Investigator Responsibilities  
Safety Reporting for Investigational 
Drugs and Devices 
 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Office of Medical Policy, 301-796-
3093; (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-
402-8010; or (CDRH) Office of Clinical Evidence and Analysis, 
CDRHClinicalEvidence@fda.hhs.gov.  
 
 
 
 
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) 
Center for Devices and Radiological Health (CDRH) 
 
 
 
September 2021 
Drug Safety 
35087675dft.docx   
Investigator Responsibilities  
Safety Reporting for Investigational 
Drugs and Devices 
 
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     
and/or 
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email:  CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products  
 
 
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) 
Center for Devices and Radiological Health (CDRH) 
 
September 2021 
Drug Safety 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEFINITIONS .................................................................................................................. 4 
A.  DRUGS ........................................................................................................................................... 4 
1. Adverse Event (21 CFR 312.32(a)) .................................................................................................. 4 
2. Adverse Reaction and Suspected Adverse Reaction (21 CFR 312.32(a)) ........................................ 4 
3. Serious (21 CFR 312.32(a)) ............................................................................................................. 5 
B.  DEVICES ........................................................................................................................................ 6 
1. Unanticipated Adverse Device Effect (21 CFR 812.3(s)) ................................................................ 6 
2. Serious ............................................................................................................................................. 6 
IV.  INVESTIGATOR REPORTING TO SPONSORS FOR IND STUDIES ................... 7 
A.  Assessment of Causality ................................................................................................................ 8 
B.  Study Endpoints ............................................................................................................................. 8 
C.  Nonserious Adverse Events ........................................................................................................... 9 
V.  INVESTIGATOR REPORTING TO INSTITUTIONAL REVIEW BOARDS FOR 
IND STUDIES ............................................................................................................................... 9 
A.  Adverse Events as Unanticipated Problems That Must Be Reported to the IRB .................... 9 
B.  Other Unanticipated Problems Requiring Reporting to the IRB ............................................ 10 
VI.  INVESTIGATOR REPORTING TO SPONSORS AND  INSTITUTIONAL 
REVIEW BOARDS FOR IDE STUDIES................................................................................. 11 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Investigator Responsibilities   
2  Safety Reporting for Investigational Drugs and Devices  
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance is intended to help clinical investigators comply with the following safety 
17  reporting requirements: 
18   
19    Investigational new drug application (IND) studies2 under  312.64(b) (21 CFR 
20  312.64(b))  
21   
22    Investigational device exemption (IDE) studies under  812.150 (21 CFR 812.150) 
23   
24  Recommendations are provided to help investigators identify the following: 
25   
26  1.  For drugs  Identify safety information that is considered an unanticipated problem 
27  involving risk to human subjects or others and that therefore requires prompt reporting to 
28  institutional review boards (IRBs) under  312.66 (21 CFR 312.66) 
29   
30  2.  For devices  Identify safety information that meets the requirements for reporting 
31  unanticipated adverse device effects (UADEs) to sponsors and IRBs under 
32   812.150(a)(1) (21 CFR 812.150(a)(1)) 
33   
34  This document  incorporates concepts pertaining to investigator responsibilities for adverse event 
35  reporting described in the guidance for industry and investigators Safety Reporting Requirements 
36  for INDs and BA/BE Studies (December 2012) (the 2012 final guidance) and in the guidance for 
 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
in cooperation with the Center for Biologics Evaluation and Research and the Center for Devices and Radiological 
Health at the Food and Drug Administration. 
 
