Characterizing, Collecting, and 
Reporting Immune-Mediated 
Adverse Reactions in Cancer 
Immunotherapeutic Clinical 
Trials  
 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 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 (OCE/CDER) Marc Theoret at 301-796-
4099 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 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
October 2022 
Clinical/Medical
   
Characterizing, Collecting, and 
Reporting Immune-Mediated 
Adverse Reactions in Cancer 
Immunotherapeutic Clinical 
Trials 
 
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, rm. 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 
Oncology Center of Excellence (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2022 
Clinical/Medical
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ........................................................................................................ 2 
III.  IMMUNE-MEDIATED SAFETY DATA COLLECTION AND EVALUATION .... 2 
A.  Identifying Potential imARs........................................................................................... 3 
B.  Protocol and Case Report Form Considerations Related to imARs ................................... 4 
C.  Sponsor Classification of Adverse Events as imARs ......................................................... 5 
D.  NDA or BLA - Additional imAR Safety Data Considerations ........................................... 6 
E.  Labeling Recommendations ........................................................................................... 6 
1.  WARNINGS AND PRECAUTIONS Section ................................................................... 7 
2.  DOSAGE AND ADMINISTRATION Section ................................................................. 8 
 
   
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Characterizing, Collecting, and Reporting Immune-
1 
Mediated Adverse Reactions in Cancer Immunotherapeutic 
2 
Clinical Trials 
3 
4   Guidance for Industry1 
 
5 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is 
not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements 
of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page 
 
6   
7   
8  I.  INTRODUCTION 
9   
10  Cancer immunotherapeutic drugs and biological products (hereafter referred to as cancer 
11  immunotherapeutic drugs) can modulate (i.e., stimulate or suppress) the endogenous immune 
12  system to produce an anticancer effect. Adverse events2 that are consistent with an autoimmune 
13  etiology should be evaluated as potential immune-mediated adverse reactions (imAR)3 to guide 
14  patient management and inform the drug labeling or investigator brochure, as applicable.  
15   
16  For the purpose of this guidance, the term imAR refers to adverse reactions that occurred in the 
17  context of exposure to a cancer immunotherapeutic drug and are consistent with the development 
18  of an autoimmune reaction, and are not attributable to another cause (e.g., infection, trauma, 
19  other drugs). While corticosteroids and other immunosuppressive drugs are regularly used to 
20  manage imARs in cancer clinical trials, the absence of a history of immunosuppressive treatment 
21  for an adverse reaction does not preclude its characterization as an imAR, especially for low-
22  grade imARs that result in dose interruption.  
23   
 
1 This guidance has been prepared by the Oncology Center of Excellence (OCE), Center for Drug Evaluation and 
Research (CDER), and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 
 
2 An adverse event means any untoward medical occurrence associated with the use of a drug in humans whether or 
not considered drug related (21 CFR 312.32(a)).  See also guidance for industry:  Adverse Reactions Section of 
Labeling for Human Prescription Drug and Biological Products  Content and Format (January 2006). We update 
guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.   
 
