Guidance for Clinical
 

Investigators,
 

Sponsors, and IRBs
 

Adverse Event Reporting to IRBs ­


Improving Human Subject Protection
 

u.s. Department of Health and Human Services
 

Food and Drug Administration
 

Office of the Commissioner (OC)
 

Center for Drug Evaluation and Research (CDER)
 

Center for Biologics Evaluation and Research (CBER)
 

Center for Devices and Radiological Health (CDRH)
 

Good Clinical Practice Program (GCPP)
 

January 2009
 

Procedural
 
Guidance for Clinical 

Investigators, 

Sponsors, and IRBs 

Adverse Event Reporting to IRBs — 

Improving Human Subject Protection 

Additional copies are available from: 

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Center for Drug Evaluation and Research 

Food and Drug Administration 

 (Tel) 301-827-4573 

 http://www.fda.gov/cder/guidance/index.htm 

and/or 

 Office of Communication, Training and 

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Center for Biologics Evaluation and Research 

Food and Drug Administration 

 http://www.fda.gov/cber/guidelines.htm. 

(Tel) 800-835-4709 or 301-827-1800

and/or 

Office of Communication, Education, and Radiation Programs 

Division of Small Manufacturers, International, and Consumer Assistance (HFZ-220) 

Center for Devices and Radiological Health 

Food and Drug Administration 

http://www.fda.gov/cdrh/ggpmain.html 

Email: dsmica@cdrh.fda.gov; Fax: 301.443.8818 

(Tel) Manufacturers Assistance: 800.638.2041 or 301.443.6597 

(Tel) International Staff Phone: 301.827.3993 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner (OC) 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

Center for Devices and Radiological Health (CDRH) 

Good Clinical Practice Program (GCPP) 

January 2009 

Procedural
Contains Nonbinding Recommendations 

TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. REPORTING AEs TO IRBs IN CLINICAL TRIALS OF DRUG AND 

BIOLOGICAL PRODUCTS CONDUCTED UNDER IND REGULATIONS .......... 3

A. How to Determine If an AE is an Unanticipated Problem that Needs to Be Reported ...........3

B. How to Report Unanticipated Problems to IRBs........................................................................5

IV. REPORTING AEs TO IRBs IN CLINICAL TRIALS OF DEVICES UNDER THE 

IDE REGULATIONS....................................................................................................... 6

V. CONCLUSION ................................................................................................................. 6
Contains Nonbinding Recommendations 

Guidance for Clinical Investigators, Sponsors, and IRBs1

Adverse Event Reporting to IRBs — Improving Human Subject 

Protection 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION 

This guidance is intended to assist the research community in interpreting requirements for 

submitting reports of unanticipated problems, including certain adverse events reports, to the 

institutional review board (IRB) under Title 21 of the Code of Federal Regulations (21 CFR) part 

56 (Institutional Review Boards), part 312 (Investigational New Drug Application), and part 812 

(Investigational Device Exemptions). Specifically, the guidance provides recommendations for 

sponsors and investigators conducting investigational new drug (IND) trials to help them 

differentiate between those adverse events that are unanticipated problems that must be reported 

to an IRB and those that are not. The guidance also makes suggestions about how to make 

communicating adverse events information to IRBs more efficient. 

FDA developed this guidance in response to concerns raised by the IRB community, including 

concerns raised at a March 2005 public hearing,2

 that increasingly large volumes of individual 

adverse event reports submitted to IRBs—often lacking in context and detail—are inhibiting, 

rather than enhancing, the ability of IRBs to protect human subjects. 

FDA regulations use different terms when referring to an adverse event. For example, adverse 

effect is used in 21 CFR 312.64; adverse experience is used in § 312.32; and unanticipated 

problems is used in § 312.66. For the purposes of this guidance, the term adverse event is used, 

except when quoting specific regulations. For device studies, part 812 uses the term 

unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

 

1

 This guidance has been prepared by the Office of the Commissioner, the Center for Drug Evaluation and Research 

(CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health 

(CDRH), and the Good Clinical Practice Program (GCPP) at the Food and Drug Administration. 2 Federal Register, “Reporting of Adverse Events to Institutional Review Boards; Public Hearing,” (70 FR 6693, 

March 21, 2005). 