2 This guidance also provides relevant information for companies reporting serious adverse events (SAEs) for IND-
exempt bioavailability (BA)/bioequivalence (BE) studies under  320.31(d)(3) (21 CFR 320.31(d)(3)).   
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37  clinical investigators, sponsors, and IRBs Adverse Event Reporting to IRBsImproving Human 
38  Subject Protection (January 2009) (the 2009 procedural final guidance).3 
39   
40  When finalized, this guidance will supersede corresponding sections in the 2012 final guidance 
41  and the 2009 procedural final guidance.  Until that time, however, the 2012 final guidance and 
42  the 2009 procedural final guidance continue to represent FDAs current thinking on investigator 
43  responsibilities for safety reporting for investigational medical products.4 
44   
45  The contents of this document do not have the force and effect of law and are not meant to bind 
46  the public in any way, unless specifically incorporated into a contract.  This document is 
47  intended only to provide clarity to the public regarding existing requirements under the law.  
48  FDAs guidance documents, including this guidance, should be viewed only as 
49  recommendations, unless specific regulatory or statutory requirements are cited.  The use of the 
50  word should in Agency guidances means that something is suggested or recommended, but not 
51  required.  
52   
53   
54  II.  BACKGROUND  
55   
56  In the Federal Register of September 29, 2010 (75 FR 59935), FDA published a final rule  
57  (referred to in this guidance as the 2010 IND safety reporting rule) amending the IND safety 
58  reporting requirements under  312.32 and adding safety reporting requirements for persons 
59  conducting bioavailability (BA) and bioequivalence (BE) studies under  320.31 (21 CFR 
60  320.31).  Subsequently, the 2012 final guidance was published to help sponsors and investigators 
61  comply with safety reporting requirements for INDs and for IND-exempt BA/BE studies.   
62   
63  Recently, the recommendations for investigators provided in the 2012 final guidance were 
64  updated, merged, and published for notice and comment purposes in the draft guidance for 
65  industry Sponsor ResponsibilitiesSafety Reporting Requirements and Safety Assessment for 
66  IND and Bioavailability/Bioequivalence Studies (June 2021) (the merged 2021 draft guidance).5  
67  The merged 2021 draft guidance does not, however, include the recommendations for 
68  investigator responsibilities that are included in the 2012 final guidance, and such 
69  recommendations on investigator responsibilities are the primary focus of this guidance. 
70   
 
3 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.  
 
4 For combination products as defined in 21 CFR 3.2(e), safety reporting under the IDE or IND should include a 
complete discussion of the event with respect to the combination product as a whole, including each constituent part 
of the product, as appropriate, based on the available information.  If you have questions related to safety reporting 
for your investigational product, please contact the lead review division for the IND or IDE.  You may also contact 
the Office of Combination Products at combination@fda.gov for further assistance as needed. 
 
5 When final, this guidance will represent FDAs current thinking on this topic. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
71  The IND safety reporting requirements in  312.32 apply to sponsors,6 not investigators.  
72  However, investigators may find it helpful to understand overall sponsor responsibilities 
73  regarding IND safety reporting requirements.  The regulations in  312.32(c)(1) require the 
74  sponsor to notify FDA7 and all participating investigators (i.e., all investigators to whom the 
75  sponsor is providing the drug under the sponsors INDs or under any sponsor-investigators 
76  IND) in an IND safety report of potential serious risks identified from clinical trials8 or any other 
77  source, as soon as possible, but in no case later than 15 calendar days after the sponsor 
78  determines that the information qualifies for reporting under  312.32(c)(1)(i) through (iv), 
79  which includes any of the following: 
80   
81    Serious and unexpected suspected adverse reactions9 
82    
83    Findings from epidemiological studies, pooled analyses of multiple studies, or clinical 
84  studies that suggest a significant risk in humans exposed to the drug 
85   
86    Findings from animal or in vitro testing that suggest a significant risk in humans exposed 
87  to the drug 
88   
89    Any clinically important increase in the rate of a serious suspected adverse reaction over 
90  that listed in the protocol or investigator brochure 
91   
92  For IND-exempt BA/BE studies,  320.31(d)(3) states that [t]he person conducting the study, 
93  including any contract research organization, must notify FDA and all participating investigators 
94  of any serious adverse event, as defined in  312.32(a), observed during the conduct of the study 
95  as soon as possible but in no case later than 15 calendar days after becoming aware of its 
96  occurrence.   
97   
98  Section 320.31(d)(3) also requires the person conducting the study (including any contract 
99  research organization) to notify FDA of any fatal or life-threatening adverse event from the 
100  study as soon as possible but in no case later than 7 calendar days after becoming aware of its 
101  occurrence.  However, the regulation does not require all investigators to be notified of such 
102  events within that time frame. 
103   
104  For device studies under an IDE, the regulations in  812.150(a)(1) require investigators to 
105  submit to the sponsor and to the reviewing IRB a report of any UADE occurring during an 
106  investigation as soon as possible, but no later than 10 working days after the investigator first 
 
6 Requirements under  312.32 also apply to sponsor-investigators, as defined in  312.3. 
 
7 A sponsor-investigator who receives an IND safety report for another study for which they are not the sponsor does 
not need to submit that IND safety report to FDA if it has already been submitted.  See the draft guidance for 
industry Sponsor ResponsibilitiesSafety Reporting Requirements and Safety Assessment for IND and 
Bioavailability/Bioequivalence Studies. 
 
