertainty should be included in the 
429  CLINICAL STUDIES section.  Such information should be presented alongside any other 
430  statements about efficacy results in subgroups that are included in the section (e.g., description of 
431  efficacy in subgroups such as age, gender, and race).  A cross-reference to the Immunogenicity 
432  subsection should be included.   
433   
434  C.  Anti-Drug Antibodies With No Clinically Significant Effect on Effectiveness 
435   
436  If data are sufficient to support a determination that there is no clinically significant effect of 
437  anti-drug antibodies on the effectiveness of a product, immunogenicity information should be 
438  included only under the Immunogenicity subsection (assuming that the products anti-drug 
439  antibodies also do not affect safety), accompanied by the statement that there is no clinically 
440  significant effect of anti-drug antibodies on effectiveness (and pharmacokinetics, 
441  pharmacodynamics, and safety, as applicable) (see section IV.B.3 of this guidance).  
442   
443   
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444  VII.  WARNINGS AND PRECAUTIONS SECTION 
445   
446  The WARNINGS AND PRECAUTIONS section should contain a succinct description of 
447  (1)  clinically significant adverse reactions or other risks from anti-drug antibodies (e.g., a 
448  possible causal association between anti-drug antibodies and immune-mediated adverse reactions 
449  such as hypersensitivity reactions, including anaphylaxis) and (2) clinically significant changes 
450  in effectiveness associated with anti-drug antibodies. 
451   
452  The adverse reaction or other risk information should include, if known: a numerical estimate of 
453  the rate of each clinically significant adverse reaction or other risk; risk factors for the adverse 
454  reaction or other risk; and, if appropriate, any clinically actionable recommendations (e.g., use of 
455  premedication or concomitant medications to reduce the risk of hypersensitivity reactions; 
456  discontinuation of the product).  
457   
458  Cross-reference(s) should be made to the ADVERSE REACTIONS section and/or the 
459  CLINICAL STUDIES section, as applicable, for example: 
460   
461  5   WARNINGS AND PRECAUTIONS 
462  ... 
463  5.x   Severe Hypersensitivity Reactions Including Anaphylaxis 
464  Severe hypersensitivity reactions (bronchospasm, angioedema, and anaphylaxis) have 
465  occurred in DRUG-X-treated patients. In Studies A, B, and C, 2 out of 1,200 DRUG-X-
466  treated patients with psoriasis developed anaphylaxis during the 6-month treatment period; 
467  one of those patients developed anti-drugimab-wxyz antibodies [see Adverse Reactions (6.1) 
468  and Clinical Pharmacology (12.6)]. In both patients, anaphylaxis occurred after the second 
469  DRUG-X dose. If DRUG-X-treated patients develop a severe hypersensitivity reaction, 
470  discontinue DRUG-X [see Contraindications (4)]. 
471   
472   
473  VIII.  OTHER SECTIONS OF LABELING 
474   
475  Less commonly, immunogenicity-related information may be relevant to, and appropriate to 
476  include in, other sections of the labeling (e.g., BOXED WARNING, DOSAGE AND 
477  ADMINISTRATION, CONTRAINDICATIONS).  Applicants should refer to the general 
478  concepts described in available section-specific and other guidances to determine whether 
479  immunogenicity-related information is appropriate to include in these sections.30     
480   
481   
 
30 Additional labeling guidances are available to assist applicants with developing labeling that complies with 
content and format requirements for human prescription drug and biological products.  See the Prescription Drug 
Labeling Resources web page at https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-
resources.   
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482  IX.  PROCEDURAL INFORMATION  UPDATING IMMUNOGENICITY 
483  INFORMATION IN THE LABELING 
484   
485  Labeling must be updated when new information becomes available that causes the labeling to 
486  become inaccurate, false, or misleading.31  Therefore, when new immunogenicity data or 
487  information becomes available that could affect prescribing decisions or the clinical management 
488  of patients receiving the product, applicants should submit to FDA the proposed revised labeling 
489  containing the updated immunogenicity information for review as a supplement to the 351(a) 
490  biologics license application (BLA) (or to the new drug application (NDA), for applicable drug 
491  products).   
492   
493  To enable health care practitioners to easily access, understand, and use immunogenicity 
494  information in the labeling (e.g., placing immunogenicity information in a consistent manner 
495  within and across appropriate sections and subsections of labeling), FDA recommends, when this 
496  guidance is final, that regardless of whether new immunogenicity data or information becomes 
497  available application holders propose updates to their biological product labeling to be consistent 
498  with the format and organizational recommendations in this guidance (e.g., during the next 
499  planned prior approval supplement32 to their 351(a) BLAs (or NDAs, for applicable drug 
500  products)).  
501   
502  If labeling for an approved biological product already includes a subsection 12.6 covering a 
503  clinical pharmacology topic other than immunogenicity, the existing subsection 12.6 (and 
504  subsections thereafter, if applicable) should be renumbered (see section III.B.1 of this guidance).   
 
31 21 CFR 201.56(a)(2). 
 
32 FDA encourages an application holder who is not planning to submit an efficacy or labeling prior approval 
supplement (PAS) in the near future to voluntarily update the labeling by submitting a labeling PAS with proposed 
changes consistent with the format and organizational recommendations in this guidance. 
15