Adverse Events,
Unanticipated
Problems,
Protocol
Deviations &
other Safety
Information
Which Form 4
to Use?
Reason for Reporting
Unanticipated Problems
“to assure the protection of the
rights and welfare of the human
subjects”
UTHSC IRB Submission
Forms
 4a:
Reportable local adverse events
 4b: Reportable external adverse events
 4c: Protocol problem or protocol
deviation/violation
 4d: Non-reportable local or external adverse
events or problems
 4e: Methodist Hospital & Le Bonheur Children’s
Hospital adverse event
 Data Safety Monitoring Board (DSMB)/Annual
Reports
Adverse Event
(adverse effect, adverse experience, unanticipated
problem or unanticipated adverse device effect)
 Any
untoward or unfavorable medical
occurrence in a human subject, including any
abnormal sign (for example, abnormal physical
exam or laboratory finding), symptom, or
disease, temporally associated with the
subject’s participation in the research, whether
or not considered related to the subject’s
participation in the research.
Internal vs. External Adverse
Events (AEs)
 Internal


For a multi-center trial, those AEs experienced by
subjects enrolled by the local investigator at the
institution
For a single center trial, all AEs would be
considered internal
 External

Adverse Events
Adverse Events
Those AEs experienced by subjects enrolled by
investigators at other institutions engaged in the
clinical trial
Serious Adverse Event (AE)






Death
Life-threatening (places the subject at immediate
risk of death from the event as it occurred
Inpatient hospitalization or prolongation of existing
hospitalization
Persistent or significant incapacity or substantial
disruption of the ability to conduct normal life
functions
Congenital anomaly/birth defect
Any other AE that, based upon appropriate
medical judgment, may jeopardize the subject’s
health and may require medical or surgical
intervention to prevent one of the other outcomes
listed
Unexpected Adverse Event
(AE)
An AE or suspected adverse reaction is
considered “unexpected” if it is:
 Not listed in the investigator’s brochure (IB),
package inserts, or product labeling, or not
listed at the specificity or severity that has
been observed
 Not consistent with the risk information
described in the general investigational plan
(protocol) or elsewhere in the current
application (consent form)
Relationship of AE to Research
What is the likelihood that the AE, incident,
experience or outcome may have been
caused by the procedures involved in the
research:
 Possibly;
 Probably; or
 Clearly caused by research intervention
IRB Procedures for submitting
Unanticipated Problems/AE
Use the appropriate Form 4 via iMedRIS:
 4a: Reportable local adverse events
 4b: Reportable external adverse events
 4d: Non-reportable local or external adverse
events or problems
 4e: Methodist Hospital & Le Bonheur Children’s
Hospital adverse event
Data Safety Monitoring Board
(DSMB) or Data Monitoring
Committee (DMC)
The FDA defines a DSMB as:
“a group of individuals with pertinent experience
that reviews on a regular basis accumulating
data from an ongoing trial. The DSMB advised the
sponsor regarding the continuing safety of current
participants and those yet to be recruited, as well
as the continuing validity and scientific merit of
the trial.”
Purpose of a DSMB or DMC







Identify unacceptably slow rates of accrual
Identify high rates of ineligibility determined after
randomization
Identify protocol violations that suggest
clarification of changes to protocol are needed
Identify unexpectedly high dropout rates that
threaten the trial’s ability to produce credible
results
Ensure the credibility of the study
Ensure the validity of study results
Protect the safety of trial participants
Is a DSMB necessary for my
study?





Is there a large study population, or are there multiple
study sites?
Is the trial intended to provide definitive information about
effectiveness and/or safety of a medical intervention?
Do prior data suggest that the intervention being studied
has the potential to induce unacceptable toxicity?
Does the trial evaluate mortality or another major
endpoint, such that inferiority of one treatment arm has
safety and effectiveness implications?
Would it be ethically important for the trial to stop early if
the primary question addressed has been definitively
answered, even if secondary questions or complete safety
information were not yet fully addressed?
IRB Procedure
Use the iMedRIS Submission Form “Data Safety
Monitoring Board/Annual Reports” for the
following:
 FDA Safety Alerts
 FDA Public Health Advisories
 DSMB/DMC Reports
 Sponsor Interim or Annual Reports
*Must be submitted with 10 working days of
receipt by the investigator
Protocol Deviations/Violations
A failure to follow procedures specified in the
approved research protocol in the absence of a
protocol waiver.
Major vs. Minor Protocol Deviations
Minor Protocol Deviation:
 has no substantive effect on the risks or benefits for the
individual research subject, and
 has no substantive effect on the value of the data
collected, and
 does not result from willing or knowing misconduct on the
part of an investigator or study staff.
Major Protocol Deviation:
 has harmed or has posed a significant risk of substantive
harm to the individual research subject, or
 has compromised the scientific integrity of the data
collected for the study, or
 appears to result from the willing or knowing misconduct
on the part of an investigator or study staff, or
 appears to involve some other serious or continuing
noncompliance with federal, state or local research
regulations.
Protocol Waiver (Eligibility
Exception or Eligibility Waiver)
A prospective decision by a sponsor or
investigator to permit accrual of a subject who
does satisfy the approved inclusion/exclusion
criteria for enrollment.
IRB Procedure
Submit a Form 4c: Protocol problem or
protocol deviation/violation via iMedRIS
 All major protocol deviations must be
reported with 5 working days
 Minor protocol deviations are not required
to be submitted for IRB review
 Protocol waivers from a study sponsor
must include supporting documentation
from the sponsor
iMedRIS
https://ris01.uthsc.edu
UTHSC IRB Website
http://www.uthsc.edu/research/research_compliance/IRB/policie
s.php