8 For the purposes of this guidance, FDA uses the terms clinical trial and clinical investigation interchangeably. 
 
9 Note that if the suspected adverse reaction is fatal or life-threatening, the requirement is to report as soon as 
possible but no later than 7 calendar days after the sponsors initial receipt of the information (see  312.32(c)(2)). 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
107  learns of the effect.  In addition, the regulations in 21 CFR 812.46(b) and 812.150(b)(1) require 
108  sponsors to conduct an evaluation of any UADE and to report the results to FDA, all reviewing 
109  IRBs, and all participating investigators within 10 working days after the sponsor first receives 
110  notice of the effect. 
111   
112   
113  III.  DEFINITIONS 
114   
115  A.  DRUGS 
116   
117  The 2010 IND safety reporting rule defined a number of terms related to safety reporting.  
118  Although the terms defined in  312.32 refer to sponsor reporting responsibilities, FDA is using 
119  these terms consistently for the purposes of the investigator reporting requirements for drugs10 
120  discussed in this guidance.  These definitions, accompanied by further explanation and examples, 
121  can also be found in the merged 2021 draft guidance.  For ease of reference, the following 
122  definitions from  312.32(a) are included in this guidance as well, along with additional thinking 
123  about the meaning of these terms. 
124   
125  1.  Adverse Event (21 CFR 312.32(a)) 
126   
127  Adverse event (AE) means any untoward medical occurrence associated with the use of a drug 
128  in humans, whether or not considered drug related ( 312.32(a)). 
129   
130  FDA considers an adverse event (also referred to as an adverse experience) to include any 
131  unfavorable sign (e.g., an abnormal laboratory finding), symptom, or clinical outcome 
132  temporally associated with the use of a test drug, active control, or placebo, regardless of 
133  whether the event is thought to be related to the drug.  An adverse event can arise during any use 
134  of a drug or biologic (e.g., use for a purpose other than FDA-approved indication or in 
135  combination with another drug) and with any route of administration, formulation, or dose, 
136  including an overdose. 
137   
138  2.  Adverse Reaction11 and Suspected Adverse Reaction (21 CFR 312.32(a)) 
139   
140  An adverse reaction means any adverse event caused by a drug.  Suspected adverse reaction 
141  means any adverse event for which there is a reasonable possibility that the drug caused the 
142  adverse event.  For the purposes of IND safety reporting, reasonable possibility means there is 
143  evidence to suggest a causal relationship between the drug and the adverse event.  Suspected 
 
10 For the purposes of this guidance, drug or drug product is used to refer to human drugs and human biological 
products that are regulated as drugs. 
 
11 For the purposes of prescription drug labeling, the term adverse reaction is defined to mean 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 (21 CFR 201.57(c)(7); see also 21 CFR 201.80(g)). 
 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
144  adverse reaction implies a lesser degree of certainty about causality than adverse reaction . . . . 
145  (emphasis added) ( 312.32(a)).   
146   
147  Both an adverse reaction and a suspected adverse reaction require evidence of a causal 
148  relationship between the drug and the adverse event ( 312.32(a)).  Therefore, if no drug has 
149  been administered, an adverse event is not reportable under IND safety reporting regulations.12,13 
150   
151  The following examples provided in the safety reporting regulation ( 312.32(c)(1)(i)) illustrate 
152  the meaning of reasonable possibility with respect to a determination that there may be a causal 
153  relationship between the drug and the adverse event: 
154   
155    A single occurrence of an event that is uncommon and known to be strongly associated 
156  with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
157   
158    One or more occurrences of an event that is not commonly associated with drug exposure 
159  but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture). 
160   
161    An aggregate analysis of specific events observed in a clinical trial, indicating that they 
162  occur more frequently in the drug treatment group than in a concurrent or historical 
163  control group.  Such events may be known consequences of the underlying disease or 
164  condition or events that commonly occur in the study population independent of drug 
165  therapy.  Such events could also be related to an intervention or therapy that is standard 
166  of care for the disease (e.g., background treatment).  
167   
168  To determine whether an adverse event should be classified as a suspected adverse reaction or 
169  an adverse reaction, the sponsor must evaluate the available evidence ( 312.32(b)) and make a 
170  judgment about the likelihood that the drug caused the adverse event.   
171   
172  3.  Serious (21 CFR 312.32(a)) 
173   
174  An adverse event, adverse reaction, or suspected adverse reaction is considered serious 
175   
176  if, in the view of either the investigator or the sponsor, it results in any of the 
177  following:  death, a life-threatening adverse event, inpatient hospitalization or 
178  prolongation of existing hospitalization, a persistent or significant incapacity or 
179  substantial disruption of the ability to conduct normal life functions, or a 
180  congenital anomaly/birth defect.  Important medical events that might not result in 
181  death, are not life-threatening, and do not require hospitalization may be 
182  considered serious when, based upon appropriate medical judgment, they may 
183  jeopardize the patient or subject and may require medical or surgical intervention 
 