1
Contains Nonbinding Recommendations 

 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND 

FDA regulates clinical studies authorized under sections 505(i) (drugs and biologics) and 520(g) 

(devices) of the Federal Food, Drug, and Cosmetic Act. All such clinical studies must be 

reviewed and approved by an IRB before the study is initiated, in accordance with the 

requirements of 21 CFR part 50 (Protection of Human Subjects), part 56 (Institutional Review 

Boards), and either part 312 (Investigational New Drug Application) or part 812 (Investigational 

Device Exemptions) (see §§ 50.1, 56.101, 312.23(a)(1)(iv), 312.40(a), 812.2(b)(1)(ii), 812.2(c) 

and 812.62(a)).3

 After the initial review and approval of a clinical study, an IRB must conduct 

continuing review of the study at intervals appropriate to the degree of risk presented by the 

study, but at least annually (§ 56.109(f)). The primary purpose of both initial and continuing 

review of the study is “to assure the protection of the rights and welfare of the human subjects” 

(§ 56.102(g)). To fulfill its obligations during the conduct of a clinical study, an IRB must have, 

among other things, information concerning unanticipated problems involving risk to human 

subjects in the study, including adverse events (AEs) that are considered unanticipated problems 

(§§ 56.108(a)(3), (4), (b)).4

 

For clinical investigations of drug and biological products conducted under an investigational 

new drug (IND) application, information about adverse events5 must be communicated among 

investigators, sponsors, and IRBs as follows: 

• Investigators are required to report promptly “to the sponsor any adverse effect that may 

reasonably be regarded as caused by, or probably caused by, the drug. If the adverse 

effect is alarming, the investigator shall report the adverse effect immediately” (§ 

312.64(b)). 

• Sponsors are specifically required to notify all participating investigators (and FDA) in a 

written IND safety report of “any adverse experience associated with the use of the drug 

that is both serious and unexpected” and “any finding from tests in laboratory animals 

that suggests a significant risk for human subjects” (§ 312.32(c)(1)(i)(A),(B)). And, more 

generally, sponsors are required to “keep each participating investigator informed of new 

observations discovered by or reported to the sponsor on the drug, particularly with 

respect to adverse effects and safe use” (§ 312.55(b)). 

3

 As described below, there are some differences between the requirements for investigational new drug and 

investigational device exemption studies, as they concern obligations to report to a reviewing IRB. 4

 Unanticipated problems may be adverse events or other types of problems, i.e., adverse events are a subset of 

unanticipated problems. 

5

 The IND regulations use the term adverse effect (§ 312.64) and adverse experience (§ 312.32). These terms are 

interchangeable with adverse event. 

2
Contains Nonbinding Recommendations 

• Investigators are required to report promptly “to the IRB... all unanticipated problems

involving risks to human subjects or others,” including adverse events that should be 

considered unanticipated problems (§§ 56.108(b)(1), 312.53(c)(1)(vii), and 312.66). 

A critical question for studies conducted under part 312 is what adverse events should be 

considered unanticipated problems that merit reporting to an IRB. In the years since the IRB 

and IND regulations issued, changes in the conduct of clinical trials (e.g., increased use of multicenter studies, international trials) have complicated the reporting pathways for adverse event 

information described in the regulations. In particular, the practice of local investigators 

reporting individual, unanalyzed events to IRBs, including reports of events from other study 

sites that the investigator receives from the sponsor of a multi-center study—often with limited 

information and no explanation of how the event represents an unanticipated problem—has led 

to the submission of large numbers of reports to IRBs that are uninformative. IRBs have 

expressed concern that the way in which investigators and sponsors of IND studies typically 

interpret the regulatory requirement to inform IRBs of all "unanticipated problems" does not 

yield information about adverse events that is useful to IRBs and thus hinders their ability to 

ensure the protection of human subjects. This guidance is intended to help differentiate those 

adverse events that should be considered unanticipated problems (and thus reported to the IRB) 

from those that should not, thereby helping to ease the burden on IRBs and make the adverse 

events information they receive more informative and useful. 

III. REPORTING AEs TO IRBs IN CLINICAL TRIALS OF DRUG AND 

BIOLOGICAL PRODUCTS CONDUCTED UNDER IND REGULATIONS 

A. How to Determine If an AE is an Unanticipated Problem that Needs to Be 

Reported 

In general, an AE observed during the conduct of a study should be considered an unanticipated 

problem involving risk to human subjects, and reported to the IRB, only if it were unexpected, 

serious, and would have implications for the conduct of the study (e.g., requiring a significant, 

and usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or 

including a new monitoring requirement, informed consent, or investigator’s brochure). An 

individual AE occurrence ordinarily does not meet these criteria because, as an isolated event, its 

implications for the study cannot be understood. 