3 An adverse reaction is an undesirable effect, reasonably associated with use of a drug, that may occur as part of the 
pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all 
adverse events observed during use of a drug, only those adverse events for which there is some basis to believe 
there is a causal relationship between the drug and the occurrence of the adverse event.  See 21 CFR 201.57(c)(7). 
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24  This guidance is intended for sponsors of cancer immunotherapeutic drugs that modulate the 
25  endogenous immune system and may disrupt immunologic tolerance to normal organs and 
26  tissues. Examples of such cancer immunotherapeutic drugs include monoclonal antibodies, 
27  anticancer vaccines, and cytokines. Adoptively transferred cell-based cancer immunotherapeutics 
28  that target a tumor-associated antigen (TAA) and directly exert an anticancer effect (e.g., a TAA-
29  directed genetically modified T-cell immunotherapy) are outside the scope of this guidance.   
30   
31  This guidance provides recommendations regarding the data that should be collected and 
32  evaluated to assess whether adverse events qualify as imARs and the data on imARs that should 
33  be included in a new drug application (NDA) or biologics license application (BLA) for a cancer 
34  immunotherapeutic drug. 
35   
36  The contents of this document do not have the force and effect of law and are not meant to bind 
37  the public in any way, unless specifically incorporated into a contract.  This document is 
38  intended only to provide clarity to the public regarding existing requirements under the law.  
39  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
40  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
41  Agency guidances means that something is suggested or recommended, but not required. 
42   
43   
44  II.  BACKGROUND 
45   
46  Cancer immunotherapeutic drugs utilize the immune system to exert an anti-cancer treatment 
47  effect.  Recently, cancer immunotherapeutic drugs have demonstrated safety and efficacy across 
48  a wide breadth of cancer types and are becoming standard of care treatmentsas monotherapy 
49  and as part of combination therapy regimensfor patients with hematologic and solid tumor 
50  malignancies.  In general, the safety concerns of cancer immunotherapeutic drugs predominantly 
51  consist of immune-mediated risks, which are off-tumor immune responses generated as a result 
52  of exposure to the drug, with the spectrum of toxicities reflecting the underlying mechanism of 
53  action of the drug.  For example, immunotherapeutic drugs that activate the endogenous immune 
54  system by breaking peripheral tolerance may lead to inflammation involving almost any organ 
55  system, whereas immunotherapeutic drugs that direct the immune system with specificity for a 
56  TAA may lead to toxicities of normal tissues that share the same target (e.g., off-tumor, on-target 
57  toxicity) or a molecularly similar target (e.g., cross reactivity based on sequence or structural 
58  homology).  Adverse events that are unrelated to the drug may also occur during a trial, and it is 
59  critical to have a comprehensive understanding of imARs to allow an assessment of the benefits 
60  and risks of the drug and to provide information in the drug labeling to inform clinical use.   
61   
62   
63  III.  IMMUNE-MEDIATED SAFETY DATA COLLECTION AND EVALUATION 
64   
65  When designing trials evaluating cancer immunotherapeutic drugs, sponsors should develop a 
66  prospective approach for collecting and characterizing imARs.  Sponsors should prospectively 
67  design the protocol and case report form (CRF) to capture the information needed to determine 
68  whether an adverse event is an imAR.  Evaluation of a potential imAR involves consideration of 
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69  how to discriminate between 1) effects of the immunotherapeutic and 2) effects not related to the 
70  immunotherapeutic such as those attributable to the underlying disease itself, another condition 
71  (e.g., infection, trauma), or another drug.  It is also important to consider potential interactions 
72  among these factors.  
73   
74  Sponsors developing cancer immunotherapeutic drugs should discuss collection, 
75  characterization, and reporting of immune-mediated safety data with the clinical review division 
76  early in development and prior to implementing a cancer immunotherapeutic drug trial.  
77   
78  A.  Identifying Potential imARs 
79   