12 However, for clinical investigations that involve an invasive procedure that would not occur other than due to 
participation in the trial (e.g., intrahepatic artery administration or a kidney biopsy), FDA may request that sponsors 
also report SAEs associated with such a procedure, even if the investigational product is not administered. 
 
13 Investigator reporting requirements under  312.64(b) and 312.66 may still apply even where no drug has been 
administered.   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
184  to prevent one of the outcomes listed in this definition.  Examples of such medical 
185  events include allergic bronchospasm requiring intensive treatment in an 
186  emergency room or at home, blood dyscrasias or convulsions that do not result in 
187  inpatient hospitalization, and the development of drug dependency or abuse.  
188  ( 312.32(a)) 
189   
190  The sponsor and the investigator must evaluate whether an event meets the definition of serious.  
191  See  312.32(c)(1)(i) and 312.64(b).  Because identifying serious adverse events (SAEs) is 
192  critically important for the evaluation of potential significant safety problems, FDA considers it 
193  important to take into account both the investigators and the sponsors assessments.  Therefore, 
194  if the sponsor or investigator believes that the event is serious, the event must be considered 
195  serious and must be evaluated by the sponsor for expedited reporting ( 312.32(a) and 
196  312.32(c)(1)). 
197   
198  B.  DEVICES 
199   
200  1.  Unanticipated Adverse Device Effect (21 CFR 812.3(s)) 
201   
202  An unanticipated adverse device effect (UADE) 
203   
204  means any serious adverse effect on health or safety or any life-threatening 
205  problem or death caused by, or associated with, a device, if that effect, problem, 
206  or death was not previously identified in nature, severity, or degree of incidence 
207  in the investigational plan or application (including a supplementary plan or 
208  application), or any other unanticipated serious problem associated with a device 
209  that relates to the rights, safety, or welfare of subjects.  ( 812.3(s)) 
210   
211  2.  Serious  
212   
213  What qualifies as a serious adverse effect, as that term is used in the definition of UADE, would 
214  be specific to the device and the study in which it is being used or tested.  Generally, a serious 
215  adverse effect is one that is determined by the investigator or sponsor to be life-threatening, 
216  require hospitalization, result in disability or permanent damage, result in a congenital anomaly 
217  or birth defect, or require an intervention to prevent permanent impairment or damage.  In the 
218  protocol, the sponsor should include information on adverse effects that helps investigators 
219  determine what would qualify as a serious adverse effect.  Examples of adverse effects that could 
220  be considered serious include organ perforation and thrombus formation inside an aortic 
221  endovascular graft. 
222   
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223   
224  IV.  INVESTIGATOR REPORTING TO SPONSORS FOR IND STUDIES14  
225   
226  Most of the information about the safety of a drug prior to marketing comes from clinical trials.  
227  Adverse event reports from investigators are therefore critically important, given that it is the 
228  investigators who observe subjects responses to an investigational drug.  The investigator must 
229  immediately report to the sponsor any SAEs,15 regardless of whether the investigator believes the 
230  SAEs are related to the drug ( 312.64(b)).  This requirement includes those SAEs (1) listed in 
231  the safety surveillance plan as anticipated to occur in the study population independent of drug 
232  exposure or (2) listed in the investigator brochure as predicted to occur with the drug.16  The one 
233  exception to this requirement (discussed in section IV.B of this guidance) involves study 
234  endpoints that are also SAEs (e.g., myocardial infarction, stroke, or death in trials evaluating 
235  drugs intended to treat cardiovascular conditions), which must be reported in accordance with 
236  the protocol unless there is evidence suggesting a causal relationship between the drug and the 
237  event. . . .  In that case, the investigator must immediately report the event to the sponsor. 
238  ( 312.64(b)).  Non-serious AEs must be reported according to the timetable for reporting 
239  specified in the protocol ( 312.64(b)).   
240   
241  For the purposes of this guidance, the Agency interprets immediately to be as soon as feasible 
242  after the investigator recognizes an event is an SAE and obtains relevant information for the 
243  sponsor.  Such information would generally include a specified subject, a suspected drug (if 
244  any), the reporting source (if not the investigator themself), and a clinical description of the 
245  event, including an assessment of whether a reasonable possibility exists that the drug caused the 
246  event.  Although more data may be collected and submitted later, the initial report must be 
247  submitted as soon as possible ( 312.64(b)).  FDA recommends that this time frame for 
248  submitting such initial information also be specified in the protocol and anticipates that it will 
249  generally be no longer than 1 calendar day.  Investigators are not required to determine whether 
250  an event is unexpected (as defined in  312.32(a));17 this determination is a sponsors 
251  responsibility (see  312.32(c)(1)(i)). 
252   
 