Many types of AEs generally require an evaluation of their relevance and significance to the 

study, including an aggregate analysis of other occurrences of the same (or similar) event, before 

they can be determined to be an unanticipated problem involving risk to human subjects. For 

example, an aggregate analysis of a series of AEs that are commonly associated with the 

underlying disease process that the study intervention is intended to treat (e.g., deaths in a cancer 

trial), or that are otherwise common in the study population independent of drug exposure (e.g., 

cardiovascular events in an elderly population) may reveal that the event rate is higher in the 

drug treatment group compared to the control arm. In this case, the AE would be considered an 

unanticipated problem. In the absence of such a finding, the event is uninterpretable. 

3
Contains Nonbinding Recommendations 

 

The major exceptions to the general rule that an isolated event is not informative are serious AEs that are uncommon 

and strongly associated with drug exposure, such as angioedema, agranulocytosis, anaphylaxis, hepatic injury, or 

Stevens Johnson syndrome. In most cases, a single, unexpected occurrence of this type of event would be 

considered an unanticipated problem involving risk to human subjects and, thus, must be reported to the IRB. 

Similarly, one or a small number of serious events that are not commonly associated with drug exposure, but are 

otherwise uncommon in the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy) 

should be considered an unanticipated problem involving risk to human subjects. 

Because they have been previously observed with a drug, the AEs listed in the investigator’s 

brochure would, by definition,6

 not be considered unexpected and thus would not be 

unanticipated problems. Possible exceptions would include situations in which the specificity or 

severity of the event is not consistent with the description in the investigator’s brochure, or it can 

be determined that the observed rate of occurrence for a serious, expected AE in the clinical trial 

represents a clinically important increase in the expected rate of occurrence. 

Therefore, FDA recommends that there be careful consideration of whether an AE is an 

unanticipated problem that must be reported to IRBs. In summary, FDA believes that only the 

following AEs should be considered as unanticipated problems that must be reported to the IRB. 

• A single occurrence of a serious, unexpected event that is uncommon and strongly 

associated with drug exposure (such as angiodema, agranulocytosis, hepatic injury, or 

Stevens-Johnson syndrome). 

• A single occurrence, or more often a small number of occurrences, of a serious, unexpected 

event that is not commonly associated with drug exposure, but uncommon in the study 

population (e.g., tendon rupture, progressive multifocal leukoencephalopathy). 

• Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an 

unanticipated problem. There should be a determination that the series of AEs represents a 

signal that the AEs were not just isolated occurrences and involve risk to human subjects 

(e.g., a comparison of rates across treatment groups reveals higher rate in the drug treatment 

arm versus a control). We recommend that a summary and analyses supporting the 

determination accompany the report. 

• An AE that is described or addressed in the investigator’s brochure, protocol, or informed 

consent documents, but occurs at a specificity or severity that is inconsistent with prior 

observations. For example, if transaminase elevation is listed in the investigator’s brochure 

and hepatic necrosis is observed in study subjects, hepatic necrosis would be considered an 

6

 An unexpected adverse drug experience is defined as “[a]ny adverse drug experience, the specificity or severity of 

which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or 

available, the specificity or severity of which is not consistent with the risk information described in the general 

investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic 

necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated 

hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 

virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. Unexpected, as used 

in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the 

investigator brochure), rather than from the perspective of such experience not being anticipated from the 

pharmacological properties of the pharmaceutical product.” (21 CFR 312.32(a)) 

4
Contains Nonbinding Recommendations 

 

unanticipated problem involving risk to human subjects. We recommend that a discussion 

of the divergence from the expected specificity or severity accompany the report. 

• A serious AE that is described or addressed in the investigator’s brochure, protocol, or 

informed consent documents, but for which the rate of occurrence in the study represents a 

clinically significant increase in the expected rate of occurrence (ordinarily, reporting would 

only be triggered if there were a credible baseline rate for comparison). We recommend that 

a discussion of the divergence from the expected rate accompany the report. 

• Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would 

cause the sponsor to modify the investigator’s brochure, study protocol, or informed consent 

documents, or would prompt other action by the IRB to ensure the protection of human 

subjects. We recommend that an explanation of the conclusion accompany the report. 

