Adverse Event

1. Adverse Events and Unanticipated
Problems
Presented by:
Karen Jeans, PhD, CCRN, CIP
COACH Program Analyst

2. Objectives
• Define “adverse event”
• Describe “unanticipated problems involving risks
to subjects to others”
• Identify examples of adverse events and
unanticipated problems involving risks to
subjects to others

3. Why Report Adverse Events and
Unanticipated Problems?
• Because it helps ensure the safety of
participants in human subject research, by
providing information to the IRB and cognizant
oversight agencies, and
• Because it is required

4. Regulatory Background
• Common Rule
• “Adverse Events” do not exist
• Unanticipated problems involving risks to
subjects or others (38 CFR 16.103(a))

5. Regulatory Background
• FDA Regulations
• Adverse Event (21 CFR 312.30)
• Adverse Experience (21 CFR 312.32)
• Adverse Effect (21 CFR 312.64)
• Unanticipated Adverse Device Effect
(21 CFR 812.46)
• Unanticipated Problems involving risks to
subjects or
others (21 CFR 56.108(b))

6. The Common Rule Requires:
“… written procedures for ensuring prompt
reporting to the IRB, appropriate institutional
officials, and the Department or Agency head of (i)
any unanticipated problems involving risks to
subjects or others or any serious or continuing
noncompliance … ; and (ii) any suspension or
termination of IRB approval.”
Source: 38 CFR 16.103(b)(5)

7. Criteria for IRB Approval (.111)
A. Required determinations:
1. Risks to subjects are minimized
(i) By using procedures consistent with sound research design…
(ii) When appropriate, using procedures already being performed…
2. Risks are reasonable in relation to benefits
3. Selection of subjects is equitable
4. Informed consent will be sought prospectively
5. Informed consent is appropriately documented
6. Research plan makes adequate provisions for safety monitoring
7. There are adequate provisions to protect privacy and confidentiality
B. When appropriate, additional protections for Vulnerable Subjects

8. What Is An Adverse Event (AE)?
• An AE is any untoward occurrence (physical,
psychological, economic, social, or legal) which affects a
study subject
• Includes any abnormal sign, symptom, or disease
temporally associated with the subject’s participation in
the research
• An AE does not require (or imply) a causal relationship
with the research.
Source: Modified from definition of Adverse Events in the 1996 International Conference on
Harmonization E-6 Guidelines for Good Clinical Practice in OHRP Guidance on Reviewing and
Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events –
January 15, 2007

9. What Is An Adverse Event (AE) according
to VHA requirements?
• An AE is any untoward physical or psychological
occurrence in a human subject participating in research.
• Can be unfavorable and unintended event
• Includes any abnormal laboratory finding, symptom, or
disease associated with the research or the use of a
medical investigational test article.
• Does not necessarily have to have a causal relationship
with the research.
Source: VHA Handbook 1058.01, Paragraph 4(b)

10. Adverse Event Definitions
VHA OHRP Guidance
• An AE is any untoward
physical or psychological
occurrence in a human subject
participating in research.
• Can be unfavorable and
unintended event
• Includes any abnormal
laboratory finding, symptom, or
disease associated with the
research or the use of a
medical investigational test
article.
• Does not necessarily have to
have a causal relationship with
the research.
• An AE is any untoward
occurrence (physical,
psychological, economic,
social, or legal) which affects a
study subject
• Includes any abnormal sign,
symptom, or disease
temporally associated with the
subject’s participation in the
research
• An AE does not require (or
imply) a causal relationship
with the research.

11. Types of Adverse Events
• Unanticipated (unexpected)
• Local (internal)
• Non-local (external)
• Related
• Not related
• Serious
• Not Serious

12. Types of Adverse Events: Unanticipated
• Unanticipated (unexpected)
• Event or problem that is new or greater than
previously known in terms of nature, severity,
or frequency, given the population described
in protocol-related documents and the
characteristics of the study population.
Source: VHA Handbook 1058.01, Paragraph 4(bb)

13. Types of Adverse Events:
Local and Non-Local
• Local (internal)
• Adverse event occurring at the reporting
individual’s own facility
Source: VHA Handbook 1058.01, Paragraph 7(c)
• Non-local (external)
• Adverse events occurring by subjects enrolled
by investigators at other institutions

14. Types of Adverse Events: Related
• Related
• There is a reasonable possibility based upon
the available information that the event or
outcome may have been caused by or
resulted from participation in the research by
the subject.