14 Guidance provided in this section may be applicable for companies conducting IND-exempt BA/BE studies to 
comply with  320.31(d)(3). 
 
15 Study endpoints that are SAEs must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the drug and the event ( 312.64(b)). 
 
16 For further information about anticipated and expected adverse events, see the draft guidance for industry Sponsor 
ResponsibilitiesSafety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence 
Studies. 
 
17 An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. . . .  Unexpected, as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation ( 312.32(a)).   
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253  A.  Assessment of Causality 
254   
255  FDA believes that the sponsor is generally better positioned than the individual investigator to 
256  determine whether an SAE should be classified as a suspected adverse reaction.  This is 
257  especially true for events that may warrant analysis of more than a single event to determine if 
258  any are possibly related to the drug, because the sponsor may have access to SAE reports from 
259  multiple study sites and multiple studies and would be able to aggregate and analyze these 
260  reports.  Moreover, the sponsor is likely to be more familiar with the drugs mechanism of 
261  action, class effects, and other information.  To determine whether an SAE meets the definition 
262  of a suspected adverse reaction, the sponsor must evaluate the available evidence (as separately 
263  required by  312.32(b)) and make a judgment about the likelihood that the drug actually caused 
264  the adverse event.  For these reasons, except for most study endpoints, investigators must 
265  immediately report any SAE to the sponsor (as mentioned previously), whether or not the 
266  investigator considers the event to be drug related ( 312.64(b)). 
267   
268  Although the sponsor is ultimately responsible for determining whether an SAE should be 
269  classified as a suspected adverse reaction, the investigators view is important for the sponsor to 
270  carefully consider when assessing the safety of the drug and determining whether to report an 
271  event expeditiously to FDA.  The investigator, who monitors the subjects response to the drug, 
272  is knowledgeable about the subjects clinical state (e.g., medical history, concomitant 
273  medications, symptoms, pertinent test results, timing of events relative to drug exposure).  
274  Therefore, the investigator may be sensitive to distinctions between events that may be related to 
275  study drug exposure versus those caused by the underlying disease process and/or concomitant 
276  therapies.   
277   
278  For these reasons, the investigator must include in the report to the sponsor an assessment of 
279  whether there is a reasonable possibility that the drug caused the event ( 312.64(b)).  For the 
280  purposes of  312.64(b), FDA interprets reasonable possibility to mean there is evidence to 
281  suggest a causal relationship between the drug and the adverse event.  This interpretation is 
282  consistent with the definition of suspected adverse reaction in  312.32(a).  Factors that should 
283  be considered when making a causality assessment include, but are not limited to, temporal 
284  relationship of the event to drug administration; biologic plausibility, based on the mechanism of 
285  action of the drug or similar drugs in the same class; nonclinical evidence; and dechallenge-
286  rechallenge information. 
287   
288  B.  Study Endpoints 
289   
290  In studies where trial endpoints meet the criteria for SAEs (such as myocardial infarction or 
291  death), the investigator must report these as endpoints, in accordance with the protocol, and not 
292  as SAEs to the sponsor ( 312.64(b)).  An exception to this requirement, however, is when there 
293  is evidence suggesting a causal relationship between a drug and an event (e.g., death from 
294  anaphylaxis after exposure).  Even if such an event is a component of the endpoint (e.g., all-
295  cause mortality), SAEs meeting this criterion must be immediately reported to the sponsor 
296  ( 312.64(b)).   
297   
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298  C.  Nonserious Adverse Events 
299   
300  The investigator must record nonserious adverse events and report them to the sponsor according 
301  to the timetable specified in the protocol ( 312.64(b)).  Often, nonserious events are recorded 
302  and are submitted to the sponsor and reviewed at regular intervals throughout the course of the 
303  investigation.  
304   
305   
306  V.  INVESTIGATOR REPORTING TO INSTITUTIONAL REVIEW BOARDS FOR 
307  IND STUDIES18  
308   
309  Investigators are required to promptly report to the IRB . . . all unanticipated problems 
310  involving risk to human subjects or others ( 312.66), including adverse events that represent 
311  unanticipated problems, as further described in this section.19  Note that the requirements for 
312  IND safety reporting under  312.32 do not address safety reporting by investigators to IRBs.  
313  The types of unanticipated problems that must be reported to the IRB are discussed in sections A 
314  and B below. 
315   
316  A.  Adverse Events as Unanticipated Problems That Must Be Reported to the 
317  IRB 
318   
319  Investigators are required under  312.66 to report all unanticipated problems involving risk to 
320  human subjects or others to the IRB.  FDA considers a serious and unexpected adverse event 
321  that meets the criteria for sponsor reporting to FDA and all investigators in an IND safety report 
322  under  312.32 to be an unanticipated problem involving risk to human subjects or others that 
323  therefore must be reported to the IRB by the investigator.20   
324   
325  IND safety reports and reports of SAEs from IND-exempt BA/BE studies21 provide FDA and 
326  participating investigators with important information relevant to the safety of human subjects 
327  receiving the investigational drug.  IND safety reports provide information on potential serious 
328  risks, including unexpected SAEs for which there is a reasonable possibility that the 
 