80  Sponsors should develop a prespecified list of potential imARs consisting of groupings of 
81  Medical Dictionary for Regulatory Activities (MedDRA) terms describing the same medical 
82  concept using all levels of the MedDRA hierarchy including Standardized MedDRA Queries 
83  (SMQs) on which data should be collected to characterize a potential imAR.  This list should be 
84  updated throughout the development program and included in relevant documents (e.g., in the 
85  protocol, investigator brochure, safety analysis plan).  When developing this list, the sponsor 
86  should consider the: 
87   
88    Mechanism of action of the drug and prior experience with the same or similar 
89  immunotherapeutics in oncology, as well as other disease settings 
90    Immunologic impact of the cancer or prior cancer therapy. 
91   
92  As an example of immunologic impact of prior cancer therapy, in allogeneic hematopoietic stem 
93  cell transplantation (HSCT), multiple non-randomized trials evaluating PD-1 targeted antibodies 
94  in patients either before or after undergoing allogeneic HSCT demonstrated an increased risk of 
95  transplant related complications, even after PD-1 targeted antibody treatment had been 
96  discontinued.  Therefore, examples of potential imARs that should be prespecified for data 
97  collection in this setting include hyperacute graft versus host disease (GVHD), acute GVHD, 
98  chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and 
99  steroid-requiring febrile syndrome (without an identified infectious cause). 
100   
101  Attributing certain adverse events to a cancer immunotherapeutic can be challenging when 
102  overlapping toxicities are expected with other drugs or anticipated for the population under 
103  study.  Sponsors should consider patient- and treatment-related factors in assessing causality, 
104  including but not limited to:  
105   
106    Current organs/sites involved with disease. 
107   
108    Previous therapy, e.g., radiation therapy.  
109   
110    Any medical history of immune based pathologies, e.g., rheumatoid arthritis, Crohns 
111  disease, systemic lupus erythematosus, or other autoimmune diseases.  
112    
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113    Combination therapy with chemotherapy or other drugs that have known toxicities in 
114  specific organs.  
115   
116  In some circumstances, individual case assessment can be clarified by a rechallenge (if 
117  appropriate), or follow-up response to immunosuppressive therapy.  Causality, however, may not 
118  be clear until sufficient exposure reveals an increase in incidence or severity of the specific 
119  imAR within the arm of interest.  Increased surveillance (e.g., defining the potential imAR as an 
120  Adverse Events of Special Interest(AESI))4 in subsequent trials for suspected imARs is 
121  appropriate to facilitate a causality assessment.  In addition, when immunotherapeutic drugs with 
122  a mechanism that decreases the threshold for disrupting peripheral immunological tolerance are 
123  used in combination with a drug infrequently associated with an organ specific toxicity, a 
124  marked increase in the frequency of organ specific toxicity should be considered an imAR until 
125  proven otherwise (e.g., evaluate for immune-mediated nephritis rather than attribute to 
126  chemotherapy-induced acute renal failure in a patient receiving an immunotherapeutic plus 
127  chemotherapy combination regimen).  These considerations should also be included in protocols 
128  to assist investigators in determining whether there is a reasonable possibility that the drug 
129  caused the adverse event.5 
130   
131  B.  Protocol and Case Report Form Considerations Related to imARs 
132   
133  The protocol should include the following:  
134   
135    Instructions for how clinical investigators should evaluate adverse events to assess 
136  immunological causality, including tissue biopsy or other laboratory test results to 
137  determine whether the adverse event is an imAR. 
138   
139    Descriptions of the imAR-related data that should be collected.  Data on potential imARs 
140  should be collected for at least 90 days after the last dose of an immunotherapeutic drug.  
141  Sponsors should have a predefined plan for capturing information regarding imARs that 
142  are known to occur beyond this period. 
143   
144  CRFs should include fields for documenting information about potential imARs.6  For example, 
145  data elements should include, but are not limited to, the following:  
146   
147    Date of onset (i.e., Start Date). 
148   
 