15. Types of Adverse Events: Serious
• FDA Regulations
• An Adverse Event that
• Results in death, a life-threatening experience,
inpatient hospitalization, a persistent or significant
disability or incapacity, or a congenital anomaly or
birth defect; or
• Requires, based on a reasonable medical judgment,
a medical or surgical intervention to prevent an
outcome described above.
Source: Section 761(a)(2) of the Food Drug &Cosmetic Act (21 U.S.C. 379aa-1(a)(2))

16. Types of Adverse Events: Serious
• VHA Requirements
• An Adverse Event in Human Research that
• Results in death, a life-threatening experience,
inpatient hospitalization, prolongation of
hospitalization, persistent or significant disability or
incapacity, congenital anomaly or birth defect.
• Also considered serious when medical, surgical,
behavioral, social, or other intervention is needed to
prevent such an outcome.
Source: VHA Handbook 1058.01, Paragraph 4(w)

17. Serious Adverse Event Definitions
VA FDA
• Results in death, a life-
threatening experience,
inpatient hospitalization,
prolongation of
hospitalization, persistent
or significant disability or
incapacity, congenital
anomaly or birth defect.
• Also considered serious
when medical, surgical,
behavioral, social, or other
intervention is needed to
prevent such an outcome.
• Results in death, a life-
threatening experience,
inpatient hospitalization, a
persistent or significant
disability or incapacity, or a
congenital anomaly or birth
defect; or
• Requires, based on a
reasonable medical
judgment, a medical or
surgical intervention to
prevent an outcome
described above.

18. What is the Difference Between Adverse Events
and Unanticipated Problems Involving Risks to
Subjects or Others?
Adverse
Events
UPs
AE/UPR

19. Definition: Unanticipated Problem
Involving Risks to Subjects or Others
• Common Rule
• Undefined
• FDA Regulations
• Undefined

20. Unanticipated Problems Involving Risks to
Subjects or Others
Any incident, experience, or outcomes that meets all three
criteria:
1. Unexpected
2. Related or possibly related to participation in
research
3. Suggests that the research places subjects or others
at a greater risk of harm than was previously known
or recognized
• May be physical, psychological, economic, or
social harm
Source: OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to
Subjects or Others and Adverse Events – January 15, 2007

21. Unanticipated Problems Involving Risks to
Subjects or Others vs. Adverse Events
• Most Adverse Events are not Unanticipated
Problems Involving Risks to Subjects or Others
• All Unanticipated Problems Involving Risks to
Subjects or Others are not Adverse Events
• All Unanticipated Problems Involving Risks to
Subjects or Others Adverse are not Serious

22. Research-related Events or Problems Which Could
Be (Or Could Reveal) Unanticipated Problems
Involving Risks to Subjects or Others
• PI-initiated changes in protocol
• Study amendments, for example:
• revision of the Consent Form;
• revision of inclusion/exclusion criteria;
• addition/deletion of study procedures; etc.
• Suspension of enrollment
• New Information (e.g., DSMB reports, publications,
sponsor alerts, etc.)

23. Reporting Adverse Events and Unanticipated
Problems Involving Risks to Subjects or Others
• Study sponsors (if multisite study) make reports to PIs,
who, in turn, report them to the IRB.
• Members of the VA research community are responsible
for reporting to the IRB per local IRB Standard Operating
Policies and Procedures
• Local IRB Standard Operating Policies and Procedures
can exceed but not be less stringent than federal
requirements

24. Reporting Adverse Events and Unanticipated
Problems Involving Risks to Subjects or Others
• The IRB determine when events, incidents, or
outcomes are Unanticipated Problems Involving
Risks to Subjects or Others and report to
Institutional Officials

25. IRB Actions
• Require study modification
• Providing additional information to subjects
• Modify informed consent process/document
• Educational plan
• Assignment of Mentor
• Require additional monitoring
• Suspension or termination of IRB approval
• Other actions as determined by the IRB

26. Reporting By The IRB And Institutional
Officials
• When the IRB determines that a study-related event is
an Unanticipated Problem involving Risk to subjects or
others, it must be reported to
• Institutional Official
• Institutional Official reports to Oversight Agencies and
entities as applicable
• Office of Research Oversight
• Office for Human Research Protections
• U.S. Food and Drug Administration
• Sponsors
• Other entities

27. Summary
• Adverse Events and Unanticipated Problems Involving
Risks to Subjects or Others are not synonymous
• Policies and procedures must describe when and how
adverse events and possible unanticipated problems
involving risks to subjects or others are reported to the
IRB.
• The IRB reviews reports and determines which are
unanticipated problems involving risks to subjects or
others