18 Guidance provided in this section may be applicable for companies conducting IND-exempt BA/BE studies to 
comply with  320.31(d)(3). 
 
19 We note that IND-exempt BA/BE studies are not subject to the requirements in  312.66.  However, they must 
still be conducted in compliance with the requirements for review by IRBs established in 21 CFR part 56.  See 
 320.31(d)(2).  Section 56.108(b)(1) provides that an IRB will ensure the prompt reporting to the IRB of any 
unanticipated problems involving risks to human subjects or others. . . .  FDA interprets this language in a manner 
consistent with the interpretation of  312.66 laid out in this guidance.   
 
20 In general, the occurrence of an SAE is very unusual in a BA/BE study because the number of subjects enrolled is 
small, the subjects are usually healthy volunteers, and drug exposure is typically brief, but often at the highest 
available dosage.  For these reasons, FDA considers the occurrence of any SAE in a BA/BE study that is subject to 
an IND to be an unanticipated problem involving risk to human subjects.  Accordingly, the investigator of a BA/BE 
study that is subject to an IND must report to the IRB any SAE that occurs in the study (21 CFR 312.66). 
   
21 See  320.31(d)(3). 
 
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329  investigational drug caused the event.  Reports of SAEs from IND-exempt BA/BE studies 
330  provide information on SAEs that occur in those studies, all of which are important to consider 
331  for human subject protection reasons because the occurrence of SAEs in BA/BE studies is 
332  unusual:  the number of subjects enrolled is small, the subjects are usually healthy volunteers, 
333  and drug exposure is typically brief, but often at the highest available dosage.    
334   
335  Reviewing IND safety reports and reports of SAEs from IND-exempt BA/BE studies is essential 
336  for protecting the safety of human subjects because each report represents important safety 
337  information regarding the investigational drug.  FDA considers the review of these reports 
338  critical to fulfilling the investigators responsibility under  312.60 (21 CFR 312.60) to protect 
339  the safety of subjects under their care.  For these reasons, investigators must review all IND 
340  safety reports and reports of safety information from IND-exempt BA/BE studies received (see 
341   312.60).  In addition, investigators must submit these reports to the IRB because the reports 
342  describe important safety information representing unanticipated problems involving risks to 
343  human subjects or others ( 312.66).  Many study protocols specify that the sponsor will submit 
344  IND safety reports to the IRB on the investigators behalf.  In these situations, where the 
345  investigator receives confirmation that the report has been sent to the IRB (e.g., the investigator 
346  is copied on the report sent to the IRB by the sponsor), FDA would not expect an investigator to 
347  provide the IRB with a duplicate copy of the report.22   
348    
349  B.  Other Unanticipated Problems Requiring Reporting to the IRB 
350   
351  Some events not meeting the criteria for reporting in an IND safety report or as a BA/BE study 
352  premarket SAE would still be considered unanticipated problems involving risk to human 
353  subjects or others and, under  312.66, would require reporting to the IRB by the investigator.  
354  Such events may occur at the subject, site, and/or study level.  Some possible examples may 
355  include reports of medication errors (such as receipt of wrong dose or contaminated study 