4 See guidance for industry:  International Council for Harmonisation (ICH) of Technical Requirements for 
Pharmaceuticals for Human Use and Draft Guidance, Optimisation of Safety Data Collection E19 (April 2019). 
When final, this guidance will represent the FDAs current thinking on this topic.  
5 See 21 CFR 312.64 
6 Additional data elements may be needed in the CRF for other purposes. For example, fields regarding whether an 
adverse event is serious, whether an adverse event is expected and unrelated to the study drug, and an assessment of 
causality regardless of whether the adverse event is immune-mediated, are needed for the purpose of IND safety 
reporting.   
 
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149    Common Terminology Criteria for Adverse Events (CTCAE)7 grade 
150  -  If CTCAE is not adequate to grade a specific imAR, the CRF should provide the 
151  grading system to be used. 
152   
153    Action taken with study drug(s) 
154    
155    Outcome of the imAR 
156   
157    Concomitant medications (including steroids, other immunosuppressive drugs, and 
158  hormone replacement therapy) with doses and duration used to treat the potential imAR 
159  and the ability to link the concomitant medication to the specific imAR. 
160   
161    Date of resolution as defined as resolution of symptoms or return to baseline and no 
162  longer requiring medical management (e.g., corticosteroids) or hormone replacement.  
163   
164    Detailed data on baseline (i.e., preexisting) medical conditions (e.g., thyroid, renal, 
165  hepatic, cardiac function, GVHD). 
166   
167    Prior treatment history that may predispose a patient to experience an imAR.  
168     
169    Clinical investigators final assessment of whether an adverse event is an imAR (e.g., 
170  [Yes/No] data field on the CRF) and a required field to document the rationale for this 
171  assessment, such as a description of the response to immunosuppressive or other therapy, 
172  rechallenge information, clinicopathologic results, increase in frequency or severity of an 
173  imAR with a pattern suggesting synergism, or other (option for free text). 
174   
175  C.  Sponsor Classification of Adverse Events as imARs 
176   
177  As described in Section IIIA, sponsors should have a prespecified method for classifying adverse 
178  events as imARs throughout the drug development program.  This method should be systematic 
179  and reproducible to allow comparison across trials and development programs.  Key principles of 
180  this method are the following:  
181   
182    Sponsors should update and revise the list of potential imARs as described in Section 
183  IIIA to accurately and fully capture and characterize these adverse events if (1) the 
184  investigator assesses the adverse event to be an imAR, regardless of whether the patient 
185  received corticosteroids, other immunosuppressive drugs, and/or hormone replacement 
186  therapy, and (2) the sponsor agrees with this assessment, which may require an 
187  evaluation of data across the development program.  Events for which imAR-directed 
188  therapy was instituted, but later stopped in favor of an alternative cause for the event 
189  should not be included in this category. 
190   
 
7 https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
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191    Adverse events that were not prespecified can be added to the relevant imAR category 
192  that describes a similar medical concept. Sponsors should consider any treatment-
193  emergent adverse event as an imAR if 
194    the patient received steroids, other immunosuppressive drugs, and/or hormone 
o
195  replacement therapy and 
196    the sponsor assessed the adverse event to be an imAR, taking into account the 
o
197  investigator assessment and rationale.   
198   
199    Sponsors should document the rationale for their agreement or disagreement with the 
200  investigator on classification of an adverse reaction as an imAR. 
201   
202  D.   NDA or BLA - Additional imAR Safety Data Considerations 
203   
204  In addition to the information recommended in section III.A and III.B. of this guidance, the 
205  analysis datasets in an NDA or BLA should include: 
206   
207    A variable in the adverse event dataset specifying the imAR if the individual event 
208  collected is part of a grouped set of MedDRA Preferred Terms (PTs) included in the 
209  prespecified imAR term. 
210   
211    Flags for investigator and sponsor assessment of imARs. 
212   
213    Outcome of the imAR at the time of data cut-off. 
214   
215    Links between the specific imAR(s) and the concomitant medication(s) used to treat the 
216  imAR(s). 
217   
218    Rechallenge information, including a designation (flag) for an imAR that recurs after a 
219  rechallenge with any study drugs. 
220   
221  The narrative safety portion of an NDA or BLA should also include a discussion of the sponsors 
222  assessment of whether adverse events are imARs and the rationale for the sponsors assessment, 
223  e.g., in the Integrated Summary of Safety. 
224   
225  E.  Labeling Recommendations  
226   
227  This section of the guidance summarizes labeling recommendations on how to incorporate imAR 
228  information into the WARNINGS AND PRECAUTIONS and DOSAGE AND 
229  ADMINISTRATION sections of labeling for cancer immunotherapeutic drugs.  The 
230  recommendations for this section of this guidance are not intended to be exhaustive.  Information 
231  about imARs may be included in other sections of labeling (e.g., PATIENT COUNSELING 
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232  INFORMATION).  For developing these and other sections of labeling, applicants should refer 
233  to statutory and regulatory labeling requirements and other FDA guidance recommendations.8 
234   
235  1.  WARNINGS AND PRECAUTIONS Section 
236   
237  Clinically significant imARs should be incorporated into one numbered subsection in the 
238  WARNINGS AND PRECAUTIONS section of labeling (e.g., 5.1 Severe and Fatal Immune-
239  Mediated Adverse Reactions).  Clinically significant imARs include those that occurred with 
240  the subject drug as well as those that occurred with drugs in the same class (e.g., same 
241  mechanism of action), as appropriate.  When imARs are based on a pooled safety database, to 
242  reduce redundancy from providing a detailed description of pooled safety data multiple times in 
243  labeling, FDA recommends including this information in the Clinical Trials Experience 
244  subsection in the ADVERSE REACTIONS section, instead of the imAR subsection in the 
245  WARNINGS AND PRECAUTIONS section.  The imAR subsection should cross-reference to 
246  the Clinical Trials Experience subsection for the detailed description of pooled safety data.  In 
247  the imAR subsection in the WARNINGS AND PRECAUTIONS section, FDA recommends:  
248   
249    Consolidating information that is applicable to different imARs (e.g., 
250  recommendations on how to prevent, mitigate, and monitor for or manage imAR(s)) 
251  in the beginning of this subsection rather than repeating this information for each 
252  imAR.  This subsection should cross-reference to the DOSAGE AND 
253  ADMINISTRATION section for detailed recommendations on dosage modifications 
254  intended to reduce the risk of an imAR. 
255   
256    Organizing information about specific common imAR(s) that are clinically significant 
257  under non-numbered headings (e.g., Immune-Mediated Pneumonitis, Immune-
258  Mediated Hepatitis).   
259   
260    Listing less common serious imARs (e.g., incidence of <1%) that do not need further 
261  description under a non-numbered heading (e.g., Other Clinically Significant 
262  Immune-Mediated Adverse Reactions) and grouping them by organ/site. Subsequent 
263  to approval of the NDA/BLA, less common, nonserious imARs should usually be 
264  only listed in the ADVERSE REACTIONS section of labeling; however, if such 
265  imARs are otherwise clinically significant (e.g., requires new patient monitoring or 
266  management) they should also be listed in under this heading in the imAR subsection 
267  in the WARNINGS AND PRECAUTIONS section.   
268   
269    If a cancer immunotherapeutic drug is approved for monotherapy and as part of a 
270  combination regimen or therapy: 
271    Including clinically significant imAR information associated with monotherapy 
o
272  and 
 