B. How to Report Unanticipated Problems to IRBs 

In a multicenter study, it is clear that individual investigators must rely on the sponsor to provide 

them information about AEs occurring at other study sites. It is also clear that the sponsor 

receives AE information from all study sites and typically has more experience and expertise 

with the study drug than an investigator. Accordingly, the sponsor is in a better position to 

process and analyze the significance of AE information from multiple sites and—when the 

determination relies on information from multiple study sites or other information not readily 

accessible to the individual investigators (e.g., a sponsor’s preclinical data that supports the 

determination)—to make a determination about whether an AE is an unanticipated problem. 

Furthermore, the regulations require the sponsor of an IND to promptly review all information 

relevant to the safety of the drug and to consider the significance of the report within the context 

of other reports (§ 312.32)7

 

The regulations state that for studies conducted under 21 CFR part 312, investigators must report 

all "unanticipated problems" to the IRB (§§ 312.66, 312.53(c)(1)(vii), and 56.108(b)(1)). 

However, as discussed above, we recognize that for multicenter studies, the sponsor is in a better 

position to process and analyze adverse event information for the entire study and to assess 

whether an adverse event occurrence is both unanticipated and a problem for the study. 

Accordingly, to satisfy the investigator’s obligation to notify the IRB of unanticipated problems, 

an investigator participating in a multicenter study may rely on the sponsor’s assessment and 

provide to the IRB a report of the unanticipated problem prepared by the sponsor. In addition, if 

the investigator knows that the sponsor has reported the unanticipated problem directly to the 

IRB, because the investigator, sponsor, and IRB made an explicit agreement for the sponsor to 

report directly to the IRB,8

 and because the investigator was copied on the report from the 

7

 Section 312.32(c)(1)(ii) requires a sponsor preparing an IND safety report to, among other things, “analyze the 

significance of the adverse experience in light of previous, similar reports.” Section 312.32(b) requires the sponsor to 

“promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any 

source . . . .” 

8

 Note that such an agreement would be required to be incorporated into the IRB’s written procedures (21 CFR 

56.108(b)(1), 56.115(a)(6)). 

5
Contains Nonbinding Recommendations 

6

sponsor to the IRB, FDA intends to exercise its enforcement discretion and would not expect an 

investigator to provide the IRB with a duplicate copy of the report received from the sponsor. 

IV. REPORTING AEs TO IRBs IN CLINICAL TRIALS OF DEVICES UNDER THE 

IDE REGULATIONS 

The investigational device exemption (IDE) regulations define an unanticipated adverse device 

effect (UADE) as “any serious adverse effect on health or safety or any life-threatening problem 

or death caused by, or associated with, a device, if that effect, problem, or death was not 

previously identified in nature, severity, or degree of incidence in the investigational plan or 

application (including a supplementary plan or application), or any other unanticipated serious 

problem associated with a device that relates to the rights, safety, or welfare of subjects” (21 

CFR 812.3(s)). UADEs must be reported by the clinical investigator to the sponsor and the 

reviewing IRB, as described below: 

• For device studies, investigators are required to submit a report of a UADE to the sponsor 

and the reviewing IRB as soon as possible, but in no event later than 10 working days after 

the investigator first learns of the event (§ 812.150(a)(1)). 

• Sponsors must immediately conduct an evaluation of a UADE and must report the results of 

the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working 

days after the sponsor first receives notice of the effect (§§ 812.46(b), 812.150(b)(1)). 

The IDE regulations, therefore, require sponsors to submit reports to IRBs in a manner consistent 

with the recommendations made above for the reporting of unanticipated problems under the 

IND regulations. 

V. CONCLUSION 

The receipt of a large volume of individual AE reports without analysis of their significance to a 

clinical trial rarely supports an IRB’s efforts to ensure human subject protection. Sponsors can 

assess the implications and significance of AE reports promptly and are required to report 

serious, unexpected events associated with the use of a drug or device, including analyses of 

such events, to investigators and to FDA. In addition, sponsors are required to report analyses of 

unexpected adverse device experiences to IRBs. FDA encourages efforts by investigators and 

sponsors to ensure that IRBs receive meaningful AE information. The ultimate goal is to provide 

more meaningful information to IRBs, particularly when sponsor analysis (including an analysis 

of the significance of the adverse event, with a discussion of previous similar events where 

appropriate) is made available to IRBs.