356  medication), breach of privacy/confidentiality (such as disclosure of personally identifiable 
357  information), untimely destruction of study records, and other scenarios.  The investigator must 
358  report any unanticipated problems involving risk to human subjects or others.  This requirement 
359  applies regardless of whether the unanticipated problem is related to the study drug or related to 
360  study procedures.  Such unanticipated problems may include serious unexpected adverse events 
361  that occur prior to test article administration or during a washout period or that are attributable to 
362  a screening procedure (e.g., renal failure after receipt of an imaging contrast agent).  
363   
364  Finally, the IRBs written procedures or institutional policy may require the investigator to 
365  submit to the IRB other unanticipated problems in addition to those that qualify for reporting 
366  under  312.66.  The investigator should be familiar with and adhere to the IRBs written 
367  procedures for reporting unanticipated problems involving risks to human subjects or others to 
368  the IRB (see 21 CFR 56.108(b)(1)).  Also, as part of their clinical trial monitoring responsibility, 
369  we understand that sponsors generally require that investigators report such unanticipated 
370  problems to the sponsors as well.    
371    
372   
 
22 Note that such an agreement should be documented. 
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373  VI.  INVESTIGATOR REPORTING TO SPONSORS AND INSTITUTIONAL 
374  REVIEW BOARDS FOR IDE STUDIES     
375   
376  The IDE regulations require investigators to report UADEs to both sponsors and IRBs.  Similar 
377  to the handling of SAEs described previously for IND studies, FDA believes that the sponsor is 
378  generally better positioned than the individual investigator to assess UADEs, given that the 
379  sponsor has access to UADE reports from multiple study sites and multiple studies and is able to 
380  aggregate and analyze these reports.  Therefore, UADE reports are critical to the process, and the 
381  IDE regulations require not only timely reporting for investigators, but also timely evaluation by 
382  sponsors, described as follows: 
383   
384    For device studies, investigators are required to submit a report of a UADE to the sponsor 
385  and the reviewing IRB as soon as possible, but in no event later than 10 working days 
386  after the investigator first learns of the effect ( 812.150(a)(1)). 
387   
388    Sponsors must immediately conduct an evaluation of a UADE and must report the results 
389  of the evaluation to FDA, all reviewing IRBs, and all participating investigators within 
390  10 working days after the sponsor first receives notice of the effect ( 812.46(b) and 
391  812.150(b)(1)). 
392   
393  What qualifies as a UADE is expected to vary depending on the specific device and the way the 
394  device is used within the study.  Therefore, sponsors are required to include risk information in 
395  the investigational plan, which may help investigators identify and assess potential UADEs 
396  ( 812.25(c) and 812.45). 
397   
398  In addition to reporting UADEs, according to  812.150(a)(3), investigators are to provide 
399  progress reports to sponsors, monitors, and IRBs23 at regular intervals, and no less than yearly.  
400  Such reports should provide information to sponsors about both anticipated and unanticipated 
401  adverse device effects.   
 
23 The terms sponsor, monitor, and IRB in the context of device studies are defined in  812.3. 
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