8 See Prescription Drug Labeling Resources website at https://www.fda.gov/drugs/laws-acts-and-rules/prescription-
drug-labeling-resources. 
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273    Only including clinically significant imAR information associated with 
o
274  concomitant use when there are novel clinically significant imAR(s) or more 
275  frequent or severe clinically significant imAR(s) compared to those that occurred 
276  with monotherapy.   
277   
278    If a cancer immunotherapeutic drug is approved for use in multiple cancer 
279  subpopulations: 
280    Including clinically significant imAR information from the pooled cancer 
o
281  populations, and  
282    Only including clinically significant imAR information for specific cancer 
o
283  subpopulation(s) if the imAR is novel, severe, or occurs at a significantly higher 
284  incidence compared to those from the pooled cancer populations. 
285   
286    For each clinically significant imAR under the appropriate heading within this 
287  subsection, including the following information, as applicable: 
288   
289    A statement(s) regarding how the imAR was defined. 
o
290    Frequency of imARs for all grades and by toxicity severity grade (2, 3, 4, and 5) 
o
291  to characterize the risk at each grade and provide management actions for each 
292  grade, if applicable (e.g., Grade 2 dosage modification, Grade 4 permanent 
293  discontinuation). 
294    Time of imAR onset (median and range) in relation to start of the drug when 
o
295  sufficient information is available for a specific imAR. 
296    Frequency of permanent discontinuation and withholding of the drug due to the 
o
297  imAR. 
298    Number and percentage of patients with the imAR who required 
o
299  immunosuppressive treatment categorized by type of therapy (local 
300  corticosteroids, systemic corticosteroids, tumor necrosis factor inhibitors, etc.). 
301    Number and percentage of patients in whom the imAR did not resolve. 
o
302    Number and percentage of patients who reinitiated the drug after symptom 
o
303  improvement (after withholding for the imAR) and the number and percentage of 
304  these patients who had an imAR recurrence. 
305   
306  2.  DOSAGE AND ADMINISTRATION Section 
307   
308  Recommendations on dosage modification intended to reduce the risks of imARs (e.g., dosage 
309  reduction, dosage interruption, or permanent discontinuation) should be included in the 
310  DOSAGE AND ADMINISTRATION section.  Such information is generally displayed in this 
311  section in a three-column table (e.g., Adverse Reaction, Severity, Dosage Modification).  This 
312  section should also include a cross-reference to the imAR subsection in the WARNINGS AND 
313  PRECAUTIONS section.      
8